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Health

SERUM GLUTAMATE TRANSAMINASES DECREASE BY PROPOLIS FROM EUPHORBIA RESINIFER

IN CHRONIC HEPATITIS C PATIENTS

Pr. Mohamed Faid

  

Hassan II Institute of Agronomy and Veterinary Medicine Department of  Food Science

PO Box 6202 Rabat-Institute, Morocco.

ABSTRACT

In previous studies propolis extracts have shown a protective effect on hepatocytes in vitro as well as in vivo. This effect has been related to the antioxidant and free radical scavenging properties of propolis. However, limited information is available on its efficacy in improving liver symptoms. Thus, the present investigation was undertaken to determine the long-term effect of the oil extract of Moroccan propolis from Euphorbia resinefera, on serum transaminase concentrations in patients treated during acute phase of viral hepatitis C.  Twenty patients were evaluated ten months after the treatment with propolis oil extract (POE) along with a low iron and non fat diet and cupping therapy. Six patients among the treated subjects were resistant to interferon administration. Activities of the serum glutamate-pyruvate transaminase (SGPT) and the serum glutamate oxaloacetate transaminase (SGOT) were analysed before, during and after 10 months of the beginning of the treatment. Propolis oil extract was administrated orally three times in dose of 70 mg/kg, mixed with one tablespoon of multifloral honey one hour before meal. Results showed a significant decrease in SGPT and SGOT, as well as a significant inhibition of fatigue symptoms in all patients including those who had been resistant to the conventional therapy. Besides some digestive troubles observed in five patients during the first days of POE intake, no adverse events were occurred, and the POE was safe and well tolerated in all subjects.

These study suggest that POE along with other adjuvant methods which could enhance the efficiency of bee products, have an improving effect on hepatic dysfunction, and confirm the beneficial effect of apitherapy in patient with chronic hepatitis, but this promising effect on virus C clearance should be confirmed in a randomised, double blinded, placebo-controlled study involving more patients.

Key words: Propolis, Euphorbia resinifera, hepatitis, virus C, glutamate transaminases.

Introduction

Hepatitis C virus (HCV) infection is a serious global health problem. Most HCV infections are persistent, leading in about 50 % of all cases to chronic hepatitis, which can lead to chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma (Alter et al., 1992). The World Health Organization (WHO) estimated the world’s population, approximately 170 million people, infected with HCV to 3 % (WHO, 1997). In Moroccan population, the prevalence of HCV is among the highest rates with 7.7 %. Other viral infections (HBV, HAV, HGV) were rare (Cacoub et al., 2000).

Interferon-α (IFN-α) and ribavirin have demonstrated efficacy in the treatment of HCV infection; however, these therapies display many side effects. Interferon-α (IFN-α) monotherapy and combination therapy of ribavirin plus intron-A (Rebetron) are the only FDA-approved agents that have demonstrated efficacy in the treatment of HCV infection (Rosen and Gretch, 1999). The IFN-α treatment leads to a sustained clearance of HCV RNA in 15–20% of patients (Hoofnagle and Lau, 1996). However, IFN therapy is associated with many side effects (especially after prolonged therapy) and is effective in only a subset of patients (Martinot Peignoux et al., 1998). The combination therapy shows a 28–66% sustained response after 48 weeks of treatment (McHutchison et al., 1998); however, ribavirin frequently causes hemolytic anemia and is a known teratogen (Sherman, 1999). Thus, the development of new therapeutic agents against HCV is required.

Propolis is a strongly adhesive resinous substance harvested by honeybees from different parts of plants such as shoots, buds and resinous exudates (Marcucci, 1995; Burdock, 1998). Used for medicinal purposes since antiquity, propolis has shown various medical properties, such as anti-microbial activities (Scazzocchio et al., 2006; Silici and Kutluca, 2006) protective effect against radiation-induced damage (El-Ghazaly and Khayyal, 1995), anti-mutagenic effect (Tavares et al., 2006), antianti-hyperalgesic action (de Campos et al., 1998) and anti-inflammatory activity (Ansorge et al., 2003), antiparasitary (Decastro and Higashi, 1995), anticarcinogenic (Orsolic and Basic, 2003) and Immunomodulation action (Fischer et al., 2007). There are literature data about antiviral action too (Manolova et al., 1985; Koenig and Dustmann, 1987 and Marcucci, 1995). Studies of its antiviral properties have concentrated mainly on herpes simplex virus (Vynograd et al., 2000), influenza virus (Serkedjieva et al., 1992) and anti-HIV  activity (Gekker et al., 2005).

Propolis constitutive characteristics, however, can vary according to the bee species, period of the year in which it is collected and, especially botanic origin (Bancova, 2005). While propolis is produced by a variety of plants, most plant species are not known. Only one plant species, Baccharis dracunculifolia, is well known source of propolis (Santos et al., 2003), although several genera, i.e. PopulusClusia and Araucaria, are regarded as additional sources of propolis (Bankova et al., 2000). Moroccan black propolis is mainly produced from a plant commonly known as “Daghmous” (Euphorbia resinifera) a large, leafless cactus-like perennial, native of the Anti-Atlas Mountains in Morocco. This species is not adapted to the natural conditions of other countries, which confers to the Moroccan black propolis chemical and biological characteristics different from the European propolis, produced predominantly from the exudates of buds of aspen (Populus sp.) (Bankova et al., 2000). The medicinal use of Euphorbium, the dried latex of E. resinifera, reflects a history more than 2000 years old, which makes resiniferatoxin (RTX) one of the most ancient drugs still in use today (Appendino and Szallasi, 1997). Recent researches proved some of the medicinal uses of E. resinifera (Kuo et al., 2006; Haratel et al., 2006; Brown et al., 2005; Hohmann and Molnar, 2004), including antiviral action (Glatthaar-Saalmuller and Fallier-Becker, 2001).

Cuting of cutane and subcutane connective tissue areas has been part of the healing practices for more than 5000 years. It has traditionally been used in different cultures (China, the Middle East, Ethiopia, or Central and North Europe). Since the rise of modern cellular pathology it slipped out the physicians’ minds, as well did other humoral therapeutic techniques. Recently several clinical studies have proved the effectiveness of cupping as an alternative therapy in the treatment of a large number of diseases (Li et al., 2006; Wan, 2005; Jiang et al., 2004; Lu  and Liu, 2004; Sang et al., 2003; Wu, 2003;  ).

In this study we aimed at proving the effect of Moroccan propolis from Euphorbia resinifera intake along with the cuping therapy and a non fat low iron diet on serum glutamate transaminases in chronic hepatitis C patients.

Materials and methods

Twenty-two patients with chronic hepatitis C virus (12 males and 8 females; mean age, 45 – 75 y; age range, 27–70 y) were enrolled in this study. All patients were infected with hepatitis C virus. Six patients had received Interferon therapy for at least 12 months before the beginning of the study, and none had responded.

Propolis samples

E. resinifera crude propolis samples were collected from beehives colonies located in Azilal, and Benimellal, the Anti-Atlas Mountains of Morocco was used for most patients. All of the above samples were collected by scraping the propolis from wooden beehive equipment and were conglomerates from an unknown number of bee colonies. To obtain clean propolis samples (uncontaminated by beeswax and woodenware), we also trapped propolis using commercial traps.

Preparation of propolis oil extract

After a full dissolution, the solution was filtered. The filtrate was collected and mixed with multifloral honey (15 %) for the non diabetic patients and with Euphorbia resinifera honey (15%) for the diabetic ones.

Preparation administration

The propolis/honey preparation (10%) was administrated orally three times a day one hour before meal.

Cupping therapy

The cupping therapy was performed 2 times, at the end of every two months by a licensed TCM, acupuncturist doctor.

Diet and lifestyle guidelines

General guidelines for individuals enrolled in this study include maintaining a healthy lifestyle, eating a well-balanced, low-fat diet, and avoiding alcohol. HCV Patients, whose serum iron level is high, were advised to avoid taking iron supplements. In addition, these patients restricted their intake of iron-rich foods, such as red meats, liver, and iron-fortified cereals, and avoided cooking with iron-coated cookware and utensils.

Patients are also advised to maintain normal weight. A sugar restricted diet was recommended for diabetic individuals. A low cholesterol diet was followed in those with hypertriglyceridemia.

Blood tests

Activities of the serum glutamate-pyruvate transaminase (SGPT) and the serum glutamate oxaloacetate transaminase (SGOT) were analysed before, during and after 10 months of the beginning of the treatment. All the biochemical tests were performed in certified medical laboratories and followed by a physician.

RESULTS AND DISCUSSION

Our results suggested that Honey-Propolis oil extract administration, along with cupping therapy and a low iron and protein diet could have an obvious improvement on the normal liver function. Figure 1 and Figure 2 showed that both SGOT and SGPT concentrations of all patients. Patients who didn’t responde to interferon therapy showed also a significant reduction during the tratment period. Besides some digestive troubles observed in five patients during the first days of the Euphorbia resinifera POE intake, no adverse events were occurred, and the POE was well tolerated in all subjects. A clear removal of fatigue symptoms was also observed in all patients.

Figure 1: Serum aspartate transaminase (SGOT) profiles in patients with

               chronic hepatitis C virus.

Figure 2: Serum alanine transaminase (SGPT) profiles in patients with

               chronic hepatitis C virus.

A variety of natural products or their derivatives have been considered as potential candidates for the treatment of hepatitis. It has been demonstrated that progression to liver fibrosis and occurrence of HCC in HCV-infected patients can be prevented as long as serum alanine aminotransferase (ALT) is maintained at low levels (Yabuuchi et al., 2000; Kasahara et al., 2000; Okanoue et al., 2002).

Therefore, it is important to maintain reduced serum ALT levels in cases that do not respond to IFN therapy or in those in whom IFN is contraindicated (Arase et al., 1997). In the present study alternative therapy; including a combination of Honey-Propolis administration, cupping therapy and a low iron non fat diet; is evaluated in the improvement of biochemical liver test in HCV patients.

The significant reduction of SGOT and SGPT observed in this study is probably due to synergic hepatoprotective action of propolis, honey and the recommended diet, enforced by the immune system activation and the blood detoxication of cupping therapy. These findings are supported by several studies.

The hepatoprotective effect of propolis ethanolic and aqueous extracts was examined in rats. Propolis restored carbon tetrachloride histopathological alteration and decreased the hepatic glutathion level (Mahran, 1996; El-Khatib et al., 2002; Shukla et al., 2004) and had a protective effect on hepatoxicity induced by acetaminophen (Seo et al., 2003). These findings are parallel to the previous investigations carried out by Lin et al (1999) who found that 30 mg/kg of propolis extract significantly prevented the increase of liver microsomal enzymes and serum transaminases, investigated in rats (Lin et al., 1997). The hepatoprotective effects of various concentrations of propolis ethanolic extract on liver damage, induced by hepatotoxic dose (300 mg/kg) of econazole, were also observed by the obvious decrement of SGOT and SGPT level and further confirmed by hepatohistological microscopic examination (Sugimoto et al., 1999).

According to the same extract dose-dependently prevented the increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities induced by D-galactosamine, and significant inhibition was observed at a dose of 30 mg/kg. These results suggested that propolis extract may have an improving effect on hepatic dysfunction.

This obvious hepatocyte protective effect of propolis extracts is probably a result of its antioxidant and free-radical-scavenging properties which in turn help to maintain the intracellular level of reduced glutathion (Mahran et al., 1996). The probable role of antioxidant activity of propolis in the prevention of hepatitis was also discussed by Rodriguez et al. (1997), who reported that Cuban red propolis extract induced reversion of the increased activity of alanine aminotransferase and malondialdehyde concentration in the serum of rats treated with galactosamine. The same explanation was reported by Liu et al. (2004, 2007) who postulated that the hepatoprotective effect of propolis extracts is most probably due to their inhibitory ability on membrane lipid peroxidation and free radical formation or to their free radical scavenging ability.

Like propolis, several investigations have indicated that honey administration improve hepatic function. Al-Waili et al. (2006) reported that during absolute rats honey feeding, ALT and AST increase following carbon tetrachloride administration was significantly less than the values obtained in control. Honey increased serum albumin, serum protein, blood glucose, and caused lower reduction in hemoglobin. Conclusively, exclusive honey feeding (50% concentration) significantly modifies and improves liver biochemical and hematological changes obtained after carbon tetrachloride injection. Similar results were obtained by Al-Waili (2003) with healthy sheep receiving different doses of honey. Results showed that Intravenous delivery of honey reduced SGOT, SGPT, and raised serum protein, serum albumin, hemoglobin, white blood cell, and neutrophil percentage, whereas in control sheep carbon tetrachloride caused significant rise of all liver enzymes.

Diet therapy, in particular restricting intake of iron-rich foods, was also recommended to CH-C patients enrolled in this study. This specific diet had also an important role in improving hepatic function. Iron is excessively accumulated in many cases of CH-C (Di Bisceglie et al., 1992; Piperno et al., 1995; Haque et al., 1996; Bonkovsky et al.,1997; Di Bisceglie et al., 2000; Fontana et al., 2000; Bonkovsky et al., 2002; Erhardt et al., 2003). Reduction of iron load by phlebotomy leads to decreased ALT levels, and maintaining iron levels to those equivalent to iron deficiency by regular phlebotomy has been shown to suppress the progression of CH-C to liver fibrosis (Yano et al., 2002). Because hepatic iron concentration is thought to be one of the predictors of the effectiveness of IFN therapy, several studies have been performed to identify the beneficial effects of iron reduction therapy before IFN in CH-C (Di Bisceglie et al., 2000; Fontana et al., 2000). Although limiting of iron intake is less effective than phlebotomy in reducing iron load, recent finding reported that the dietary restriction of energy, fat, iron, and protein intake reduces serum ALT levels in CH-C patients who were unresponsive to or were not able or unwilling to take IFN therapy (Iwasa et al., 2002). The restriction of energy, fat, iron, and protein intakes is safely tolerated, so its long-term use should be recommended to patients with long-term infection with hepatitis C virus (Iwasa et al., 2004).

The iron reduction therapy conducted in this study via low iron diet was supported by cupping therapy. There are many reports on how cupping can affect a large group of blood related disorders (Ranaei-siadat et al., 2004). However the density of biochemical factors of blood in wet cupping is statistically different from phlebotomy (Montazer, 2004), but this two therapeutic processes may have the same efficiency in removing the excess iron from the blood circulation.

Up on the foregoing the obtained results may suggest that Moroccan Euphorbia resinifera black propolis could improve hepatic function in CH-C patients. Our findings showed that the combination of propolis-honey administration along with a specific diet and cupping therapy support the hepatoprotective effect of propolis against HCV induced liver injury. However, only well-designed, randomized, controlled trials will be able to ascertain whether Euphorbia resinifera black propolis has any role in the management of patients with acute or chronic liver diseases, and further studies on a large population of CH-C patients should evaluate whether long-term apitherapy products administration can delay the development of liver cirrhosis or decrease the occurrence of HCC.

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