The Effect of Purgative Manna on the Infant Jaundice

Document Type: Research Paper

Authors

1 Department of Pharmacognosy , Faculty of Pharmacy , Mazandaran University of Medical Science, Sari, Iran

2 Department of Pediatrics, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

        Infant jaundice is observed during the first week of life in approximately 60% of term and 80% of preterm infants. Hyperbilirubinemia may lead to the development of kernicterus, hearing loss, and convulsion. The goal of therapy in hyperbilirubinemia is lowering blood bilirubin levels or at least preventing its increase. It is recommended that phototherapy and if unsuccessful, blood exchange transfusion be used to keep bilirubin in the normal levels. In the Iranian traditional medicine,Cotoneaster manna (purgative manna) is commonly used in the treatment of infant jaundice. However, no scientific data was available regarding its effectiveness. In this study, purgative manna which was obtained from Cotoneaster discolor Pojark from south eastern Iran was used as an oral drop preparation. After standardization of the manna and the drop, clinical study was performed on 200 hyperbilirubinemic newborns. The serum bilirubin was assayed twice a day, using spectrophotometric method. The results showed that 88% of the infants who were treated by purgative manna plus phototherapy were cured during the first 3 days of administration, but only 21% of the infants who were treatment by phototherapy alone were cured.

Keywords


1. Introduction

      Jaundice is one of the most common problems found in newborns, and it occurs in about 60% of term and 80% of preterm newborns [1, 2]. Bilirubin production in human is occurred by heme catabolism. In normal condition, about 80–90% of the total bilirubin is produced from the heme breakage, produced from the old and broken red blood cells [3, 4]. In the normal condition, bilirubin is conjugated with glucuronic acid in the liver and is excreted in bile [4]. Physiologic hyperbilirubinemia is defined as an excessive level of serum bilirubin during impaired liver function in neonates [5, 6].The causes of physiologic jaundice in human newborns are: temporary deficiency in the liver bilirubin absorption, impaired hepatic and intracellular bilirubin transfer, conjugation metabolism disorders, and deficiency in the bilirubin clearance [5, 7].

     The newborn jaundice is important because increased levels of bilirubin results in severe and irreversible damage to the brain cells. It leads to mild central nervous system damage and hearing lose in the premature newborns [2, 8]. The incident of mental retardation in babies below two years of age is related to the serum bilirubin levels of neonates [9]. It seems that urgent treatment is necessary in order to decrease the serum bilirubin levels.

     There are two usual methods of treatment for neonatal jaundice in the literatures: light therapy and blood exchange [10]. Blood exchange is the last way for decreasing the serum bilirubin levels [2, 11]. The use of light can decrease the need for blood exchange. In children below 2 kg, light therapy can decrease serum bilirubin between 1.6 to 2 mg/dl in 24 hours [4, 10].Therapy with light has some side effects such as faintness resulted from dehydration, diarrhea, hypokalemia, riboflavin deficit, skin rushes and so on, but it is still the most effective cure for jaundice in neonates [2,12].

    In this study decreasing the unconjugated bilirubin in serum by using a natural medicine was investigated. Purgative manna has been used as laxative, biliousness and tonic for the liver in the Iranian traditional medicine. The manna, known in Iran as Shir-Khesht, is found as dew drops falling on Cotoneaster species plants. The manna is white to yellow, round or shapeless pieces with a very sweet taste and cooling properties [13]. Cotoneaster genus, Rosaceae family, has 19 species in Iran. The manna is produced by the action of an insect; on some kinds of plants like C. numularia and C. discolor. Cotoneaster discolor is a shrub, 1–1.5 m high, with brown thin branches, elliptical leaves, and red small flowers with triangular sepals [14].

     In this research, the purgative manna was prepared as an oral drop formulation, and clinical studies were carried out in order to find out the effect of this formulation on hyperbilirubinemia in neonates.

 

2. Materials and methods

2.1. Collection of purgative manna

     Purgative manna and herbarium sample of its producer plant, Cotoneaster discolor Pojark, were obtained from the south of Khorasan, a north-eastern province of Iran, in the mid-summer 1997. The plant was authenticated in Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences.

 Figure 1. Stability test of the oral drop in room temperature.

 

Table 1. Abundance of sex, age, and weight of newborns that received the oral drop and phototherapy.


2.2. Identification of the important active materials

     Mannitol and manna spots were placed on a paper chromatography (Wattman, No.1).The mobile phase was n-propanol, ethyl acetate, and water (2:1:7, v/v/v). The spots were developed using 5% silver nitrate solution.

 

2.3. Manna extract preparation and standardization

     Four hundred grams of the manna was dissolved in 400 ml of distilled water, and the foreign matters such as wood pieces and leaves were separated by filtration. The extract was dried under reduced pressure, and the dry extract was assayed on the basis of mannitol according to British Phrmacopoeia procedure.

 

 Figure 2. Comparison of bilirubin decrease between case group (treatment with the oral drop and phototherapy) and control group (treatment with phototherapy).

 

Figure 3. Comparison of hospitalization time between case group (treatment with the oral drop and phototherapy) and control group (treatment with phototherapy).

 

2.4. Preparation of oral drop

     Propyl paraben (0.07 g) and methyl paraben (0.63 g) were dissolved in 150 ml of distilled water at 88 °C, and then 350 g of the dry extract was added to it, and the volume was made up to 350 ml by adding distilled water. The final preparation contained 1 g/ml of the dry extract, 0.02% and 0.18% of propyl paraben and methyl paraben, respectively, as preservative.

 

2.5. Product control

     Microbial limitation and preservative effect tests were performed according to USP XXIII procedure. Periodical procedure was used for stability test.

 

2.6. Clinical study procedure

     Full term neonates, without the background of any other disease, were chosen. Aquestionnaire was prepared and the infant’s information, such as: age, weight, glucose-6- phosphat dehydrogenase condition, direct bilirubin amount, direct Kombs test, and morning and afternoon bilirubin amounts, were recorded. Clinical trail was performed on 200 hospitalized newborns. One hundred newborns received the oral drop and light therapy as the case group, and 100 newborns received placebo and light therapy as control group. In each group 5 drops of the drug or placebo were administered three times a day in a double blind study.


 Figure 4. Number of newborn between case group (treatment with the oral drop and phototherapy) and control group (treatment with phototherapy) who were dismissed from hospital before each bleeding.


Figure 5. Comparison of the effect of case group (treatment with the oral drop and phototherapy) and control group (treatment with phototherapy) in newborns with G6PD deficiency.


2.7. Bilirubin assay

      Serum bilirubin level was assayed twice a day by spectrophotometry method with about ± 0.2 mg sensitivity.

 

2.8. Statistics methods

      Student’s “t” test used for the comparison of the mean serum bilirubin levels in two groups. One way analysis of variance and EPI6 and SPSS software were used for analysis of the clinical data.

 

3. Results

     The dry extract had 88.3% manna from which 50-60% was mannitol. One ml of the drop contained 610 mg active constituents based on mannitol. Microbial tests of the oral drop revealed no bacterial or fungal contamination. According to Figure 1 the stability of the oral drop was evaluated. The shelf-life of this preparation was assessed 14 months.The effect of sex, age, and weight of newborns on treatment schedules are shown in Table 1. Although the rate of treatment is the same but the results showed that addition of manna drop to the phototherapy treatment sharply decreased serum bilirubin levels compared to phototherapy alone (Figure 2).

      During the first 3 days of treatment, serum bilirubin levels decreased very rapidly, and 88% of the infants receiving the drug plus phototherapy were cured during the first 3 days (Figure 3). Only 21% of the infants in the group who received phototherapy alone were treated in the same period. Majority of the case group were cured in 3 days, but most of the newborn in control group were treated in 6 days (Figure 3). According to Figure 4, most of newborns receiving manna plus phototherapy were dismissed from hospital after the first day of hospitalization. Manna plus phototherapy also decreased the serum bilirubin level in G6PD deficient neonates much faster than phototherapy alone (Figure 5).

 

4. Discussion

      The average of serum bilirubin levels in case and control groups were not significantly different at the beginning of hospitalization, but after start of the treatment the serum bilirubin in neonates who received manna plus phototherapy declined much faster than those who received phototherapy alone, therefore, it could be concluded that rapid reduction in bilirubin serum concentration in the case group was induced by the manna.Discharge of the case group patients from hospital started after 1.5 days of hospitalization.It means that they were released before the third blood sampling. For the control group, the beginning of release from hospital was after 2.5 days of hospitalization, and most of them were released after 6.5 days.

     Some plants such as Nymphaea stellata and a poly herbal formulation containing Berberia aristata, Cordia myxa, Elettaria cardamomum,Glycyrrhiza glabra, Piper longum and Zingiber officinale could also decrease serum bilirubin(15,16). In conclusion; administration of purgative manna (Shirkhesht) could clinically useful for treating infant jaundice.

 

[1] Cashore WJ. Kernicterus and bilirubin encephalopathy. Semin Liver Dis 1988; 8: 163-7.

[2] Vreman HJ, Wong RJ, Stevenson DK.Phototherapy: current methods and future directions. Semin Perinatology 2004; 28: 326- 33.

[3] Maines MD. New developments in the regulation of heme metabolism and their implications.

CritRev Toxicol 1984; 12: 241-314.

[4] Dennery PA. Pharmacological interventions for the treatment of neonatal jaundice. Semin

Neonatal 2002; 7; 111–9.

[5] Rodgers PA, Stevenson DK. Developmental biology of heme oxygenase. Clin Prinatology

1990; 17(2): 275-91.

[6] Ennever JF. Blue light, green light, white light, more light: treatment of neonatal jaundice. Clin Perinatalogy 1990; 17(2): 467-82.

[7] Vert P. Physiopathology of neonatal hyperbilirubinemia. Arch Pediatr 1998; 5: 1028 – 30.

[8] De Vries LS, Lary S, Dubowitz LM. Relationship of serum bilirubin levels to ototoxicity and deafness in high-risk low-birth-weight infants. Pediatrics 1985; 76: 351-4.

[9] van de Bor M, van Zeben-van der Aa TM, Verloove-Vanhorick SP, Brand R, Ruys JH. Hyperbilirubinemia in preterm infants and neurodevelopmental outcome at 2 years of age: results of a national collaborative survey. Pediatrics 1989; 83(6) 915-20.

[10] Nelson WE, Behrman RE, Kliegman RM. Nelson text book of pediatrics. Philadelphia: WB Saunders Company 14th. ed., 1992; p. 467.

[11] Valaes T, Petmezaki S, Doxiadis SA. Prevention of neonatal jaundice. Iatriki 1973; 23: 244.

[12] Dennery PA, McDonagh AF, Spitz DR, Rogers PA, Stevenson DK. Hyperbilirubnemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia . Free Radic Biol Med 1995; 19: 395 – 404.

[13] Amine G. Iranian medicinal plants and traditional drugs. Tehran: Farhang Press, 1991; PP. 143 – 4.

[14] Khatamsaz M. Flora of Iran, number 6. Rosaceae family. Tehran: Research institute of forests and rangelands, 1992; PP. 229-31.

[15] Bhandarkar MR, Khan A. Antihepatotoxic effect of Nymphaea stellata Wild. against carbon

tetrachloride-induced hepatic damage in albino rats. J Ethnopharmacol 2004; 91: 61-4.

[16] Rajesh MG, Latha MS. Preliminary evaluation of the antihepatotoxic activity of Kamilari, a

polyherbal formulation. J Ethnopharmacol 2004;91: 99-104.