Ancient Use of Honey as a Medicine:
Honey has been used for thousands of years as food, medicine and in cosmetics. References to honey as a medicine are found in ancient scrolls, tablets and books - Sumarian clay tablets estimated to be from 6200 BC and Veda (Hindu scripture) of about 5000 years old. Early Egyptian were first to use honey as a component in the topical treatment of wounds as seen from their writings in the Smith papyrus (1650BC). They combined honey and animal fat to prevent bandages from drying out and adhering to the wound. They used honey for circumcision, to reduce inflammation and loosen stiff joints (Jones, 2001). Since 1430 AD, honey was mentioned in the Quran as a drink of varying colours manufactured in bee's stomach that can cure people (Surah Al-Nahal; The bee 16:68-69). Honey also was mentioned in the Talmud, the Bible, sacred books of India, China, Persia and Egypt (Beck and Smedley, 1997). All the clues point to the medicinal use of honey throughout human history.
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Honey was used for a variety of purposes including baldness, contraception and mostly in wound treatment. Honey was often mixed with herbs, grain and other botanicals depending on the geographic area. In addition, honey has been used for coughs and sore throats for centuries.
Honey as a Modern Medicine:
In the last 20 years the interest in the use of honey as a medicine has increased. Most research that has been undertaken has concentrated on the use of honey in the treatment of wounds, especially those wounds which were not healing using conventional methods. Also, the recent developments in medicine have discovered many antibiotics, and the use of honey has been overlooked in favour of the new drugs. Over the past 3 or 4 decades, new problems have arisen in terms of antibiotic resistance, and the development of multi-drug resistant organisms such as MRSA (methicillin resistant Staphylococcus aureus), VRE (vancomicin-resistant enterococci), and MDR tuberculosis. In this scenario, honey has been ''rediscovered'' in recent times as it has shown outstanding value in terms of over 4000 years of usage as a wound dressing (Zumla and Lulat, 1989)
Composition of Honey
Honey is a mixture of sugars, water, and other compounds, the specific composition depending largely on the mix of flowers consumed by the bees. It has been reported that approximately 181 substances are present in honey (Terrab et al., 2003). A typical honey analysis is shown in Figure 1 according to the U.S. National Honey Board, where it has an average composition of fructose 38.2%, glucose 31 %, sucrose 1.5%, maltose 7.2% and 17-20% water. In addition, acids, minerals, enzymes, vitamins and proteins are also found. About 18 free amino acids are known to occur in honey. However, they are present in small amounts, although proline is the most common (White, 1979; Atrouse et al., 2004).
The composition of honey varies from one honey to another depending on several factors. A major factor is the floral source, as the nectar from different plants will contain different compositions of the main sugars and trace elements. These compositions are influenced by soil type, climatic conditions (seasons) and the environment surrounding the plant (Crane, 1979).
Many plants such as flowers and trees are excellent sources of nectar for honey. The colour, odour and flavour of honey can vary depending on the nectar source. Colours range from almost water white to dark brown, with darker honey having more antioxidant potential and a stronger flavour. The flavours vary from delectably mild to distinctively bold, depending on where the honeybees worked (http://www.fao.org).
Figure 1: Diagram represents the chemical composition of U.S honey
(Adopted from the website http://www.nhb.org)
It is observed that some chemical changes occur when the nectar is grown to form honey. These changes are mainly because of the enzymes present in the honey. Raw honey contains several enzymes that help in its digestion. These enzymes are invertase (hydrolysed sucrose into glucose and fructose), amylase (diastase) and glucose oxidase (that produces gluconic acid and hydrogen peroxide from glucose in diluted honey). Other enzymes which are also present in the honey are catalase and acid phosphatase. In addition, honey contains several B vitamins such as riboflavin, niacin, folic acid, and B6. Antioxidants and traces of pollen are also present in the honey (Atrouse et al., 2004). Moreover, honey contains a number of minerals such as calcium, iron, zinc, potassium, phosphorus, magnesium, selenium, chromium and manganese (White, 1975; Atrouse et al., 2004).
Evidence of Antimicrobial Activity of Honey:
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In 1892 the antibacterial activity of honey was first recognised by Van Ketel (Dustmann, 1979). Since then there have been many pieces of research which have proved the antibacterial activity of honey against many bacterial pathogens and fungi (Efem, 1992; Molan, 1992a; Molan 1992b; Cooper et al., 1999).
A survey was carried with regard to 345 samples of New Zealand honey to assess the antibacterial activity of honey. Four types of honey were shown to have high antibacterial activity equivalent to phenol standard. In this assay, most of the honeys showed no detectable antibacterial activity when catalase was added to remove hydrogen peroxide. However, manuka and vipers bugloss honeys showed measurable amount of hydrogen peroxide which is believed to aid antibacterial activity (Allen et al., 1991).
Efem (1992) found that undiluted honey prevented the growth of Candida albicans. Wahdan (1998) showed that undiluted honey could be used in the treatment of superficial fungal infections such as ringworm and superficial candidiases.
Cooper et al., (1999) showed that honey has a significant antibacterial activity against the major wound infecting species including methicillin-resistant Staphylococcus aureus (MRSA). In the same year, Cooper et al., compared pasture and manuka honey and found out that the antibacterial activity of honey against Staph.aureus was not wholly due to its high osmolarity. It has been shown that there is not much difference in sensitivity to honey between methicillin-sensitive and methicillin-reisitant staphylococci. In 2000, Cooper et al. also reported the sensitivity of multi-resistant strains of Burkholderia cepacia isolated from cystic fibrosis patients to manuka honey at concentrations below 6% (v/v). Six commercial honey samples were tested against control organisms, Staph.aureus, Escherichia coli, Pseudomonas aeruginosa and various clinical isolates. It was found that some samples had high broad-spectrum antimicrobial activity which resisted refrigeration temperature for six months and being boiled for 15 minutes (Nezeako & Hamdi 2000).
Cooper et al. (2002b) showed the antimicrobial activity of manuka and pasture honey against 18 strains of MRSA isolated from wounds, and 8 strains of vancomycin-sensitive enterococci (VSE). The study showed MIC for both honeys was below 10% (v/v) for all strains. This means that the antibacterial activity of honey is not restricted to osmolarity, whereas artificial honey required a concentration 3 times higher to inhibit the growth. In 2002c Cooper et al., compared the antimicrobial activity of two honeys, a pasture and manuka honey against 17 strains of Pseudomonas aeruginosa isolated from burns. Both honeys maintained bactericidal activity when diluted more than 10-fold. In addition, the study showed that honey has a potential activity to control and prevent infection with coagulase-negative staphylococci (French et al., 2005)
Al-Jabri et al. (2002) compared the antibacterial activity of 16 honeys from different parts of Oman, and 8 from different countries in Africa, against three control organisms Staph.aureus, Escherichia coli, Pseudomonas aeruginosa. It was found that Dhofar honey (Oman) and Eucalyptus honey (Uganda) had highest level of activity against all the three control organisms.
Anti-Staphylococcal activity of thirty types of Omani honey was tested alone and in combination with gentamicin. It was observed that thirteen of the Omani honeys showed excellent anti-Staphylococcus aureus activity. The best honey had a killing rate of 38% of Staphylococcus aureus at 50% concentration in 30 minutes. Gentamicin (4Âµg/ml) killed 70%, while the killing rate for the combination of honey and gentamicin was superior with 92% killing in the same duration (Al-Jabri et al., 2005)
The first study of the ability of honey to prevent bacterial adherence in vitro was done by Al-Naqdy et al., (2005). Four different types of Omani honey were used in this study of growth inhibition. Bacterial adherence was assayed using Salmonella interitidis cells that had been incubated first with honey and then with intestinal epithelial cells. Results showed decreases in the number of bacteria attached to the treated epithelial cells from 25.6Â±6.5 to 6.7Â±3.3 bacteria per epithelial cell (P<0.001).
The primary host defence is the physical barrier afforded by the skin and mucous membrane; once this barrier is breached it provides a route for entry of bacteria into the body. Infection can be from patients' own flora, infectious material from carriers or other infected individuals that may reach the wound. Microorganisms associated with wound infection could be bacteria, fungi or viruses. The most frequently isolated wound pathogens are Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa and Enterobacteroceas (Bowler et al., 2001). A study done on the prevalence of wound infection showed that surgical wounds and skin infections were two of four largest categories of hospital-acquired infections (Emmerson et al., 1996). The management of infected wounds costs a considerable amount of money, Plowman et al. (2000) reported that the cost per case of hospital-acquired infection ranges between £1,618 and £2,398 per person.
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Honey and wound healing process:
Honey is an effective treatment of wounds because it is non-irritating, non-toxic, self-sterile, easy and simple of application, bactericidal, anti-inflammatory, nutritive, and more comfortable than other dressings.
Clinical Evidence of Effectiveness:
In order to determine whether honey does stimulate wound healing, an investigation was undertaken and evidence has been derived from several sources: animal studies, cell line in vitro studies, clinical observations with case studies, cohorts of patients, and clinical trails.
Honey has been used to treat infections in a range of different wound types. These are burns, leg ulcers, diabetic foot ulcers and pressure sores. Cavanagh et al., (1970) observed 12 cases of wound damage after radical vulvectomy being dressed with honey. The wounds became sterile after 3-6 days. In (1981) Salem performed a clinical trial of 45 patients diagnosed with dyspepsia who improved after treatment with only 30mls of honey before each meal. Emarah (1982) observed the improvement of patients suffering from eye infection after applying honey as an eye ointment. Moreover, honey was reported to reduce the duration of diarrhoea in clinical trials of infants with gastroenteritis in which honey was used instead of glucose in rehydration fluid (Haffejee & Moosa 1985).
In 1988, Efem reported the first large clinical cohort study involving 59 patients who had a variety of wounds ranging from Fournier's gangrene, burns and a range of ulcers. Unprocessed honey was applied on cleaned wounds daily. The use of honey on these patients resulted in successful wound healing and the clearance of infection. Suprahmanyam (1993, 1994, 1996 & 1998) reported a clinical trials on burns patients with honey compared to different treatments e.g. polyurethane film (Opsite), potato peelings, and amniotic membrane. Honey was superior to all the other treatments and the healing time was less. Tonks et al. (2001) showed that pasture and manuka honey were found to down-regulate the ROIs (reactive oxygen intermediate) synthesis from MM6 cells. ROIs are known as toxic by-products of various cellular O2 consuming redox processes, which are responsible for causing symptoms of oxidative damage if ROI production exceeds the capacity of ROI scavenging reactions. Honey aids in controlling the ROIs which are required for wound healing.
How does honey promote wound healing?
Although the water activity of honey is very low, it provides a moist environment for optimum healing conditions. The tissue does not get dehydrated because of the osmotic effect of honey in that it draws fluid through the wound tissue from the underlying circulation (Chirife et al., 1983). The topical application of nutrients to wounds has been shown to increase the growth rate of granulation tissue (Kaufman, 1984). The viscosity of honey provides a protective barrier to prevent cross-infection of wounds (Efem, 1988). Honey has been proved to have a deodorising property on wounds. It is thought to be due to the high glucose content uptake by infecting bacteria as an alternative to amino acids, resulting in production of lactic acid rather than malodorous compounds such as ammonia, sulphur compounds and amines (Molan, 1998). Moreover, the acidification of wound (pH 3-4) causes more oxygen to be released from haemoglobin, thereby promoting healing (Efem, 1988).
Some researchers have observed that honey promotes tissue regeneration through the stimulation of angiogenesis and the growth of fibroblasts and epithelial cells (Efem 1988, 1993; Subrahmanyam 1994, 1998), therefore quick healing can minimise the need for skin grafts (Subrahmanyam 1998).
This is due to poor blood supply that limits the availability of oxygen and nutrients to the cells in a skin necrotic lesion. The osmotic effect (high glucose) and mixture content of vitamins, minerals and amino acids in honey plays a role in overcoming these limitations (Molan, 1999).
In addition, after honey is applied to the wound, it forms a film of liquid between the wound and the dressing that prevents the dressing from sticking to the wound, reducing pain and not damaging the newly formed cells. As honey has no adverse effects on tissue, it can be used safely on wounds and introduced into cavities and sinuses to clear infection (Molan, 2000).
Factors Contributing Antibacterial Properties of Honey:
It was thought that the antimicrobial properties of honey are mainly because of hydrogen peroxide, but recent studies have indicated that other physical factors like acidity, osmolarity and electrical conductivity and chemical factors, volatile compounds, beeswax, propolis and pollen play a considerable role in antimicrobial activity (Cooper & Molan, 1999). It well established that honey inhibits many bacterial species. There are many reports of it being bacteriostatic and bacteriocidal (Molan, 1992b).
Honey is a super saturated solution of sugar (80%) and water (17%). The osmolarity of honey inhibits microbial growth because of the strong interaction of sugar molecules with water molecules thus, bacteria gets insufficient water supply for their normal growth (Molan, 1999). Hence, the water activity (aw) of honey is too low to support the growth of any species. Fungi can tolerate a low aw than bacteria, so reports of antifungal activity with diluted honey indicate that there is more involved than just the sugar content of honey. Also, Staph aureus has a high tolerance of low aw but it is one of the most sensitive species to the antibacterial activity of honey (Molan, 1992a). The effect of the additional antibacterial activity in honey can be seen where honey and sugar have been used comparably (Cooper et al., 2002b; 2002c).
Honey is quite acidic; normally, it has an average pH of 3.9 (with a typical range of 3.2 to 4.5). It contains a number of acids that include amino acids and organic acids which are known as flavonids. The major organic acid is gluconic acid that is produced in honey by enzyme action on glucose (White, 1975; Crane, 1980). It has been noted that the acidity is based on the gluconolactone/ gluconic acid content (Molan, 2001a; 2001b). The optimum pH for growth of many species is 7.2 - 7.4. Therefore, the low pH of honey is important to slow down or inhibits bacterial growth (Bogdanove, 1997; Molan 2000). It has been noted that the pH of honey also generates and maintains good environment for fibroblast activity (Lusby et al., 2002).
Hydrogen peroxide production
In 1919, Sackett reported that the antibacterial properties of honey are increased when diluted. This is because when honey diluted hydrogen peroxide is released with help of an enzyme (glucose oxidase) that found in honey (Molan, 1992b). This enzyme is secreted from hypopharyngeal gland of the bees that add to the nectar to assist in honey formation (Borland, 2000).
Hydrogen peroxide (H2O2) is considered to be one of the most important antibacterial agents of honey. It was referred as inhibine (White. et al., 1963) beside flavonoids and phenolic acid. The levels of H2O2 in honey are around 1000 times lower than those traditionally applied on the wounds. As a result of not to inflame a wound or damage the tissue (Molan, 1992a). In addition, it stays in the honey during storage without losing of its antimicrobial strength.
Weston (2000) stated that the level of H2O2 is related to the flora source, and it depends on the balance between the rate of its production and destruction. The destruction of H2O2 is due to catalase which derives from the pollen and nectar of plants, and the amount of catalase in different sources is variable. The enzyme is inactive in full strength honey due to the low pH, so the diluting action of fluids produced by the wound initiates the enzyme.
Several attempts were made to identify the non-peroxide antibacterial component present in the honey (Allen et al., 1991). One study has isolated an antibacterial phenolic fraction (APF) from the honey which consisted benzonic acids, cinnamic acids and flavonoids. It was suggested that APF plays a small role in non-peroxide antibacterial activity in manuka honey and that there are some other factors which are yet to be identified (Weston et al., 1999). Honey contains a variety of polyphenolic compounds that may be capable of chelating metal ions and decreasing oxidation (Rasmussen et al., 2004). Therefore, hydrogen peroxide is not the only inhibine in honey. Two important classes of inhibines are flavonoids and phenolic acid (Molan 1992; Yao et al., 2003). In a study done by Wahdan (1998), two phenolic acids were extracted for the first time; these were caffeic acid and ferulic acid. Flavonoids had shown a range of biochemical and pharmacological actions, which affect the inflammatory cells and the generation of inflammatory processes (Harborne, 1994). The use of flavonoids in medicine is increasing due to their ability to scavenge free radicals, to stimulate hormones and neurotransmitters, and to inhibit specific enzymes (Havesteen 2002).
However, it has been identified several organic components in ether extract of honey with antibacterial activity; these include 3,5-dimethoxy-4-hydroxy benzoic acid (syringic acid), and methyl 3,5-dimethoxy-4- hydroxy benzoate (methyl syringate) (Russel et al., 1988). By using high performance liquid chromatography (HPLC), some other flavonoids and phenolic acids have also been identified in different honeys, for example, pinocembrin, pinobanksin and chrysin (Bogdanove et al., 1989), caffeic acid and ferulic acid (Wahdan, 1998), and vanillic acid, cinnamic acid, and benzoic acid (Weston et al., 1999; Weston et al., 2000).
Honey has high levels of antioxidants, which are substances that protect wound tissues from oxygen radicals that hydrogen peroxide may produce and cause cellular damage (Dunford, 2000).
Gheldof et al., (2002) analysed the antioxidant in different honey fractions and determined that the most of the antioxidant components was found in water-soluble fraction. These include protein; gluconic acid; ascorbic acid; hydroxymethylfuraldehyde; and the combined activities of the enzymes glucose oxidase, catalase and peroxidise. Same study also showed that the phenolic compounds in honey contributed very significantly to its anti-oxidant capacity.
Manuka honey derived from tree (Leptospermum scoparium) is currently approved for therapeutic use. The honey is mainly taken from trees of L.scoparium variety referred to as manuka; L.ericoides commonly referred to as kanuka. These are shrubs which form bushes with height of 12-15 ft. they belong to the Myraceae family and are native to New Zealand.
Manuka honey has a unique type of antibacterial activity different from the antibacterial activity due to hydrogen peroxide that is common to all honeys (Molan & Russell 1988).
A survey of 345 New Zealand honeys found that manuka activity is retained in the presence of catalase which called non-peroxide activity , while most other types of honey were found to be inactive when catalyse is added. In this study antibacterial assays were performed using phenol as standard and Staphylococcus aureus as a reference strain. This developed a measure of activity relating to percentage of phenol which had the same degree of antibacterial activity (Allen et al., 1991). This system was then patented as the UMF or 'Unique Manuka Factor' to give a standard for purchasers. It is now advised that medical practitioner's limit the use of honey to those with a UMF of 10 or higher (equivalent activity of 10% phenol) to ensure adequate activity on diffusion into deeper tissues where severe wounds are involved. Higher UMF rating leads to more antibacterial activity (Molan 2001). The conclusion from these observations is that certain honeys contain antimicrobial factors in addition to sugar content, low pH and hydrogen peroxide generation.
Dunford et al., (2000) observed a case of multiple skin lesions of lower limbs followed by meningococcal septicaemia. Pseudomonas, Staphylococcus aureus and Enterococcus was grown from the swabs of patient leg lesions. Active manuka honey UMF '13' was applied to the lesions. Complete wound healing was observed after 10 weeks with eliminating infections.
The unique activity in manuka honey was then termed as "Active Manuka Honey" by the New Zealand Honey Food & Ingredient Advisory Service in 1998, which said:
'All of the patients in the trials who were taking the special active manuka honey, as opposed to those patients taking ordinary inactive manuka honey, had a marked improvement in their symptoms'.
Allen et al., (2000) reported that the activity of manuka honey was twice than the hydrogen peroxide activity of other honey against VRE, however in MRSA the activity of the two honeys was similar. On wounds, some hydrogen peroxide may be broken down, so honey with hydrogen peroxide activity may be less effective (Paper conference WWH 2000).
Current study reported in vitro effectiveness of manuka honey against biofilms produced by Pseudomonas aeruginosa and Staphylococcus aureus (MRSA & MSSA) with killing rate of 91%, 63% and 82%, respectively (Alandejani et al., 2009).
However, in order for honey to be accepted as an alternative to antibiotics, it is necessary to characterise the components that are responsible for its activity. Although several of the major components of the antibacterial activity of honey are known, like the sugar concentration, pH and hydrogen peroxide, these do not account for the total antibacterial activity observed in many honeys. However, no identification of antibacterial components has been achieved because of the complexity of honey itself and the possible interaction between different substances present in the honey.
At present there are two non-hydrogen peroxide honeys has been developed for clinical use. These are manuka honey in New Zealand and jellybush in Australia. Both honeys are derived from Leptospermum spp (Cooper 2005b; Cooper et al., 1999; Cooper et al., 2002c).
It was thought that non-hydrogen peroxide activity in manuka honey may be due to plant derived components such as flavonoids and phenolic compounds. Recently, two researches have reported that the activity of Leptospermum honeys correlates with the presence of methyglyoxal (MG), an alpha-oxoaldehyde that reacts with macromolecules such as DNA, RNA and proteins (Adams et al., 2008 & Mavric et al., 2008). High amount of MG was present in some manuka honey which is equivalent to the non-peroxide activity. MG was also identified as a bioactive compound which is responsible for the antibacterial activity in manuka honey (Mavric et al., 2008).
Recently, Blair et al., (2009) study the antimicrobial activity of Leptospermum Medihoney with high levels of hydrogen peroxide-dependent activity or Comvita manuka woundcare 18+ against MRSA, Acinetobacter and 6 strains of multi-drug resistant Enterobacteriaceae. MICs ranging from (4 to 5% w/v), (6.0 to 9.3% w/v) and (6.3 to 14.8% w/v) respectively. This indicated that active Leptospermum honey is potentially active against antibiotic-resistant clinical pathogens.