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Journal of Ethnopharmacology
journal homepage:www.elsevier.com/locate/jethpharm
Topical medicines for wound healing: A systematic review of Unani literature with recent advances
Mohammad Fazil
a,1, Sadia Nikhat
b,∗,1aHAK Institute of Literary and Historical Research in Unani Medicine, CCRUM, Jamia Millia Islamia Campus, New Delhi, India
bDept. of Ilaj Bit Tadbeer, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi, India
A R T I C L E I N F O Keywords:
Wound Epithelialization Inflammation Qurūh Jarāhat Healing Unani
A B S T R A C T
Ethnopharmacological relevance: Wound healing is an important area of research in contemporary medicine.
Unani is a traditional medicine system based on hundreds of years of observations and experiences. Wounds are described under the headingsqarha (arabic) andjarāhat(persian) in classical Unani texts. Several drugs of herbal, mineral and animal origin are described in Unani texts as having wound healing properties. Many of these drugs have been screened on various scientific parameters but the potential of most drugs remains un- explored.
Methodology:The study was aimed at summarizing the topical wound healing drugs mentioned in classical Unani books. The topical wound healing drugs were first identified in classical texts. Then 20 drugs were se- lected for detailed review on the basis of clinical relevance and wide availability.
Observations and results:Seventy drugs were identified in Unani texts after removal of duplicacy. Most of the drugs (85.71%) were of herbal origin, while 10% were of mineral origin and the rest 4.28% were of animal origin. Most of the herbal drugs belonged to the Fabaceae (10%) and Rosaceae (8.33%) families. Biologically active compounds such as phenols, sterols, hydrocarbons, anthocyanidins, flavonoids and tannins have been identified in almost all drugs which support classical literature.
Conclusion:Unani system of medicine has a rich legacy of effective wound healing drugs, which is reinforced by modern researches. Most drugs exert their action on multiple phases of wound healing. In addition, most drugs have no reported adverse effects in laboratory and clinical studies. Hence, Unani medicine may offer the much- needed affordable and effective wound care in a wide range of clinical settings.
1. Introduction
Unani medicine, also known as Greco-Arabian medicine, is one of the oldest systems of medicine whose foundation was laid by Hippocrates (460–377 BC). The word Unani literally means ‘Greek’
which refers to its Hellenistic origin. It was introduced in India by the Arab and Persian scholars during the eleventh century. Presently, it is popular in many Arab and Asian countries and is also recognized by World Health Organization as an alternative medicine system (Husain et al., 2010). The classical texts of Unani medicine, for example,Al- Qanoon fil Tibb(The Canon of Medicine) of Ibn Sina (980–1035 AD) (Sina, 1992a,1992b),Zakhira Khwar zam Shahi(Treasure of the King of Khwarazm) of Ismail Jurjani (1040–1136 AD) (Jurjani, 1903), and Kitab al-Tasrif (The Method of Medicine) by Abul Qasim Zahrawi (936–1013 AD) (Zahrawi, 1947), contain a detailed description of
different types of wounds and their management. The drugs used for treatment are mostly of herbal origin, while animal and mineral origin drugs including ores are also utilized in a number of diseases. Wounds are mentioned by the terms ofqarha(arabic),jarāhat(persian) andrīsh (persian) interchangeably in Unani literature. In classical Unani lit- erature,jarāhatrefers to wounds not associated with suppuration, and qarha is used for wounds primarily or secondarily associated with suppuration, while the termrīshhas been used for both types (Jurjani, 1903).
The quest for an ideal wound healing agent has been imperative to man since the very inception of human civilization. The science of wound healing aims to shorten the healing time and to minimize the undesired consequences such as infections and scarring (Maver et al., 2015). Natural drugs contain an amalgamation of many active in- gredients which interact to provide a comprehensive healing action
https://doi.org/10.1016/j.jep.2020.112878
Received 15 December 2019; Received in revised form 26 March 2020; Accepted 11 April 2020
∗Corresponding author.
E-mail addresses:[email protected](M. Fazil),[email protected](S. Nikhat).
1The authors contributed equally to this work.
Available online 20 April 2020
0378-8741/ © 2020 Elsevier B.V. All rights reserved.
T
Table 1
Topical remedies for wound healing mentioned in classical Unani literature.
S. No. Traditional and Scientific Name Family Origin Part/form used Reference
‘Araq-i-gulāb(Rosa damascenaHerrm.) Rosaceae Herbal Distillate of petals (Razi, 2004;Ali, 2010)
‘Ilk al-baṭm(Pistacia terebinthusL.) Anacardiaceae Herbal Resin Rushd (1987)
‘Inab al thaʻlab(Solanum nigrumL.) Solanaceae Herbal Leaves (Razi, 2004;Ali, 2010)
‘Ullaiq(Rubus nessensisHall.) Rosaceae Herbal Berry, Root Rushd (1987)
Ab-hal(Juniperus communisL.) Cupressaceae Herbal Berry Rushd (1987)
ʻAds muqashshar(Lens culinarisMedik.) Fabaceae (sub-family
Papilionoideae) Herbal Kernel of seed Razi (1999)
Afyūn(Papaver somniferumL.) Papaveraceae Herbal Latex Razi (1999)
Āmla(Phyllanthus emblicaL.) Euphorbiaceae Herbal Fruit Tabri (1996)
Anzarūt(Astragalus sarcocollaDymock.) Fabaceae Herbal Gum resin from root Razi (1999)
Aqāqia(Acacia nilotica(L.) Delile) Mimosaceae Herbal Extract of leaves and fruits (Sina, 1992b;Ali, 2010)
Ārad-i-gandum(Triticum aestivumL.) Poaceae Herbal Flour from seeds (Ali, 2010;Razi, 2004)
ʻAsl(Honey) – Animal Whole Zuhr (1986)
Balsān(Commiphora gileadensis(L.) C.Chr) Burseraceae Herbal Oil, aerial parts Razi (1999)
Bān(Melia azedarachL.) Meliaceae Herbal Oil Razi (1999)
Banafsha(Viola odorataL.) Violaceae Herbal Oil, aerial parts Razi (1999)
Bārtang(Plantago majorL.) Plantaginaceae Herbal Leaf, seed Razi (1999)
Bazr al-banj(Hyoscyamus albusL.) Solanaceae Herbal Seeds, whole herb (Razi, 2004;Ali, 2010)
Behī dāna(Cydonia oblongaMill.) Rosaceae Herbal Seed mucilage Zuhr (1986)
Chowb zard(Curcuma longaL.) Zingiberaceae Herbal Dried and powdered rhizome Khan (2010)
Dam-al-akhwayn(Pterocarpus marsupiumRoxb) Fabaceae Herbal Sap from bark (Khan, 2010;Tabri,
1996;Razi, 1999)
Dhaniya(Coriandrum sativumL.) Apiaceae Herbal Aerial parts Razi (1999)
Farbiyūn(Euphorbia resiniferaO. Berg) Euphorbiaceae Herbal Latex Razi (2004)
Faufal(Areca catechuL.) Arecaceae Herbal Nut Razi (2004)
Gil-i-makhtūm(Terra sigillata) – Mineral Clay Sina (1998)
Gulnār(Punica granatumL.) Punicaceae Herbal Flowers (Khan, 2010;Tabri,
1996)
Ḥabb al Ās(Myrtus communisL.) Myrtaceae Herbal Fruit (Sina, 1992b;Ali, 2010)
Ḥaṣrim(Vitis viniferaL.) Vitaceae Herbal Unripe fruit Razi (2004)
Ḩulba(Trigonella foenum-graecumL.) Fabaceae Herbal Seeds Razi (1999)
Iklīl-ul Malik(Trigonella glabrasubsp.uncata
(Boiss. & Noë) Lassen) Leguminosae Herbal Beans Razi (1999)
Īrsā(Iris ensataThunb.) Iridaceae Herbal Root Razi (1999)
Kāfūr(Cinnamomum camphora(L.) J. Presl) Lauraceae Herbal White crystalline substance obtained by
distillation of woody parts Tabri (1996)
Karsanah(Pisum sativumL.) Fabaceae Herbal Seed, decoction Zuhr (1986)
Katān(Linum usitatissimumL.) Linaceae Herbal Seeds Razi (1999)
Khiţmī(Althaea officinalisL.) Malvaceae Herbal Seeds Razi (1999)
Khurfa(Portulaca oleraceaL.) Portulacaceae Herbal Aerial parts Razi (1999)
Kibrīt(Sulphur) – Mineral Whole Rushd (1987)
Kundur(Boswellia serrataRoxb. ex Colebr.) Burseraceae Herbal Gum Razi (1999)
Kunjad(Sesamum indicumL.) Pedaliaceae Herbal Oil from seed Zuhr (1986)
Laḩyatut-tīs(Tragopogon porrifoliusL.) Asteraceae Herbal Leaf, flower Rushd (1987)
Lobān(Styrax benzoinDryand) Styracaceae Herbal Resin (Tabri, 1996)
Lu‘āb-i-raisha khaṭmi(Althaea officinalisL.) Malvaceae Herbal Mucilage from root Sina (1992b)
Maghz(Bone marrow) – Animal Red bone marrow obtained from animals such as
cow, buffalo, etc. Rushd (1987)
Mah baiḍ(Egg yolk) – Animal Whole egg yolk Razi (2004)
Maṣtagī(Pistacia lentiscusL.) Anacardiaceae Herbal Tabri (1996)
Māzū(Quercus infectoriaG. Olivier.) Fagaceae Herbal Gallnuts (Sina, 1992b;Ali, 2010)
Murdār sang(Lead monoxide) – Mineral Whole, powdered (Sina, 1992b;Ali, 2010)
Murr(Astragalus sarcocollaDymock.) Fabaceae Herbal Gum resin (Razi, 1991;Ali, 2010)
Nīm(Azadirachta indicaA. Juss.) Meliaceae Herbal Bark, Fruit, Leaves, oil from leaves (Sina, 1992b;Ali, 2010)
Nishāsta(Triticum aestivumL.) Poaceae Herbal Wheat starch Razi (1999)
Rasawt(Berberis aristataDC) Berberidaceae Herbal Root extract Zuhr (1986)
Rātīnaj(Pinussp.) Pinaceae Herbal Resinous gum from pine tree (Razi, 2004;Ali, 2010)
Roghan gul(Rosa damascenaHerrm. oil) Rosaceae Herbal Oil from petals (Razi, 2004;Zahrawi,
1947)
Roghan-i-Zaitūn(Olea europaeaL.) Oleaceae Herbal Oil from fruit Khan (2010)
Saʻd(Cyperus rotundusL.) Cyperaceae Herbal Root Razi (2008)
Safarjal(Cydonia oblongaMill) Rosaceae Herbal Fruit, seed (Sina, 1992b;Ali, 2010)
Ṣafṣāf(Salix mucronataThunb., Syn.Salix safsaf) Salicaceae Herbal Flowers, leaf, bark, gum Rushd (1987)
Ṣandal(Santalum albumL.) Santalaceae Herbal Heartwood (Sina, 1992b;Ali, 2010)
Shib yamāni(Alum, hydrated form of potassium
aluminum sulphate, KAl(SO4)2·12H2O) – Mineral Whole Razi (1999)
Şibr(Aloe vera(L.) Burm.f.) Liliaceae Herbal Leaf sap (Razi, 2004;Tabri,
1996)
Sosan(Iris ensataThumb.) Iridaceae Herbal Oil from root Razi (1999)
Sumāq(Rhus coriariaL.) Anacardiaceae Herbal Fruit epicarp Razi (2008)
Tabāshīr(Bambusa bambus(L.) Voss.) Poaceae Herbal Bluish tinged crystalline material found on stalks, nodes and hollow stems of hollow plant, Bamboo manna
Razi (1999)
(continued on next page)
(Das et al., 2017). In fact, traditional medicines are the source of many conventional drugs in the recent years (Shedoeva et al., 2019). Many recent publications have focussed on traditional therapies, medicinal plants and phytochemicals in wound healing (Periera and Bártolo, 2016). A number of biologically active compounds have been identified in medicinal plants which help in the wound healing process such as polyphenols, terpenes, glucosinolates, carotenoids, saponins, fatty acids, resins, phytosterols, peptides, and proteins etc. (Budovsky et al., 2015).
In this article, we provide an overview of the type of drugs pre- scribed for topical use in wound healing in classical books of Unani medicine. A comprehensive list of all drugs concerned with wound healing (Table 1& Table 2) from the selected books (mentioned in Section 3.3) is provided to get a comprehension of same. We also provide a detailed review of some selected drugs (Section5) which will be useful to understand the mechanism and rationale behind the use of these drugs.
2. Mechanism of wound healing
2.1. Cascade of events involved in wound healing
The acute inflammatory response is aimed towards restoring the structural stability and functional integrity to the damaged tissues.
Cutaneous wound healing classically involves four phases, (a) hae- mostasis, (b) inflammation and formation of granulation tissue, and (c) remodeling leading to wound closure (Shedoeva et al., 2019). Fol- lowing injury, the release of serotonin, prostacyclin A2 and other in- flammatory mediators by the cell membranes initiates vasoconstriction.
Concurrently, activation of the coagulation cascade occurs in response to the exposed collagen. The coagulation mechanism causes deposition of fibrin and thrombin clot at the site of wound, hence forming a physical barrier to entry of pathogens; this will also provide a milieu to the future deposition of cytokines etc. in the subsequent healing phases (Serra et al., 2017).
The inflammatory reaction starts simultaneously with the healing process and is characterized by the cardinal signs of inflammation such as oedema, pain and swelling. This phase is dominated by activity of inflammatory cells. In the initial 24 h, mainly leukocytes (the first cells to infiltrate the wound site), neutrophils, lysosomes, gamma-delta cells and Langerhans cells infiltrate the site, and release chemokines, cyto- kines such as IL-1 β, TNF-α (tumor necrosis factor alpha), and IFN-γ (interferon gamma) at the site of injury. These chemicals induce tissue repair by dissolution of fibrin, angiogenesis and re-epithelializaiton (Gonzalez et al., 2016). After about 48 h, due to chemokine signaling, monocytes migrate to the area and aid neutrophils in phagocytosis (Budovsky et al., 2015). Macrophages also release growth factors like TGF-β, MCP-1 (protein 1 chemotactic for monocytes), which help in development of new tissue through stimulation of fibroblasts, kerati- nocytes and angiogenesis. They also secrete prostaglandins, chemo- tactic factors, and cytokines, which together help in formation of granulation tissue and progression from inflammatory to proliferative phase (Gonzalez et al., 2016;Pereira and Bártolo, 2016). At the end of this stage, the dead cells are replaced by epithelial cells. Formation of extracellular matrix occurs with production of collagen, hyaluronan, proteoglycans, fibronectin, and glycosaminoglycans by fibroblasts (Pereira and Bártolo, 2016).
The proliferative phase starts 2–10 days after the injury (Budovsky et al., 2015). It is charatcterised by wound contraction, collagen for- mation, fibroplasia, neovascularization, and re-epithelialization, i.e.
formation of a functional epidermis leading to wound closure (Serra et al., 2017). This stage is dmoninated by the endothelial cells, lym- phocytes and pericytes. Pericytes occur in micro-vasculature, and are evidenced to have a pluripotent nature, by which they can differentiate into fibroblasts, leiomyocytes, and adipocytes. At the end of successful reepithelializaiton, the basal membrane is reconstructed by keratino- cytes and is differentiated into stratified epidermis (Gonzalez et al., 2016).
The phase of remodeling begins 2–3 weeks after the initial injury and may continue for a year or more. In this stage, wound contraction, Table 1(continued)
S. No. Traditional and Scientific Name Family Origin Part/form used Reference
Ushaq(Dorema ammoniacumD.
Don) Apiaceae Herbal Gum exudates Razi (1999)
Usrub(Plumbum) – Mineral Whole Rushd (1987)
Yabrūj(Atropa belladonnaL.) Solanaceae Herbal Leaves (Sina, 1992b;Ali, 2010)
Zaʻfrān(Crocus sativusL.) Iridaceae Herbal Stigma (Tabri, 1996;Zuhr,
1986)
Jāoshīr(Ferula galbanifluaBoiss.) Umbelliferrae (Apiaceae) Herbal Oleo gum-resin Rushd (1987)
Zanjār(Copper rust) – Mineral Whole Rushd (1987)
Zarāwand(Aristolchia rotundaL.) Aristolochiaceae Herbal Root (Sina, 1992a;Rushd,
1987) Momiyayī(blackish brown exudation from rocks
due to heat, containing gold and other metals) – Mineral Whole (Razi, 2008;Majusi,
1889)
Table 2
Plant parts used as topical wound healing agents.
Part useda No. of drugs and percentageb Examples of drugs
Gum and other exudates 14 (23.33%) Pistacia terebinthusL.,Papaver somniferumL.,Astragalus sarcocollaDymock.,Euphorbia resiniferaO. Berg,Boswellia serrataRoxb. ex Colebr.,Styrax benzoinDryand
Seeds 13 (21.66%) Trigonella foenum-graecumL.,Linum usitatissimumL.,Althaea officinalisL.,Sesamum indicumL.
Fruit 10 (16.67%) Rhus coriariaL.,Juniperus communisL.,Phyllanthus emblicaL.,Vitis viniferaL.
Oil, leaves 9 (15% each) Atropa belladonnaL.,Melia azedarachL.,Solanum nigrumL.,Acacia nilotica(L.) Delile Root 8 (13.33%) Rubus nessensisHall.,Iris ensataThunb.,Althaea officinalisL.
Aerial parts, flowers 4 (6.67% each) Tragopogon porrifoliusL.,Salix mucronataThunb.,Portulaca oleraceaL.
Bark 3 (5%) Pterocarpus marsupiumRoxb.,Azadirachta indicaA. Juss.,Salix mucronataThunb.
Stigma 1 (1.67%) Crocus sativusL.
a More than one part is used from most herbs, so the numbers do not represent the total number (n = 60).
b Percentage is calculated from the n = 60 herbal origin drugs included inTable 1.
Table3 Summaryofwoundhealingdrugsdescribedinthepaper. Herbs/drugFunctionsdescribedinUnani classicalbooksActiveingredientsFindingsClinicalusesinUnaniMedicineReferences ‘Araq-i-gulāb(Rosa damascenaHerrm.)Musakkin(soothing)and Mufarrih(exhilarant)Citronellol,2-phenylethylalcoholandgeraniol; andaliphatichydrocarbons(Vermaetal., 2011a,b)
ProtectionoffibroblastsagainstH2O2 induceddamage(Thringetal.,2011)Pustulareruptionsonskin,Urticaria,burns (Razi,1991)Vermaetal.(2011);Thring etal.(2011);Choiand Hwang(2003) ‘Inabalthaʻlab(Solanum nigrumL.)Muhallil(resolvent),mujaffif (desiccant),qābiḍ(astringent)PolyphenolsandAnthocyanidins(Huangetal., 2010)Bacteriostatic,anti-oxidant(Krithigaetal., 2015;Arullappanetal.,2015)Itsanalgesicactivityissaidtobecomparable toafyūn,althoughsomewhatlesspotent. Appliedlocallyonswellingsandinflammation. Alsousefulinerysipelas,glossitisandherpes (Sina,1992b).
Huangetal.(2010); Krithigaetal.(2015); Arullappanetal.,2015; Sina(1992b) Aqāqia(extractofAcacia nilotica)Qābiḍ(styptic,astringent)Phenoliccontents,flavonoids(Abdel-Faridetal., 2014)Improvedgeneexpression(Ker-Woonetal., 2015)thromogenesis,anti-infectious (Bhatnagaretal.,2013)
Papulareruptionsandalsousedas haemostatic.Maybeusedforburnsafter mixingwitheggwhite.(Sina,1992b)
Abdel-Faridetal.(2014); Bhatnagaretal.(2013); Ker-Woonetal.(2015); Sina(1992b) Bazral-banj(Hyoscyamus albusL.)Mukhaddir(anaesthtic), musakkin(analgesic),munawwim (sedative)
Hyoscyamine,Scopolamine,Calystegines (Bourebabaetal.,2016)Analgesia(possiblyduetoinhibitionof prostaglandinsecretion),anti- inflammatory,bacteriostatic(Al-Snafi, 2018)
Erysipelas.Relievespaininswellings. Haemostatic(Sina,1998)Bourebabaetal.(2016);Al- Snafi,2018;Sina(1998) Chowbzard(Curcuma longaL.)Muhallil(resolvent),musakkin maqāmi(soothing),mujaffif-i- qurūh(desiccant),jālī (detergent)
Curcumin(C21H20O6,difeurloyl-methane),the maincurcuminoidandresponsiblefortheyellow colourofturmeric(Mehrabanietal.,2015; Akbiketal.,2014)
↓inTNF-α ↑inIL-10,TGF-β1,andCD-31in granulationtissue ↑collagenformation,bettercollagenlinking (Prasadetal.,2017) Topicalapplicationonsiteofacute inflammation(Sina,1992b).Fistulaand chroniculcers(Khan,1983) Mehrabanietal.(2015); Akbiketal.,2014;Prasad etal.(2017);Sina(1992b); Khan(1983) Dam-al-akhwayn
(Pterocarpus marsupium
Roxb)
Ḥābis(styptic),Qābiḍ (astringent)Steroids,flavonoidsandphenoliccompounds (Gosettietal.,2016)Formationofgranulationtissue,(Gosetti etal.,2016)Acutewounds,cutsandulcers;tostopoozing fromwounds(Sina,1992b)Gosettietal.(2016);Sina (1992b) Farbiyūn(Euphorbia resiniferaO.Berg)Usedahealingagentfornerves, tendonsandligamentsResiniferatoxin(C37H40O9),aditerpenewitha molecularmassof628.71g/mol(Parisietal., 2017)
TRPV1agonist,antiallodynic(Parisietal., 2017;Kissinetal.,2011)Chronicwounds(Sina,1992b),wounds involvingnerves,ligamentsandtendons(Razi, 2004) Parisietal.(2017);Kissin etal.(2011);Razi(2004) Faufal(ArecacatechuL.)Qābiḍ(astringent),Ḥābis (styptic)Arecoline(N-methyl-1,2,5,6-tetrahydropyridine- 3-carbonicacidmethylester)(Sharanetal., 2012)
Nootropic,styptic,mAChRagonist(Peng etal.,2015)Usedinhardswellingsandconjunctivitis (Sina,1992b)Sharanetal.(2012);Peng etal.(2015);Sina(1992b) Gil-i-makhtūm(Terra sigillata)Mujaffif(desiccant),mubarrid (cooling),hābis-i-dam (haemostatic)
––Prescribedasdesiccantandhaemostaticfor wounds(Rushd,1987).Rushd(1987) Gulnār(Punicagranatum L.)Qābiḍ(astringent),Ḥābis (styptic)Polyphenols,TanninsInhibitionof5-lipoxygenase,anti- inflammatory,anti-microbial(Bekiretal., 2013;Pirbaloutietal.,2010) Haemostatic;usefulinchroniculcersandacute injuriesalso.Stopsexudationfromwounds (Sina,1992b).
Sina(1992b);Bekiretal. (2013);Pirbaloutietal., 2010 ḤabbalĀs(Myrtus communisL.)Musakkinmaqāmi(local analgesic),hābis(styptic)Semi-myrtocommunolone,α-pinene,1,8-cineol, limoneneandlinalool(Jinousetal.,2015)InhibitionofIL-8secretion,anti-microbial (Alipouretal.,2014)Erysipelas,pustulareruptions,herpes,acute ulceration,urticaria,burns,haemorrhagefrom wounds(Sina,1992b) Jinousetal.(2015);Alipour etal.(2014);Sina(1992b) Ḥaṣrim(Unripegrape, VitisviniferaL.)Muṣaffī(cleansing)Resveratrol,calciumions,flavonoids,triterpenes (Nassiri-Asletal.,2016)Inhibitionofneutrophilsaggregation,anti- microbial,specificactiononH.pylori (Farzaeietal.,2013)
UlcerationsofGIT(Razi,2004)Nassiri-Asletal.(2016); Farzaeietal.(2013) Mahbaiḍ(Eggyolk)UsedashealingagentforburnsFattyacids(oleicandlinoleicacid)(Rastegar etal.,2011)Re-epithelization,neovascularization (Yenilmezetal.,2015)Acuteinjury,pustules,ulceration,infected wounds,burns(Sina,1992b)Yenilmezetal.(2015); Rastegaretal.(2011);Sina (1992b) Māzū(Quercusinfectoria G.Olivier.)Qābiḍ(astringent),mujaffif (desiccant),hābis-ul-dam(anti- haemorrhagic),dāfa‘-i-ta'ffun (anti-septic)
Tannins,flavonoids,steroidalcompounds (Chusrietal.,2012)Anti-bacterial,anti-oxidant,inhibitionof macrophagesandneutrophils,re- epithelialization(Ahmadetal.,2014) Prescribedinringwormandstomatitis.Also usedashaemostaticandinadditionreduces exudationfromwounds(Sina,1992b).
Chusrietal.(2012);Ahmad etal.(2014);Sina(1992b) Murdārsang(Lead monoxide)Jālī(cleansing),akkāl (corrosive),Mujaffif(desiccant)–UseofMurdārsangisbannedowingtoits toxiceffects(Nagarajanetal.,2014)–Sina(1992b);Razi(1991); Nagarajanetal.(2014) (continuedonnextpage)
degradation, reorganization, and resynthesis of extracellular matrix occurs, in an attempt to achive maximum tensile strength and recover the normal tissue. At the end of this stage, there is formation of scar tissue (Gonzalez et al., 2016). There is clinical evidence to suggest that shorter healing time is associated with less fibrosis and scarring. While full-thickness or partial thickness wounds are slow to heal and result in fibrosis or hypertrophic scars. Normallly, most of the functional in- tegrity, homeostasis, skin pliability and physiological functions are re- stored within 4 weeks’ time. Wounds which fail to show these char- acteristics within 6 weeks are considered as chronic wounds (Shedoeva et al., 2019).
2.2. Wound-healing drugs in Unani medicine
In Unani medicine, wounds are categorized on the basis of clinical characteristics like presence or absence of sepsis, severity of in- flammation, presence of maggots, infected/non-infected, burns and chronicity (Sina, 1992a;Jurjani, 1903). According to Galen (131–199 AD), the management ofjarāhat(non-infected wounds) should focus on healthy closure of wound. If tissue destruction is not extensive, anti- inflammatory and healing drugs are recommended, alongwithkhiyāṭa (suturing). On the other hand, if tissue destruction is severe,munbit-i- lahm(drugs which help in tissue proliferation) likezift(pix nigra) and zarāwand(Aristolochia longaL.) should be used first (Sina, 1992a;Razi, 2004). For the management of qurūh (plural of qarha, suppurating wounds),mujaffif(desiccant) drugs should be given priority to reduce and re-absorb exudates. According to the legendary physician Ibn Sina (980–1035 AD), if the wound is infected, thenakkāl(corrosive drugs), or cauterization should be prescribed (Kabiruddin, 2015). Analgesia, haemostasis, and nutrition should be given due consideration in all cases (Jurjani, 1903;Zahrawi, 1947).
Delay in wound healing is attributed to many factors like decreased perfusion, old age, sepsis, site of wound (wounds in brain, heart, liver, and intestines are said to be fatal), wounds over bony prominence or ligaments, geographical location (humid season is said to increase the chances of sepsis, and hence delay healing). In these cases, treatment should focus on the alleviation of the cause (Razi, 2004). For deep wounds that lead to osteomyelitis, it is recommended to cauterize the damaged area or perform debridement to remove the damaged part of the bone; in severe cases, amputation may be performed (Jurjani, 1903). The description and management of wounds bears close re- semblance to contemporary medicine concepts.
3. Methodology 3.1. Need of the study
Natural medicines offer incomparable chemical diversity which leads to a comprehensive action through several interconnected me- chanisms. Over the past few decades, various traditional medicine systems are becoming increasingly popular all over the world due to their holistic nature. In India, Unani medicine is integrated in the na- tional healthcare system (Yuan et al., 2016). However, like all tradi- tional systems of medicine, there is a need for identification of potential safety concerns and scientific evaluation of efficacy before being au- thoritatively introduced as wound healing agents (Maver et al., 2015).
In addition, the wound healing activities of Unani medicines could be an interesting area of research (Hosseinkhani et al., 2017). The purpose of this review was to present the potential strength areas of Unani medicines as wound healing agents in a comprehensive manner.
3.2. Objectives
The present review was performed to summarize the topical wound healing drugs mentioned in classical Unani books. We also intended to find out the applicability of Unani drugs in the light of recent Table3(continued) Herbs/drugFunctionsdescribedinUnani classicalbooksActiveingredientsFindingsClinicalusesinUnaniMedicineReferences Nīm(AzadirachtaindicaA. Juss.)Muṣaffī-i-dam(bloodpurifying), Dāfa’-i-ta'ffun(anti-septic)Phytosterols(sitosterols,sigmasterol,and campasterol),flavonoids,andtriterpenoids (Gautametal.,2015)
Fibroblastproliferation,collagensynthesis andneovascularization(Gautametal., 2015) Skininfections(Sina,1992b;Razi,1991)Gautametal.(2015);Sina (1992b);Razi(1991) Rātīnaj(Pineresin)Mujaffif(desiccant)Abieticacid(Parketal.,2017)Angiogenesis,proliferationofhuman umbilicalveinvascularendothelialcells (HUVECs)(Parketal.,2017)
Chronicnon-healingwounds,especiallyin anaemicpatients(Razi,2004).Parketal.(2017);Razi (2004) Roghangul(Rosa damascenaoil)Muhallil(resolvent)Essentialoils(Vermaetal.,2011a,b)Antioxidant,anti-inflammatory(Fahimi etal.,2015)Ifinflammationoccursinsurgicalwound (Zahrawi,1947),Analfissures(Khan,1983), Burns(Razi,2004)
Vermaetal.(2011);Fahimi etal.(2015);Khan(1983); Razi(2004);Zahrawi (1947) Roghan-i-Zaitūn(Olea europaeaL.)oilOilfromripeolives:Muhallil (resolvent),Musakkin(analgesic) Oilfromunripeolives:Qābiḍ (astringent),Mujaffif(desiccant)
Oleuropin,linoleicacid(Gorzynik-Debickaetal., 2018)Anti-oxidant,anti-inflammatory, accelerateswoundclosure(Karimietal., 2019) Erysipelas,herpes, Urticaria,acuteinflammations,scabies,ulcers withsuppurationandringworm.Local applicationimmediatelyafterexposuretoheat alsopreventsblistersinburns(Sina,1992b; Rushd,1987).
Gorzynik-Debickaetal. (2018);Karimietal. (2019);Sina(1992b); Rushd(1987) Şibr(AloeveraL.)Muhallil(resolvent),mundamil (healing)Acemannan,Glucomannan,Mannose(Sahu etal.,2013;Hashemietal.,2015)Stimulationofmacrophages,increased collagenproductionandsecretion, promotionofangiogenesis(Sahuetal., 2013;Hashemietal.,2015)
Analandpenileswelling,ocularulcers,anal fissures,oozingofbloodfromwounds(Sina, 1992b).
Sahuetal.(2013);Hashemi etal.(2015);Sina(1992b)
researches, for which selected drugs were reviewed in detail.
3.3. Eligibility criteria and search strategy
In the first phase, we collected information regarding Unani drugs used as topical wound healing agents. For this purpose, the classical books of Unani medicine available in the library of School of Unani Medical Education and Research, Jamia Hamdard; and Hakim Mohd.
Said Central Library, Jamia Hamdard were studied. Eight important textbooks of Unani medicine available in the above-mentioned libraries were reviewed for this purpose. The reviewed books are: Al-Ikseer-e- Azam by Hakim Azam Khan (1211–1320 AD), Al-Qanoon fil Tibb of Ibn Sina (980–1035 AD), Zakhira Khwar zam Shahi by Ahmad al-Hasan Jurjani (12thcent. AD), Kitab Al-Hawi by Zakariya Razi (865–925 AD), Kitab al-Mansoori by Zakariya Razi (865–925 AD), Kitab al-Kulliyat by Ibn Rushd (1126–1198 AD), Kitab al-Taisir by Ibn Zuhr (1092–1162 AD), and Jarahiyat-e-Zahrawi (30thVolume of Kitab al-Tasrif by Abul Qasim al-Zahrawi, 936–1013 AD). The drugs included in the paper were those which (i) had a direct effect on skin or mucous membranes e.g. conjunctiva and (ii) their identity could be established. The drugs which are no longer available or have toxic effects were excluded from the review. Only two such drugs (Terra sigillataand Litharge) were in- cluded for detailed review owing to academic interest. Duplicacy was also removed at this stage.
In the second phase, we randomly selected 20 drugs for a detailed review. The drugs which (i) had a wide application on different types of wounds, (ii) were clinically relevant and (iii) available in most parts of the world, were selected for the detailed review (Fig. 1). Then we searched the major scientific search engines (PubMed, Web of science) for detailed information regarding the active ingredients and efficacy of these drugs, especially for clinical use. Keywords used for the search
were ‘wound healing’, ‘clinical trial’ and ‘injury’ alongwith the name of each drug. The search was restricted to papers published between the years 2010 to 2019. Preference was given to human studies and those studies where the drugs were used in the same form as mentioned in Unani literature (e.g. decoction, powder etc.).
3.4. Data extraction and interpretation
Data extracted included information about the efficacy of drug, form of use, availability, toxic effects, methodology of study and out- come presentation. Any disagreements were resolved with discussion.
The results were interpreted and discussed keeping in view the clinical and research applications of the drugs.
4. Observations
Based on eligibility criteria, a total of 70 drugs (summarized in Table 1) were located in the Unani books after removal of duplicacy.
Out of these, 60 (85.71%) drugs were of herbal origin, while 7 (10.00%) were of mineral origin and the rest 3 (4.28%) were of animal origin. Most of the herbal drugs belonged to the Fabaceae (10%) and Rosaceae (8.33%) families, while rest of the drugs belonged to varied families such as Apiaceae, Liliceae, etc. The plant parts used were gum and other exudates (23.33%), seeds (21.66%), fruit (16.67%), oil, leaves (15% each), root (13.33%), aerial parts, flowers (6.67% each) and stigma (1.67%) (Table 2).
5. Detailed review of selected drugs (summarized inTable 3) 5.1. Aqāqia (Acacia nilotica (L.) Delile, family: Mimosaceae)
According to Ibn Sina (980–1035 AD),aqāqiarefers to the extract of qaraz(A.nilotica tree), commonly known as Gum arabic tree,babūland mughīlān(Persian) (Sina, 1992b). For obtainingaqāqia, the leaves and fruits of the tree are pounded and extract is obtained (Sina, 1998).
However, according to Ibn Rushd (1126–1198 AD),aqāqiarefers to the extract obtained from pods ofA. nilotica(Rushd, 1987).A. niloticais a famous perennial tree widely found throughout the tropical and warm temperate regions of the world, often grown for ornamental purpose (Sharma et al., 2014). It may be 5–20 m tall with dense spherical crowns, branchlets and stem which are usually dark to black coloured and a fissured bark which appears grayish-pink on slashing and exudes a reddish gum (Auwal et al., 2014). In Unani medicine, it has been described as a qabiz(styptic, astringent). A poultice of fresh acacia leaves is prescribed for wounds and as azimād(paste) over the eye in conjunctivitis (Ali, 2010). Recent studies have demonstrated significant anti-bacterial, astringent and anti-microbial activity of acacia leaves (Ali et al., 2012).
A. niloticacontains saponins, phenolic compounds, flavonoids, car- bohydrates, anthocyanin and TAC (ascorbic acid equivalent) (Abdel- Farid et al., 2014). Crude extract ofAcacia arabicaleaves showed sig- nificant anti-viral effect and also prophylactic activity against viral in- fection in a recentin vitrostudy (Ghoke et al., 2018).A. niloticaleaf cold extract showed significant (p = 0.001) anti-microbial activity as compared to chlorhexidine (Shekhar et al., 2015). It also has a high phenolic content due to which it exerts a strong anti-oxidant action (Kalaivani et al., 2011). When combined with zinc oxide nanoparticles, it reduces the toxicity while preserving anti-bacterial and healing ac- tivity (Baravkar et al., 2008).In vitrostudies have demonstrated the wound healing action of acacia honey through increased expression of proteins and genes related to wound healing (Ker-Woon et al., 2015).
Acaciaalso has a potent thrombogenetic, haemostatic and anti-bacterial activity which improves wound cicatrization (Bhatnagar et al., 2013).
Fig. 1.Method of literature search and selection of drugs.
5.2. ‘Araq-i-gulāb (Rosa damascena Herrm. distillate, family: Rosaceae)
‘Araq-i-gulāb, commonly known as rose water, is the hydrolate from the petals of Rosa species (Ali, 2010). For medicinal purposes, rose water is generally obtained from R. damascena Herrm. flower, also known asgul-i-mohammadi,ward,gul-i-surkh,gulāb, Damask rose and Rose plant (Boskabady et al., 2011). Rose plant is a popular ornamental plant, with large colourful flowers. It is a perennial shrub, bushy in appearance and reaches 1–2 m in height. Damask rose originated in the Middle East and is now cultivated all over the world including Europe, Iran, Turkey, India and Bulgaria.‘Araq-i-gulābcontains 10–50% rose oil which is one of the costliest natural oils (Verma et al., 2011a,b). In Unani medicine, rose water is described as havingmusakkin(soothing) andmufarrih(exhilarant) effects (Zahrawi, 1947), and is prescribed for wounds in internal organs like gastric ulcers etc. (Ali, 2010).
The major components of rose water obtained from North Indian rose are citronellol, 2-phenyl ethyl alcohol and geraniol; and aliphatic hydrocarbons like heneicosane, nonadecane, tricosane, pentacosane and eicosane similar to the Iranian rose, although in lesser concentra- tion (Boskabady et al., 2011), while rose oil obtained from southern India contains mainly phenyl ethyl alcohol, octadecane and hexadecane (Mahboubi, 2015). In a recentin vitrostudy, aqueous extract of rose was found to have a significant anti-elastase, anti-collagenase, and anti- oxidant activity. In addition, it had a protective effect on fibroblast cells against hydrogen peroxide induced damage (Thring et al., 2011).
5.3. Chowb zard (Curcuma longa L., family: Zingiberaceae)
The rhizome ofC. longa, commonly known as turmeric orhaldi, is a widely used household spice in Asian sub-continent and an important herbal medicine used in most traditional medicine systems. The rhi- zome is ginger-like in appearance, yellowish-brown on the exterior and dull orange interiorly (Lal, 2012). In classical Unani textbooks, it is mentioned by the name ofaṣābiʻ-ṣifr(yellow fingers). It is prescribed for crush injuries, chronic wounds (Ali, 2010), anal fistula (Khan, 2010) etc. in the form of dusting powder and ointment (Ali, 2010).C. longa contains three types of curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) (Osorio-Tobón et al., 2016) of which a highly pleiotropic polyphenol curcumin [1,7-bis(4-hydroxy-3-methox- yphenyl)-1,6-heptadiene-3,5-dione] has been proven as having anti- infective, anti-inflammatory, anti-oxidant, anti-mutagenic, anti-coagu- lant, anti-carcinogenic (Akbik et al., 2014), anti-bacterial, ant-viral and anti-fungal activities (Prasad et al., 2014a,b).
On topical application, curcumin has a remarkable wound healing activity and hastens the recovery at various stages of the natural process of healing. In the initial few minutes, it retards blood flow by inducing hemostasis; during the inflammatory phase in the next few days, topical application of curcumin has been shown to reduce inflammation and oxidation process. Over the proliferative phase in the subsequent week, application of curcumin promotes collagen deposition, formation of granulation tissue and aids re-epithelization. During the stage of re- modeling, topical application of curcumin has been shown to promote wound contraction and scar tissue formation (Akbik et al., 2014). The multitude of effects is due to the complex molecular structure of cur- cumin, and its ability to interact with several signaling molecules (Zhang et al., 2014). In a recent study, topical curcumin ointment sig- nificantly decreased the levels of cytokine TNF-α (Tumor necrosis factor α) while increasing the levels of interleukin-10 (IL-10), TGF- β1 (Transforming growth factor-β1) and angiogenic marker protein CD-31 (Cluster of differentiation-31) in granulation tissue (Prasad et al., 2017). There is also evidence to suggest that synthetically derived metabolites of curcumin have decreased efficacy or different biological activity compared to the parent curcumin (Prasad et al., 2014a,b).
5.4. Murdār sang (litharge, lead monoxide)
Murdār sang, commonly known as litharge, is one of the polymorphs of lead monoxide (Worthing et al., 1985), which occurs in nature as reddish brown crystals or a yellowish brown powder (Sina, 1992b).
Roasting of lead in air also transforms metal lead into its oxides like lead monoxide, lead tetraoxide, lead dioxide and lead sesquioxide (Nagarajan et al., 2014).Murdār sanghas been prescribed as a topical wound healing agent in Unani medicine; in the form of powder and ointment. However, its oral use is discouraged in traditional Unani medicine owing to the toxic effects (Razi, 1991;Sina, 1992b;Ali, 2010).
In recent years, several adverse effects have been reported even with topical use of lead compounds (Nagarajan et al., 2014). Therefore, it is no longer used in medicines.
5.5. Mah baiḍ (hen Egg yolk)
Hen eggs have been utilized as a nutritional food since antiquity.
The yolk of hen egg was prescribed by the legendary Unani physician Rhazes for topical application on burns and scalds. Egg yolk mixed with Roghan Gulis also prescribed as a healing and soothing agent if blisters are formed (Razi, 2004). The potential of egg yolk in healing wounds was rediscovered by Ambroise Pare in 1545 (Broughton et al., 2016).
There is still a dearth of data on the efficacy of egg yolk as a wound healing agent in human beings; however some animal studies have shown promising results. In a recent study, chitosan gel mixed with egg yolk oil showed re-epithelization, formation of granulation tissue and new vein formation which was significantly better than the standard control group (p < 0.001) (Yenilmez et al., 2015). In another standard controlled study, third degree burns in experimental animals were treated with egg yolk oil. Wound size was significantly smaller in the egg yolk group on 7th, 14thand 30th day (p < 0.001). Histological examination revealed epithelization with no scar or crust formation.
Healthy granulation tissue with formation of new capillaries with no evidence of haemorrhage was also seen (Rastegar et al., 2011). The healing effects of egg yolk are multi-dimensional and are attributed to the presence of the various proteins, fatty acids and cholesterol present in it. Linoleic and oleic acid present in egg yolk release various cyto- kines and modulate the inflammatory process. In addition, topical ap- plication of fatty acids improves hydration and elasticity which pre- vents skin breakdown (Yenilmez et al., 2015). Overall, egg yolk reduces catabolism, increases matrix synthesis and promotes re-epithelization in burn injuries (Rastegar et al., 2011).
5.6. Dam-al-akhwayn (Pterocarpus marsupium Roxb.; family:
Leguminosae/Fabaceae)
Dam-al-akhwaynis the red-coloured sap obtained from incising the bark of certain trees; of which the most famous isDracaena cinnabari Balf. f. or Dragon's blood tree of the Socotra region. Thedam-al-akh- wayndescribed in traditional Unani medicine was obtained from the fruits of Daemonorops draco Blume. found in the Sumatra region.
Presently, in most of the European countries and Indian sub-continent, dam-al-akhwaynis obtained fromPterocarpus marsupiumRoxb. tree, also known as Bijasar or Kino tree (Ali, 2010;Khare, 2007).Dam-al-akhwayn is prescribed as a healing agent in various conditions such as fissures, chronic non-healing wounds etc. (Khan, 2010), as dusting powder or ointment (Tabri, 1996). After drying in shade, the sap appears as red coloured pieces, and is available in markets with the name of ‘Kino’
(Ali, 2010).
Although extensive researches regarding the wound healing activity of the sap are not available; however, some studies have been done on P. marsupiumbark which provide convincing results. In a recent animal study, topical application ofP. marsupiumextract was associated with increased dry and wet weight and hydroxyproline content of the granulation tissue (Singhal et al., 2012). The effects are attributed to
