Int J Pharm Pharm Sci, Vol 14, Issue 10, 10-17Review Article

KAFUR (C. CAMPHORA L.)–AN UPDATED REVIEW OF ITS ETHNOPHARMACOLOGY, PHYTOCHEMISTRY AND PHARMACOLOGY

QAMRUL ISLAM USMANI1*, NASREEN JAHAN2, SOFIYA2

1Department of Ilmul Advia (Pharmacology), Inamdar Unani Medical College and Hospital, Sedam Road, Kalaburagi, Karnataka, India, 585105, 2Department of Ilmul Advia (Pharmacology), National Institute of Unani Medicine, Bangalore, Karnataka, India, 560091
Email: qamar.som@gmail.com

Received: 07 Jul 2022, Revised and Accepted: 17 Aug 2022

ABSTRACT

The objective of present review was to provide comprehensive information on Cinnamomum camphora L. on its ethnomedicinal uses, phytochemical, and pharmacological activities and provide insights into potential opportunities for future research. A thorough literature search was done to gather all the available updates on Kafūr for its mizāj (temperament), medicinal properties, and traditional uses. Classical Unani books and books on ethnomedicine and ethnobotany in English were referred for literature review. The information on phytochemical and pharmacological activities of C. camphora was collected from PubMed, Science Direct, Google Scholar, and Research Gate using keywords C. camphora, Kafūr, kapur, and camphor. The species name was checked with www. theplantlist. org. The material published in Urdu, Persian, Arabic, and English was included in the review. C. camphora is used as an analgesic and antiseptic in Unani and other traditional systems of medicine for a long. It possesses various bioactive compounds viz. terpenoids, flavonoids, glycosides, coumarins, fatty acids, lignans, alkaloids, etc. Out of all these, camphor is one of the volatile compounds which has many pharmacological activities including anti-nociceptive, anti-oxidant, anti-bacterial, anti-microbial, wound healing, and hepatoprotective.

Keywords: Camphor, Kafoor, Kapur, Unani medicine

© 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijpps.2022v14i10.45766. Journal homepage: https://innovareacademics.in/journals/index.php/ijpps.

INTRODUCTION

Camphor is a natural product of the Cinnamomum camphora L. trees and belongs to the Lauraceae family. It is colorless, transparent crystalline, with blocks of strict consistency or pulverulent masses known as the ‘flower of camphor’ and yields from all parts of a broad, large-diameter camphor tree [1]. It is said that one hundred horsemen may rest in the shade of a single tree [2]. Some say snakes wind themselves around these trees in summer because they are cold [3].

Due to its peculiar fragrant and medicinal properties, the camphor tree is not only a high-quality timber resource, but it also plays an essential role in the fragrance, pharmaceutical, and chemical industries. For the preparation of camphor, small chips from old tree wood are taken and subjected to steam distillation and resulting in semisolid raw camphor oil, after the centrifugation and sublimation process camphor is obtained. Gustaf Komppa (1903) first synthesized (+)-camphoric acid followed by the synthesis of (+) camphor in 1908 [1]. During the Second World War, camphor was prepared synthetically from pinene from American turpentine oil [4, 5]. Kafūr is obtained under the trade names of Laurel camphor, Formosa camphor, Alcamfor, and Camphre du Japon [1]. Camphor is a common ingredient in many analgesic ointments for external application, and it also helps with fibromyalgia. Recently, carbon nanotubes (CNT) were successfully synthesized using camphor in a chemical vapor deposition process and are said to be the green biological source with high efficiency due to the carbon ring (pentagonal and hexagonal) contained in it [6]. Various applications of CNT are carriers for drug delivery, genetic engineering, artificial implant, preservative, diagnostic, and catalysts [7].

Camphor tree has six different chemical variants called chemotypes, which are camphor, 1,8-cineole, nerolidol, linalool, borneol, and safrole. The chemical variants seem dependent upon the area of origin of the tree [8]. Camphor has been used in traditional medicine for antiseptic antirheumatic, skin disorders, uterine pain, muscle, and joint sprains, and various inflammation-related conditions such as liniments and balms; also used for expectorant, carminative and anti-aphrodisiac action [9–12]. This review aims to explore the hidden potential of Kafūr as mentioned Unani and other traditional systems of medicine with its phytochemical and pharmacological advancement.

Description of kafūr in unani literature

Vernaculars

Arabic: Aakal [13]; English: Camphor, Borneo camphor, Formosan wood [9]; Hindi: Kaphur, Kapoor; Persian: Kapoor; Kannada: Kapooram; Tamil: Karupporam, Indu [10]; Unani: Kafūr

Morphology (Māhiyat)

Kafūr is a plant’s gum, with a pungent odor, and viscous fluidity. Camphor’s odor suppresses the fragrance of most of the scents and hides them. That is why it is famous for this name [14]. This plant was found naturally and cultivated in Japan and the Island of Formosa. The best quality of camphor is found on Borneo Island. Camphor’s plant is about 20-25 feet tall in length. This plant is evergreen; its leaves are broad, thick, and shiny green in color. Its wood is white and with a very good scent [5]. Camphor is found in the cavities of wood and stem; chiefly distilled from the root trunk and branches, and is purified by sublimation and condensed into balls, tablets, or sublime powder [15]. There are different types of Kafūr like Rīyāhi, Āzād, Asfarak, Azraq, and Qaisūri [12, 13, 15]. Its Qaisuri type is the best of all, which is found in Qaisur [17]. The Qaisuri type resembles gum, found in layers, looks transparent and clean, extracted from the cavity of the stem. According to Ibn Sina (Avicenna), its wood is reddish-white and light-weighed [12, 13]. It is mentioned in Annabhoot Chikitsa Sagar, that among the various types of camphor three are best: Arthat Kapoor, Chiniya Kapoor, Bheemseni Kapoor. Veda describes two kinds of camphor; Pakva, and Apakva under the name of karpura [5].

Parts used (Hasas-i-Musta’mla)

Leaves, bark, fruit, the sublime product (camphor), and camphor oil [5, 17].

Temperament (Mizaj)

Hot and dry in the third degree [2, 5, 16, 18, 19].

Action and uses (Af ̒ al aur Mawaq-i-istemal)

It has several pharmacological properties such as mubarrid (refrigerant: an agent which reduces the body temperature from normal limits), mujaffif (desiccant: an agent which constricts blood vessels and decreases exudation from them and thus helps in healing of wounds) [13]; musakkin (sedative: substance which help in neutralizing the heat of humours) [5, 20]; mufarrīh (refrigerant: a drug that reduces tachycardia, palpitation of heart), muqaww-i-qalb wa dimāgh (an agent that strengthens the heart and brain), dafi‘-i-ta‘affun (antiseptic: an agent which prevents infection by inhibiting the growth of Ajsam khabitha or by changing the composition of putrefied matter or by any other mean hinders the putrefaction process), dafi‘-i-tashannuj (antispasmodic: an agent which decreases the contractibility of muscles by acting through the CNS), kasir-i-riyāḥ (carminative: an agent which expels the gases from the gastrointestinal tract), muḥarrik-i-mi ̒da (gastric stimulant), mukhaddir zaeef (weak anaesthetic: an agent which causes loss of sensation in the organ) [5, 20]; qaṭi‘-i-bah (anaphrodisiac: an agent which suppresses the libido) [12, 16]; qāṭi‘-i-dam (haemostatics: an agent which suppresses the bleeding), hābis ishāl wa arq (reduces diarrhoea and sweat), naf-i-aṭash wa ḥummā (anti-thirst and antipyretic) [17].

It is used for the Ḥummā sil wa diqq (hectic fever) [5, 16], ḥummā ‘ufuniyya (septic fever), ishāl safrawi (bilious diarrhoea), sozish-i bawl (burning micturition) [5]; naksīr (epistaxis) [5, 12, 20], awrām ḥārra (hot inflammation), ṣudā‘ḥārra (headache due to excessive heat) [2, 5, 12, 16], qulā ̒ (stomatitis/thrush) [2, 12, 16] and ramad hār (conjunctivitis) [13, 16].

Method of use

Dose (Miqdār-i-khorāk)

In Unani literature, the dose of Kafūr has been described as 1-2 ratti (182 mg to 364 mg) [5, 14, 20]. Camphor powder, up to 0.5 gm a day divided into three or four intakes [24]. In other traditional literature, the dose is described as 0.12 to 0.3 gm [25]. The concentration of 3%-11% has been approved by the FDA for topical use [6].

Adverse effects (Muzir)

It is harmful to kidneys and testicles and produces burūdat (Coldness); harmful for the persons of cold and weak temperament, stomach and libido [20]; produces headache, kidney and bladder stone [14].

Corrective (Musleḥ)

Hot and aromatic drugs like Amber (Ambergris), Mushk (Musk), Jundbaidastar (Castorium); Roghan Sosan (Iris ensata oil), Banafsha (Viola odorata), and Nargis (Narcissus tazetta) [23]. For headache Neelofer (Nymphaea alba), Gulqand (Rose petal jam), Zafran (Crocus sativa), Mushk [5, 13].

Substitute (Badal)

Sandal safed (Santalum album), Kahruba (Vateria indica) in the same dose; Tabasheer (Bambusa arundinacea Willd.) in a double dose [5, 13, 22].

Unani formulations

Kafūr is used as an ingredient in the following compound formulation.

Table 1: Kafūr is used as an ingredient in the following compound formulation

Internal use References External Use References
Qurṣ Kafūr, Qurṣ Zaḥīr, Qurṣ Atash, Jawārish Kafūr Ḥabb Qābiz, Ḥabb Nafsuddam Sillī, Ḥabb Pechish, Ḥabb Iksīr Bukhār, Jawhar Kafūr, Jawhar Naushādar, Imsākīn, [14, 25, 26] Arq Ajeeb, Marham Safeda Kafūri, Marham Khārish Jadīd, Marham Hina, Kahl Māmīrān, Barūd Kafūri, Barūd Soẓish Chashm, Sunūn Muqaww-i-Dandan, Pāyorīn, Roghan Benazīr, Zarūr Qula, Ṭila Nishāt angeẓ [26]

Qurṣ Sartān Kafūri, Qurṣ Tabāshīr Kafūri, Ḥabb Jawāhar Mūllif, Ḥabb Kafur Marwareedi, Ḥabb Taun Jawaharwali,

Halwa Supāripāk, Mufarriḥ Shaikh ar Raīs, Mufarriḥ Yāqūti Moatadil, Sayyal Kafūr

 [27] Saiyāl Kafūr, Kahl Jawahar, Kahl Kafūr, Kahl Muqawwi Basr, Marham Raal, Marham Kafūri, Zimad khwab aawar, [27]

Uses of Kafūr (Camphor) in other traditional medicine

Camphor has a long history of herbal use. Camphor and its essential oil have anodyne, antiseptic, stimulant of skin and heart, rubefacient, anti-spasmodic, narcotic, sedative, diaphoretic, expectorant, carminative, anthelmintic, antirheumatic, and tonic properties; it is anti-aphrodisiac in a large dose [9–11]. In uterine pains, 6-8 grain (389-518 mg) pills are administered, and camphor's liniment is rubbed on the abdomen. Pills containing 3-4 grains (194-260 mg) of camphor and an equal quantity of asafoetida administered for asthma, insomnia, and delirium give much relief. In pruritis and eczema of the genitals, the application of camphor ointment is beneficial. Camphor in olive oil or rectified spirit is used externally in rheumatic pains of joints and muscles [10]. In Asia and Europe, camphor is applied to sprains, inflammations, gout, and rheumatic joints and taken internally to calm hysteria, abate convulsions, and epileptic attacks [29]. Externally, it is used in liniments for joint and muscle aches and balms for chilblains, chapped lips, cold sores, and other skin conditions, and as an inhalant for bronchial congestion [11]. In folk and traditional Chinese medicine, it has been employed for a long for the treatment of inflammation-related diseases, including rheumatic arthritis, muscular strains, abdominal pain, rheumatism, cough, and bronchitis [12].

Description of Kafūr in scientific literature

Taxonomical classification

Kingdom: Plantae; Division: Magnoliopsida; Order: Laurels; Family: Lauraceae; Genus: Cinnamomum; Species: C. camphora

Synonyms

Camphora officinarum Nees; Laurus camphora L.; Persea camphora (L.) Spreng.; Camphora hippocratei Lukman.

Habitat and distribution

The camphor tree is native to China, Japan, Taiwan, Korea, India, Mongolia, Sri Lanka, Vietnam, Formosa, Malaya, and the Southern United States; a large number of these fragrant evergreen trees are grown, particularly in Florid [6]. They are naturally distributed in tropical or subtropical Asian countries and Pacific islands; they are artificially planted for road and garden landscaping purposes or provide wood, essential oils, spices, and medicine [30]. The C. camphora grows in full sun or partial shade and is tolerant of drought, but not remarkably tolerant of cold [11].

Botanical description

Usually, the Camphor tree is 12 meter height but attains 35-40 ft. It has a short and aromatic trunk; dark grey or dark brown, rough, fissured bark; Leaves are simple, alternate, ovate to oblong, lanceolate, entire, pinnate, leaf blade 5-12.5 cm long and 2.5-5 cm broad, with 3-5 prominent nerves beginning a little above the base, dark green, evenly colored on both sides, or lighter or glaucous on the underside, fragrant, leathery and long-stalked; Flower in a short axillary cluster, calyx yellowish-white slightly longer than the pedicel, 3 mm long and 5 mm wide; fruits are round-oval, less than 0.5 inches, fleshy, berry, black with a single seed [28, 30].

Physical description

Camphor is a colorless or white colored crystals, granules, or crystalline masses which burn readily with a bright smoky flame; pungent and aromatic taste; fragrant and penetrating odor; boiling point 205-209 °C; melting point 174-179 °C; molecular weight 152.23; specific optical rotation+41° to+43° (synthetic camphor is optically inactive) [31, 32].

Identification

It burns readily with a bright smoky flame and volatilizes slowly at room temperature.

1g sample of camphor in a test tube and add 5 ml of acetone. Shake the mixture well for 3 to 5 min at room temperature and allow the tube to stand for 30 min. The result shows a clear solution with completely dissolved crystals indicates the purity of camphor. If hexamine is present, it will be insoluble in acetone [32].

Phytochemistry

Chemical taxonomy of camphor

Kingdom: Organic compound, Superclass: Lipids and lipid-like molecules, Class: Phenol lipid, Subclass: Monoterpenoids, Molecular framework: Aliphatic homo polycyclic compound [34].

The main bioactive compounds of Kafūr (Camphor) with a focus on their isolation and identification are listed in table 2.

Table 2: The main secondary metabolites identified from C. camphora

Chemical constituents PubChem CID Dosage form/Parts used Analytical method References
Monoterpene
1,8-Cineol (eucalyptol) 2758 E. oil/leaves, fruit, bark GC-MS [35]
E. oil/leaves GC-MS [36]
D-Camphor 159055 E. oil/leaves, fruit, bark GC-MS [35]
E. oil/leaves GC-MS [37]
Sabinene 18818 E. oil/leaves GC-MS [35, 37, 38]
α-pinene 6654 E. oil/leaves GC-MS [35, 37, 39]
β-pinene 6654 E. oil/leaves GC-MS [38, 39]
Borneol 64685 E. oil/leaves GC-MS [40]
Linalool 6549 E. oil/leaves GC-MS [35, 37]
Trans linalool oxide 6432254 Methanolic extract/leaves GC-MS [41]
Limonene 22311 Methanolic extract/leaves GC-MS [41]
D-Limonene 440917 E. oil/leaves GC-MS [39]
α-terpinene 7462 E. oil/leaves GC-MS [38]
β-terpinene 66841 E. oil/leaves GC-MS [39]
γ-terpinene 7461 E. oil/leaves GC-MS [38, 39]
terpinen-4-ol 11230 E. oil/leaves GC-MS [38]
E. oil/Bark GC-MS [35]
α-terpineol 442501 E. oil/leaves GC-MS [38, 39]
E. oil/Bark GC-MS [35]
(+)-α-terpineol 442501 E. oil/leaves GC-MS [38]
Terpinolene 11463 E. oil/leaves GC-MS [38, 40]
δ-terpineol --- E. oil/leaves GC-MS [38]
p-Menth-1-en-8-ol 17100 E. oil/leaves, fruit GC-MS [35]
β-Terpinyl acetate 88693 E. oil/Fruit GC-MS [35]
α-phellandrene 7460 Methanolic extract/leaves GC-MS [41]
E. oil/Fruit GC-MS [35]
β-phellandrene 11142 E. oil/leaves GC-MS [36]
Myrcene 31253 E. oil/leaves GC-MS [40]
β-Myrcene 31253 E. oil/leaves GC-MS [39]
4-thujanol 101626350 E. oil/leaves GC-MS [38]
2-thujene 520384 E. oil/leaves GC-MS [35, 37]
Cymene --- E. oil/leaves GC-MS [40]
O-Cymene 10703 E. oil/Fruit GC-MS [35]
Cis-sabinine hydrate --- E. oil/leaves GC-MS [38]
Camphene 6616 E. oil/leaves GC-MS [35, 37]
Sesquiterpene
α-cubebine 86609 E. oil/Bark GC-MS [35]
β-cadinine 10657 E. oil/Bark GC-MS [35]
γ-elemene 6432312 E. oil/leaves GC-MS [35]
Humulene 5281520 E. oil/leaves GC-MS [38, 40]
E-Nerolidol --- Methanolic extract/leaves GC-MS [41]
Spathulenol 92231 Methanolic extract/leaves GC-MS [41]
Proximadiol 165258 Methanolic extract/leaves GC-MS [41]
Caryophyllene --- E. oil/leaves GC-MS [35, 37]
α-Caryophyllene 6508206 E. oil/leaves GC-MS [39]
β-Caryophyllene 5281515 E. oil/leaves GC-MS [40]
Caryophyllene oxide 1742210 Methanolic extract/leaves GC-MS [41]
Germacrene --- E. oil/leaves GC-MS [40]
Bicyclogermacrene ---
Germacrene B 5281519
Coumarins
Scopoletin 5280460 Hydro methanolic extract/Aerial HPLC [42]
Coumaran 10329 Methanolic extract/leaves GC-MS [41]
6,7-dimethoxycoumarin 8417 Hydro methanolic extract/Aerial HPLC [42]
7-hydroxycoumarin 5281426 Benzene extract/Branch wood GC-MS [43]
Anthraquinone
1-hydroxy-3,6-dimethoxy-8-methyl-anthraquinone
Triterpene
oleanolic acid 10494 Pet. ether+ethanol/Twigs CC [43]
Sterols
β-sitosterol 222284 Pet. ether+ethanol/Twigs CC [44]
Methanolic extract/Root CC [45]
β-Sitosterol Palmitate 9852570 Petroleum ether–acetone/Root CC [45]
Daucosterol 5742590 Methanolic extract/Twigs CC [44]
Methanolic extract/Root CC [45]
Campesterol 173183 Methanolic extract/Root CC [45]
Cerevisterol 10181133 Acetone extract/Branch wood GC-MS [43]
Stigmasterol 5280794 Pet. ether+ethyl acetate CC [45]
3-O-β-D-[6′-(3′′-Methylbutanoate) glucopyranosyl-β-sitosterol --- Methanolic extract/Root CC [45]
Flavonoids
Luteolin 5280445 Hydro methanolic/Twigs CC [44]
Luteolin-7-O-β-D-glucoside --- Hydro methanolic/Twigs CC [44]
Tricetin-7-methyl ether --- Hydro methanolic/Twigs CC [44]
Quercetin 5280343 Hydro methanolic extract/Aerial HPLC [42]
Quercetin-3-O-β-D-glucoside 4',6,7-trimethoxyflavone --- Hydro methanolic/Twigs CC [44]
Dihydrokaempferol --- Hydro methanolic extract/Aerial HPLC [42]
(-)-(2R,3R)-5,7-dimethoxy-3’,4’-methylenedioxy-flavan-3-ol --- Hydro methanolic extract/Aerial HPLC [42]
4',6,7-trimethoxyflavone 12377628 Hydro methanolic extract/Aerial HPLC [42]
(2S, 3S)-3’-hydroxy-5,7,4’-trimethoxy-flavan-3-ol --- Hydro methanolic extract/Aerial HPLC [42]
Pelargonidin 3-O-glucoside 443648 Ethanolic extract/Seed kernel HPLC [46]
Isorhamnetin 3-O-glucoside 5318645 Ethanolic extract/Seed kernel HPLC [46]
Fatty acid
Tricosanoic acid 17085 Hydro methanolic/Twigs CC [44]
Methyl linolenate 5319706 Methanolic extract/leaves GC-MS [41]
Octadecanol acetate 69968 Methanolic extract/leaves GC-MS [41]
3-Methyl-2-pentanone 11262 Methanolic extract/leaves GC-MS [41]
Glycosides
Hydroxytyrosol 1-O-glucoside 13845930 Ethanolic extract/Seed kernel HPLC [46]
Verbascoside 354009 Ethanolic extract/Seed kernel HPLC [46]
Dihydroferulic acid 4-O-glucuronide 190069 Ethanolic extract/Seed kernel HPLC [46]
1-O-Feruloylglucose 13962927 Ethanolic extract/Seed kernel HPLC [46]
1-O-Sinapoylglucose 6168296 Ethanolic extract/Seed kernel HPLC [46]
Lusitanicoside 442799 Ethanolic extract/Seed kernel HPLC [46]
Lignans
Piperitol 10282 Hydro methanolic extract/Aerial HPLC [42]
(+)-episesaminone 10523159 Hydro methanolic extract/Aerial HPLC [42]
Fargesin 10926754 Acetone extract/Branch wood GC-MS [43]
(-)-Sesamin 382073 Pet. ether+ethyl acetate/Stem bark CC [47]
9α-Hydroxysesamin --- Pet. ether+ethyl acetate/Stem bark CC [47]
Obtusilactone A 6442492 Pet. ether+ethyl acetate/Stem bark CC [47]
Isomahubanolide --- Pet. ether+ethyl acetate/Stem bark CC [47]
Dimethyl matairesinol 1286 Hydro methanolic/Twigs CC [44]
Alkaloids
Isocoridine --- Ethanolic extract/Seed kernel HPLC [46]
Papaverine 4680 Ethanolic extract/Seed kernel HPLC [46]
Bocconoline 181121 Acetone extract/Branch wood GC-MS [43]
Protopine 4970 Acetone extract/Branch wood GC-MS [43]
Others (Organic compound)
Hotrienol 5366264 Methanolic extract/leaves GC-MS [41]
Isobutyl acetate 8038 Methanolic extract/leaves GC-MS [41]
3-Methyl− 2-pentanone 11262 Methanolic extract/leaves GC-MS [41]
Mesityl oxide 8858 Methanolic extract/leaves GC-MS [41]
3-Heptanone 7802 E. oil/leaves GC-MS [38]

Table 3: Pharmacological studies on C. camphora

Pharmacologi-cal activity Tested on Part/Dosage form/Conc. Model used Outcome Reference
Analgesic --- Borneol, 5, 25, 50 mg/kg Acetic-acid writhing, Formalin test, Hot plate test Significantly (p˂0.05) reduces pain behavior [50]
--- 0.25, 1 ml/kg Migraine mouse model It inhibits the expression of NF-κB and iNOS and thus induces NO production and reduces neurogenic inflammatory response due to the presence of nerolidol and (E)-α atlantone [51]
Anti-inflammatory --- Aerial part, Ethanolic extract, 1 μg/ml NO assay, MTT assay, Luciferase reporter gene assay on lipopolysaccharide-stimulated RAW 264.7 macrophage By inhibiting NF-kB regulated inflammatory response [42]
--- Leaves, Borneol E. oil Xylene induced ear oedema IL-Iβ, IL-6, (TNF-α) level reduced [40]
SD rat Seed kernel oil High-fat diet induced obese rats Reduced the levels of inflammatory markers (TNF-α, IL-6, and P65) [52]
Anti-oxidant --- Leaves, Flavonoids DPPH free radical scavenging Significant activity [53]
Anti-microbial E. coli, P. aeruginosa, Salmonella enterica, S. aureus, B. subtilis Leaves, Pinoresinol solution, 10 μl Agar disk diffusion, Broth dilution MIC and MBC ranges (3.9-31.25 μg/ml and 7.8–62.5 μg/ml), most effective against P. aeruginosa and B. subtilis [54]
E. coli, S aureus, B. subtilis, S. aeruginosa Nano-particle (Ag-Nps) from callus extract --- Inhibition zone 19.6±0.8–15.1±0.4 mm, due to attaching of Ag-Nps to bacterial membrane it damages and stops ATP production causes bacterial cell death. [55]
Escherichia coli E. oil, 200 μl MIC and MBC Significant bactericidal action [56]

S. aureus, E. faecalis, B. subtilis, S. gallinarum,

E. coli

Leaves,

E. oil

 Micro broth dilution method Significant activity, probably due to increasing apoptosis rate and disrupting cell structure, decreases the activity of TCA-related enzymes disturbing amino metabolism. [57]
E. coli, Pseudomonas, B. cerus Leaves, E. oil, 100-500 μl/ml Well diffusion method Significant maximum activity with methanolic and acetone extract [58]
Anti-fungal Aspergillus niger, Candida albicans, Scolorotium Leaves extract, 100-500 μl/ml Well diffusion method Significant antifungal activity was found at 200 mg with all extracts. [58]
Choanephora cucurbitarum Leaves, (1R)-(+)-and (1S)-(−)-camphor Diffusion assay, Poison food technique (1R)-(+)-camphor showed strong activity due to cytoplasm coagulation and hyphal lysis [59]
Larvicidal Anopheles stephensi Leaves, E. oil Probit analysis method The E. oil showed strong, dose-dependent activities with LC95 0.237% at 12 h, and 0.128% at 24 h [39]
A. aegypti, Culex pipiens and C. quinquefasciatus E. oil, 20 μg/ml --- Exhibited strong activity with LC50 10.0, 46.4, and 15.1 [36]
Algicidal Microcystis aeruginosa and Chlamydomonas reinhardtii Leaves, Methanolic extract The neutral red staining method Potent inhibitory effects by inducing photosynthetic pigment degradation and declining PSII efficiency [41]
Insecticidal Coptotermes curvignathus E. oil from wood Repellence test Increasing concentration increased the mortality (p˂0.001) [60]
Lasioderma serricorne E. oil from leaves Fumigant Toxicity Bioassay and contact toxicity Strong fumigant toxicity with an LC50 value of 2.50 mg/l [37]
Aphis gossypii E. oil from leaves, twigs, and seeds Contact toxicity bioassay by topical application With LC50 values of 245.79, 274.99, and 146.78 mg/l after 48 h respectively [61]
Insect repellence Tribolium castaneum Stem bark, Lipophilic extract Repellence bioassay Significant anti-insect property [47]
Anti-allergic Female BALB/c mice Ethanolic leave extract 1% 2,4-dinitrochlorobenzene induced atopic dermatitis Remarkable improvement of symptoms [62]
Human myeloma U266 cells (in vitro) Methanol leaves extract/10, 30, 120 μg/ml Enzyme-Linked Immunosorbent Assay of IgE Decrease the amount of IgE in culture medium at dose-dependent [63]
Anti-obesity Male SD rats Seed kernel oil High-fat diets Body weight and fat deposition are lower significantly. [64]
Wound healing Wistar albino rats Ethanolic extract Excision wound healing model Significant increases in wound healing parameters [65]
Anticonvulsant and Neuroprotective Wistar albino rats Methanolic extract of leaves/50, 100 mg/kg Maximal electroshock seizure and Pentylene tetrazole induced seizure Significant (p˂0.05) increased the time of onset and decreased the duration of seizures, increasing the % protection [66]

Pharmaceutical products

Kafūr is used in various dosage forms viz. ointment, cream, spray, liquid, drops, gel, oil, patch, tincture, jelly, lotion, stick, emulsion liniment, and aerosol; many pharmaceutical products contain camphor as an ingredient are available over the counter drug. A few examples are Air Saloupas Topical Spray (3%), Bayer Muscle and Joint Cream (4%), Campho-Phenique Pain and Itch relief Antiseptic Gel (10.8%), Flexall 454 Ultra Plus Pain-Relieving Rub (4%), Panalgesic Gold Topical Liquid (3.1%), Vicks VapoRub Cream (5.2%) [6, 48]. Camphor-Phenol Oral Rinse (10.8%), Heet Liniment (3.6%), Mentholatum Decongestant Analgesic (9%), Nuevo Cream (4.8%), Sarna Lotion (0.5%) and TheraFlu Vapor Stick (4.8%) [49]; 714­X, Padma 28 [6].

Pharmacological studies

The crude extract and purified constituents of C. camphora were demonstrated by in vivo and in vitro experiments for analgesic, anti-inflammatory, antioxidant, antimicrobial, anti-helminthic, antifungal, and insecticidal activities. Studies reported that it reduces body fat deposition, heals wounds, and has neuroprotective properties (table 3).

DISCUSSION

In Unani medicine, there is a vast collection of single drugs, derived from three sources: plant, animal, and mineral. However, plant-origin drugs are most used. Though many pharmacological properties characterize all single drugs, each drug has a distinct or primary activity due to mizāj (temperament) or active principle. Following a review of both Unani and conventional literature, it was noted that Kafūr possesses a wide spectrum of pharmacological activities, including notable efficacy as an analgesic and antimicrobial (table 3). Kafūr is used since ancient times for its antiseptic and antimicrobial activity in epidemics. Its fumigation is advised to decontaminate the surroundings. Its many pharmaceutical products are used worldwide [49]. Arq Ajeeb is an essential Unani pharmacopeial formulation in which camphor is combined with menthol and thymol; this formulation has been proven to be particularly useful in the prevention and treatment of Covid-19. When a few drops are used in steam inhalation, it reduces dyspnoea. After local application, Arq Ajeeb provides immediate relief from headaches, colds, and coryza, as well as any form of somatic pain.

As mentioned in the Unani literature regarding its mechanism of analgesia that Kafūr has Musakkin (sedative) and Mukhaddir (anesthetic) actions, which diminishes the sensation in the concerned part. It is beneficial in desensitizing the local nerve which carries the impulse of pain [19]. The sensation is mainly composed of harārat and rutubat, which perceive pain and an unpleasant feeling in pathological conditions. Hence, the contrasting quality of mukhadderāt, which is generally cold and dry in temperament, prevents the transmission of rūḥ nafsāni (the sensation of pain) to a specific organ. Further, due to the cold temperament of mukhadderāt, the nerve fibers become dense, causing a greater reduction in conduction velocity of rūḥ nafsāni (neurotransmission for pain) that is why kafūr is found very effective in diminishing the sensation of pain [2].

Studies performed with extracts and essential oil of plants containing camphor as one of the significant constituents demonstrated a reduction of inflammatory mediators, such as proinflammatory cytokines (IL-1β, IL-6, and TNF) and prostaglandin E2 in macrophages culture [67]. Borneol (a chemical variant of C. camphora) showed significant anti-nociceptive activity in various pain models [50]. Another constituent of Kafūr is linalool which has shown to ease pain and might be due to the suppression of proinflammatory cytokines and regulation of NMDA receptor [68] and eugenol, that block calcium from into the cell and thus loss the pain sensation [69]. C. camphora essential oils reduced serum and brain tissue nitric oxide and PGE2 levels. Nitric oxide is an important neurotransmitter involved in the nociceptive process, and it contributes to the development of central sensitization [8]. Camphor activates and then desensitizes transient receptor potential vanilloid-1 (TRPV1) [70] but inhibits the TRPA1 channel, expressed in most nociceptive DRG neurons. Camphor-activated TRPV1 currents underwent significant desensitization and tachyphylaxis, which might exhibit analgesic properties together with inhibition of TRPA1 [71].

Apart from analgesic, Kafūr has also been reported for many other pharmacological activities might be due to the presence of monoterpenes, phenolic derivatives, flavonoids, lignans, sterols, and terpenoids [34, 37, 39, 40, 43-45, 46]; which are reported to have antinociceptive/analgesic [49, 50], antioxidant [52], antimicrobial [53-57] and wound healing properties [64]. The antibacterial activity was achieved by different mechanisms like partial degradation of the cell membrane, increased membrane permeability, cytoplasm leakage, noticeable distortion, shrinkage of bacterial cells, and membrane protein structural changes [56]. Eucalyptol, (1, 8-cineole) and α-pinene are involved in the larvicidal activity in conjunction with other compounds [39]. Camphor, α-terpineol, and linalool were found to involve in algicidal activity by inducing photosynthetic pigment degradation and declining PSII efficiency [41]. D-camphor, linalool, limonene, etc. from the essential oil of camphor were reported to be repellent and insecticidal [36, 46, 59, 60].

Not just the Kafūr or its active ingredients, but also its wood, leaves, seed kernel, and aerial section in the form of extract or oil have been found to have antiseptic and antimicrobial properties. Many pharmaceutical preparations and Unani Pharmacopeial formulations bear witness to their efficacy in treating a variety of ailments.

CONCLUSION

After reviewing the literature and scientific investigations, it can be concluded that Kafūr is a drug that has been used effectively in the Unani system of medicine for the treatment of pain and infection for a long time. It has a variety of formulations that are used both internally and externally to treat several ailments. Its mechanism of action is further supported by phytochemical and pharmacological research.

ACKNOWLEDGMENT

The authors are highly obliged to the Director and Librarian, NIUM, Bangalore, to provide facilities in the library to review the literature regarding the topic. Furthermore, the authors are thankful to the authors, editors, and publishers of all those books and journals from which the literature of this article has been reviewed.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All the authors have contributed equally.

CONFLICT OF INTERESTS

There is no conflict of interest.

REFERENCES

  1. Jaber SM, Mahinoud MAH. Analytical profiles of drug substances Florey K, editor. Academic Press, Inc, Ltd.; 1984. p. 27-94.

  2. Maseehi AAIQ. Kitabul Umda fil Jarahat (Urdu translation by CCRUM). Vol. I. New Delhi: central Council of Research in Una ni Medicine Publication; 2000.

  3. NP. The Garden of Life. London: an imprint of Harper. Collins Press; 1993. p. 162.

  4. Kokate CK, Purohit AP, Gokhle SB. Pharmacognosy. Vol. I and II. 47th ed. Pune: Nirali Prakashan; 2012.

  5. Ghani N. Khazain ul Advia, 3rd ed. New Delhi: Idara kitab us-shifa; 2011. p. 202-1004.

  6. Hamidpour R, Hamidpour S, Hamidpour M, Shahlari M. Camphor ( Cinnamomum camphora ), a traditional remedy with the history of treating several diseases. IJCRI. 2013;4(2). doi: 10.5348/ijcri-2013-02-267-RA-1.

  7. Hirlekar R, Yamagar M, Garse H, Vij M, Kadam V. Carbon nanotubes and its applications: a review. Asian J Pharm Clin Res. 2009;2(4):17-27.

  8. Yang J, Yang N, Fan L. Phytochemical composition of essential oils from Cinnamomum camphora leaves of different areas and their analgesic properties. Iran J Pharm Sci. 2019;15(2):61-74.

  9. Kritikar KR, Basu BD. Indian medicinal plants. Vol. II. Dehradun: III: International Book Distributors; 2008.

  10. Nadkarni KM. Indian materia medica. 3rd ed. Vol. I. Mumbai: Popular Press Prakashan Limited; 2009.

  11. Chelliah DA. Biological activity prediction of an eth no medicinal plant Cinnamomum camphora through Bio-informatics. Ethnobotanical Leafl. 2008 Apr;12:181-90.

  12. Lee HJ, Hyun EA, Yoon WJ, Kim BH, Rhee MH, Kang HK. In vitro anti-inflammatory and anti-oxidative effects of cinnamomum camphora extracts. J Ethnopharmacol. 2006;103(2):208-16. doi: 10.1016/j.jep.2005.08.009, PMID 16182479.

  13. Al Baitar I. Al-Jam-e-ul-Mufradat-Al-Adviah-Wal-Aghziya (Urdu translation) Vol. IV. New Delhi: central Council of Research in Una ni Medicine publication; 2003.

  14. Khan M. Muheet e Azam. (Urdu translation) Vol. IV. New Delhi: central Council of Research in Una ni Medicine publication; 2018.

  15. Kabeeruddin M. Makhzan ul Mufredat New Delhi: idara kitab us-shifa. 3rd ed; 2014.

  16. Antaki D. Tazkira ulul Albab Wal Jamia Lil Ajbul ijab (Arabic). 2nd ed. New Delhi: central Council of Research in Una ni Medicine Publication; 2008.

  17. Tonekaboni Momin M. Tohfat ul Momineen (Persian). Matba Hasni. 1855.

  18. Said HM. Medicinal herbal. 1st ed. Pakistan: Hamdard Foundation; 2007.

  19. Ibn Sina. Al-Qanoon fit Tib (Urdu translation by Kantoori GH) Vol. 2. New Delhi: idara kitab ul-shifa; 2007.

  20. Ibn Rushd. Kitab ul Kulliyat (Urdu Translation). Lahore: Maktaba Daniyal Urdu Bazar Lahore; 2017.

  21. Abdul Hakeem M. Bustan Al-Mufradat Jadid New Delhi: idara kitab us-shifa; 2002.

  22. Zakaria RAB. Kitab-ul-Hawi Fit tib. Arabic version. Vol. 23. Hydrabad: Dairatul Marif, Osmania University; 1970. p. 72-5.

  23. Hussain M. Makhzan-ul-Advia. Lucknow: Matba Munshi Naval Kishor; 1937.

  24. Pamplona Roger G. Encyclopedia of medicinal plants. Vol. II. Spain: editorial Safeliz, SL. Madrid; 2000. p. 217-8.

  25. Gupta SR. Ghosh’s pharmacology materia medica and therapeutics. Calcutta: Hilton Publishing, and Co.; 1976. p. 915.

  26. Baghdadi IH. Al Mukhtarat Fit Tib. (Urdu translation) Vol. II. New Delhi: central Council of Research in Una ni Medicine publication; 2005.

  27. Anonymous. National formulary of Una ni Medicine, Part I. Vol. I-VI. New Delhi: Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH) Government of India; 2007.

  28. Kabeeruddin M. Bayaz-e-Kabeer, Part II. New Delhi: idara kitabu-us-shifa-Part II; 2010.

  29. Akbar S. Handbook of 200 medicinal plants: a comprehensive review of their traditional medical uses and scientific justifications. Springer; 2020. p. 243-9. doi: 10.1007/978-3-030-16807-0.

  30. Chen H, Wang Q, Huang WW, Hu HL, Hu TX, Li ZB. Allelopathic effects of decomposing leaf litter of camphor (Cinnamomum camphora (L.) Presl) on harvested seeds germination and seedlings growth of balsamine (Impatiens balsamina L.) and morning glory (Ipomoea nil (L.) Roth). Allelopath J. 2020 Sep;51(1):41-56. doi: 10.26651/allelo.j/2020-51-1-1289.

  31. Singh R, Jawaid T. Cinnamomum camphora (Kapur): Review. Pharmacogn J. 2012;4(28):1-5. doi: 10.5530/pj.2012.28.1.

  32. Annonymous. The ayurvedic pharmacopia of India Part 1. 1st ed. Vol. VI. New Delhi: Department of ayurveda, yoga and naturopathy, unani, siddha and homoeopathy (AYUSH) government of India; 2008. p. 210-1.

  33. PubChem Browser [Internet]. Bethesda (MD):U.S. National Center for Biotechnology Information. Available from: https://go.drugbank.com/drugs/DB01744. [Last accessed on 15 May 2022]

  34. go.drugbank.com. Canada: educe design and innovation Inc. Available from: https://go.drugbank.com/drugs/DB01744. [Last accessed on 15 May 2022]

  35. Guo S, Geng Z, Zhang W, Liang J, Wang C, Deng Z. The chemical composition of essential oils from Cinnamomum camphora and their insecticidal activity against the stored product pests. Int J Mol Sci. 2016;17(11):1-9. doi: 10.3390/ijms17111836, PMID 27827929.

  36. Zhang J, Huang T, Zhang J, Shi Z, He Z. Chemical composition of leaf essential oils of four Cinnamomum species and their larvicidal activity against anophelus sinensis (Diptera: Culicidae). J Essent Oil Bear Plants. 2018;21(5):1284-94. doi: 10.1080/0972060X.2018.1552205.

  37. Chen HP. Chemical constituents and insecticidal activities of the essential oil of cinnamomum camphora leaves against Lasioderma serricorne. J Chem. 2014:1-6.

  38. Shang A, Gan RY, Zhang JR, Xu XY, Luo M, Liu HY. Optimization and characterization of microwave-assisted hydro-distillation extraction of essential oils from cinnamomum camphora leaf and recovery of polyphenols from extract fluid. Molecules. 2020;25(14):1-17. doi: 10.3390/molecules25143213, PMID 32674448.

  39. Xu Y, Qin J, Wang P, Li Q, Yu S, Zhang Y. Chemical composition and larvicidal activities of essential oil of cinnamomum camphora (L.) leaf against anopheles stephensi. Rev Soc Bras Med Trop. 2020;53:e20190211. doi: 10.1590/0037-8682-0211-2019, PMID 31994661.

  40. Xiao S, Yu H, Xie Y, Guo Y, Fan J, Yao W. The anti-inflammatory potential of cinnamomum camphora (L.) J. Presl essential oil in vitro and in vivo. J Ethnopharmacol. 2021;267:113516. doi: 10.1016/j.jep.2020.113516. PMID 33141054.

  41. Chen S, Zheng T, Ye C, Huannixi W, Yakefu Z, Meng Y. Algicidal properties of extracts from cinnamomum camphora fresh leaves and their main compounds. Ecotoxicol Environ Saf. 2018;163(6):594-603. doi: 10.1016/j.ecoenv.2018.07.115, PMID 30077157.

  42. Li YR, Fu CS, Yang WJ, Wang XL, Feng D, Wang XN. Investigation of constituents from cinnamomum camphora (L.) J. Presl and evaluation of their anti-inflammatory properties in lipopolysaccharide-stimulated RAW 264.7 macrophages. J Ethnopharmacol. 2018;221:37-47. doi: 10.1016/j.jep.2018.04.017, PMID 29660467.

  43. Liu X, Chen Y, Zhang Z, Ma Q, Meng Y, Geng X. Diverse bioactive components from cold-acclimated cinnamomum camphora branches by different extraction. EKOLOJI. 2019;28(108):117-21.

  44. Wu L, Xiong W, Hu JW, Wu J, Li ZJ, Gao Y. Secondary metabolites from the twigs of Cinnamomum camphora. Chem Nat Compd. 2019;55(2):345-7. doi: 10.1007/s10600-019-02686-8.

  45. Fan F, Li GQ, Li ZJ, Zhang J, Yuan E, Wu L. Steroidal compounds from roots of Cinnamomum camphora. Chem Nat Compd. 2020;56(1):177-9. doi: 10.1007/s10600-020-02979-3.

  46. Zhang G, Yan X, Wu S, Ma M, Yu P, Gong D. Ethanol extracts from Cinnamomum camphora seed kernel: potential bioactivities as affected by alkaline hydrolysis and simulated gastrointestinal digestion. Food Res Int. 2020;137(9):109363. doi: 10.1016/j.foodres.2020.109363. PMID 33233066.

  47. Wang Y, Zhang LT, Zhang D, Guo SS, Xi C, Du SS. Repellent and feeding deterrent activities of butanolides and lignans isolated from cinnamomum camphora against tribolium castaneum. J Chem. 2020 Jan;2020:1-7. doi: 10.1155/2020/5685294.

  48. Clinical Pharmacology. Electronic drug information and medication management resourse. Tampa, (FL): Gold Standard Multimedia; 2004.

  49. Manoguerra AS, Erdman AR, Wax PM, Nelson LS, Caravati EM, Cobaugh DJ. Camphor poisoning: an evidence-based practice guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(4):357-70. doi: 10.1080/15563650600671696, PMID 16809137.

  50. Almeida JR, Souza GR, Silva JC, Saraiva SR, Junior RG, Quintans Jde S. Borneol, a bicyclic monoterpene alcohol, reduces nociceptive behavior and inflammatory response in mice. Scientific World Journal. 2013 Mar;1-5. doi: 10.1155/2013/808460, PMID 23710149.

  51. Fan LY, Lin Q, Yang NY, Chen LH. Analgesic effects of the essential oil from Cinnamomum camphora against nitroglycerin-induced migraine in mice. Indian J Pharm Sci. 2020;82(1):166-70. doi: 10.36468/pharmaceutical-sciences.634.

  52. Fu J, Zeng C, Zeng Z, Wang B, Gong D. Cinnamomum camphora seed kernel oil ameliorates oxidative stress and inflammation in diet-induced obese rats. J Food Sci. 2016;81(5):H1295-300. doi: 10.1111/1750-3841.13271, PMID 27003858.

  53. Liu X, Bian J, Li D, Liu C, Xu S, Zhang G. Structural features, antioxidant and acetylcholinesterase inhibitory activities of polysaccharides from stem of Physalis alkekengi L. Ind Crops Prod. 2019;129(12):654-61. doi: 10.1016/j.indcrop.2018.12.047.

  54. Zhou H, Ren J, Li Z. Antibacterial activity and mechanism of pinoresinol from Cinnamomum camphora leaves against food-related bacteria. Food Control. 2017;79:192-9. doi: 10.1016/ j.foodcont.2017.03.041.

  55. Aref MS, Salem SS. Bio-callus synthesis of silver nanoparticles, characterization, and antibacterial activities via Cinnamomum camphora callus culture. Biocatal Agric Biotechnol. 2020;27:101689. doi: 10.1016/j.bcab.2020.101689.

  56. Wu K, Lin Y, Chai X, Duan X, Zhao X, Chun C. Mechanisms of vapor ‐ phase antibacterial action of essential oil from Cinnamomum camphora var. linaloofera Fujita against Escherichia coli. Food Sci Nutr. 2019;7(8):2546-55. doi: 10.1002/fsn3.1104, PMID 31428342.

  57. Chen J, Tang C, Zhang R, Ye S, Zhao Z, Huang Y. Metabolomics analysis to evaluate the antibacterial activity of the essential oil from the leaves of cinnamomum camphora (Linn.) Presl. J Ethnopharmacol. 2020;253(10):112652. doi: 10.1016/j.jep.2020.112652. PMID 32035880.

  58. Ankita S, Chandra SS, Arti T. Phytochemical studies and antimicrobial activities of Cinnamomum camphora. World J Pharm Res. 2014;3(2):2287-94.

  59. Pragadheesh VS, Saroj A, Yadav A, Chanotiya CS, Alam M, Samad A. Chemical characterization and antifungal activity of Cinnamomum camphora essential oil. Ind Crops Prod. 2013;49:628-33. doi: 10.1016/j.indcrop.2013.06.023.

  60. Roszaini K, Nor Azah MA, Mailina J, Zaini S, Mohammad Faridz Z. Toxicity and antitermite activity of the essential oils from cinnamomum camphora, cymbopogon nardus, melaleuca cajuputi and dipterocarpus sp. against coptotermes curvignathus. Wood Sci Technol. 2013;47(6):1273-84. doi: 10.1007/s00226-013-0576-1.

  61. Jiang H, Wang J, Song L, Cao X, Yao X, Tang F. Gc×Gc-tofms analysis of essential oils composition from leaves, twigs and seeds of cinnamomum camphora L. Presl and their insecticidal and repellent activities. Molecules. 2016 Mar;21(4):423. doi: 10.3390/molecules21040423, PMID 27043503.

  62. Kang NJ, Han SC, Yoon SH, Sim JY, Maeng YH, Kang HK. Cinnamomum camphora leaves alleviate allergic skin inflammatory responses in vitro and in vivo. Toxicol Res. 2019;35(3):279-85. doi: 10.5487/TR.2019.35.3.279, PMID 31341557.

  63. Tanabe H, Fukutomi R, Yasui K, Kaneko A, Imai S, Nakayama T. Identification of dimethylmatairesinol as an immunoglobulin e-suppressing component of the leaves of cinnamomum camphora. J Health Sci. 2011;57(2):184-7. doi: 10.1248/jhs.57.184.

  64. Fu J, Wang B, Gong D, Zeng C, Jiang Y, Zeng Z. Camphor tree seed kernel oil reduces body bat deposition and improves blood lipids in rats. J Food Sci. 2015;80(8):912-7.

  65. Sen PK, Garg S. Wound repair and regenerating effect of ethyl acetate soluble fraction of ethanolic extract of cinnamomum tamala leaves in diabetic rats. J Drug Deliv Ther. 2019;9:(4-s). doi: 10.22270/jddt.v9i4-s.3834.

  66. Jawaid T, Kamal M, Singh R, Shukla D, Devanathadesikan V, Sinha M. Anticonvulsant and neuroprotective effects of methanolic extract of cinnamomum camphora leaves in rat brain. Orient Pharm Exp Med. 2018;18(3):237-46. doi: 10.1007/s13596-018-0306-1.

  67. Luo YM, Li SR, Yin XY. Studies on chemotypes of cinnamomum camphora. AMR 2011;343-344:1193-7. doi: 10.4028/www.scientific.net/AMR.343-344.1193.

  68. Peana AT, D’Aquila PS, Chessa ML, Moretti MDL, Serra G, Pippia P. (-)-Linalool produces antinociception in two experimental models of pain. Eur J Pharmacol. 2003;460(1):37-41. doi: 10.1016/s0014-2999(02)02856-x, PMID 12535857.

  69. Thombre NA, Gaikwad SM. A review on analgesic herbals. Indian J Drugs. 2019;7(3):81-8.

  70. Xu H, Blair NT, Clapham DE. Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J Neurosci. 2005;25(39):8924-37. doi: 10.1523/JNEUROSCI.2574-05.2005, PMID 16192383.

  71. Nagata K, Duggan A, Kumar G, Garcia Anoveros J. Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci. 2005;25(16):4052-61. doi: 10.1523/JNEUROSCI.0013-05.2005, PMID 15843607.