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CC BY 4.0 · Planta Med 2024; 90(09): 664-674
DOI: 10.1055/a-2307-8183
Biological and Pharmacological Activity
Reviews

The Clinical Translation of α-humulene – A Scoping Review

Nishaanth Dalavaye    *
1   Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, UK
,
Martha Nicholas   *
1   Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, UK
,
Manaswini Pillai   *
1   Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, UK
,
Simon Erridge
1   Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, UK
2   Curaleaf Clinic, London, UK
,
Mikael H. Sodergren
1   Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, UK
3   Curaleaf International, London, UK
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Abstract

α-humulene, a sesquiterpene found in essential oils of various plant species, has garnered interest due to its potential therapeutic applications. This scoping review aims to consolidate α-humuleneʼs evidence base, informing clinical translation, and guiding future research directions. A scoping review was conducted of EMBASE, MEDLINE, and PubMed databases up to 14th July 2023. All studies describing original research on α-humulene extraction, as well as pre-clinical and clinical research, were included for review. Three hundred and forty articles were analysed. α-humulene yields ranged from negligible to 60.90% across plant species. In vitro experiments demonstrated cytotoxicity against adenocarcinomas (such as colorectal, pulmonary, breast, prostatic, lung, and ovarian), with varying responses in other cell models. Mechanistic insights revealed its involvement in mitochondrial dysfunction, diminished intracellular glutathione levels, and the induction of oxidative stress. In rodent studies, oral administration of α-humulene at 50 mg/kg reduced inflammation markers in paw oedema and ovalbumin-induced airway inflammation. Intraperitoneal administration of α-humulene (50 – 200 mg/kg) exhibited cannabimimetic properties through cannabinoid 1 and adenosine A2a receptors. α-humulene also exhibited a multitude of properties with potential scope for therapeutic utilisation. However, there is a paucity of studies that have successfully translated this research into clinical populations with the associated disease. Potential barriers to clinical translation were identified, including yield variability, limited isolation studies, and challenges associated with terpene bioavailability. Consequently, rigorous pharmacokinetic studies and further mechanistic investigations are warranted to effectively uncover the potential of α-humulene.

Keywords

terpenes - anti-bacterial agents - α-humulene - Humulus lupulus - Cannabis indica - Cannabis sativa - Cannabaceae

* Nishaanth Dalavaye, Martha Nicholas, and Manaswini Pillai are to be considered as joint first authors


Supporting Information

    Supplementary Material A: References for studies of extraction yields for different species

    Supplementary Material B: Reported yields of α-humulene

    Supplementary Material C: Search strategy

  • Ergänzendes Material


Publikationsverlauf

Eingereicht: 30. September 2023

Angenommen nach Revision: 16. April 2024

Accepted Manuscript online:
16. April 2024

Artikel online veröffentlicht:
08. Mai 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Degenhardt J, Köllner TG, Gershenzon J. Monoterpene and sesquiterpene synthases and the origin of terpene skeletal diversity in plants. Phytochemistry 2009; 70: 1621-1637
    CrossrefPubMedSuche in Google Scholar
  • 2 Masyita A, Mustika Sari R, Dwi Astuti A, Yasir B, Rahma Rumata N, Emran TB, Nainu F, Simal-Gandara J. Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives. Food Chem X 2022; 13: 100217
    CrossrefPubMedSuche in Google Scholar
  • 3 Yang W, Chen X, Li Y, Guo S, Wang Z, Yu X. Advances in pharmacological activities of terpenoids. Nat Prod Commun 2020; 15
    CrossrefPubMedSuche in Google Scholar
  • 4 Mander L, Hung-Wen L. Comprehensive Natural Products II: Chemistry and Biology, Volumes 1 − 10. München: Elsevier Science; 2010
    Suche in Google Scholar
  • 5 Simonsen JL, Todd AR. 32. Cannabis indica. Part X. The essential oil from Egyptian hashish. J Chem Soc 1942; 188-188
    CrossrefPubMedSuche in Google Scholar
  • 6 Ugai T, Sasamoto N, Lee HY, Ando M, Song M, Tamimi RM, Kawachi I, Campbell PT, Giovannucci EL, Weiderpass E, Rebbeck TR, Ogino S. Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat Rev Clin Oncol 2022; 19: 656-673
    CrossrefPubMedSuche in Google Scholar
  • 7 Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM. Chronic inflammation in the etiology of disease across the life span. Nat Med 2019; 25: 1822-1832
    CrossrefPubMedSuche in Google Scholar
  • 8 Andersson DI, Balaban NQ, Baquero F, Courvalin P, Glaser P, Gophna U, Kishony R, Molin S, Tønjum T. Antibiotic resistance: turning evolutionary principles into clinical reality. FEMS Microbiol Rev 2020; 44: 171-188
    CrossrefPubMedSuche in Google Scholar
  • 9 Harada H, Yu F, Okamoto S, Kuzuyama T, Utsumi R, Misawa N. Efficient synthesis of functional isoprenoids from acetoacetate through metabolic pathway-engineered Escherichia coli. Appl Microbiol Biotechnol 2009; 81: 915-925
    CrossrefPubMedSuche in Google Scholar
  • 10 Leite GM, Barbosa MO, Lopes MJP, Delmondes GA, Bezerra DS, Araújo IM, Carvalho de Alencar CD, Coutinho HDM, Peixoto LR, Barbosa-Filho JM, Felipe CFB, Barbosa R, Alencar de Menezes IR, Kerntof MR. Pharmacological and toxicological activities of α-humulene and its isomers: A systematic review. Trends Food Sci Technol 2021; 115: 255-274
    CrossrefPubMedSuche in Google Scholar
  • 11 Ambrož M, Šmatová M, Šadibolová M, Pospíšilová E, Hadravská P, Kašparová M, Hanušová Skarková V, Králová V, Skálová L. Sesquiterpenes α-humulene and β-caryophyllene oxide enhance the efficacy of 5-fluorouracil and oxaliplatin in colon cancer cells. Acta Pharm 2019; 69: 121-128
    CrossrefPubMedSuche in Google Scholar
  • 12 Ambrož M, Matoušková P, Skarka A, Zajdlová M, Žáková K, Skálová L. The effects of selected sesquiterpenes from Myrica rubra essential oil on the efficacy of doxorubicin in sensitive and resistant cancer cell lines. Molecules 2017; 22: 1021-1028
    CrossrefPubMedSuche in Google Scholar
  • 13 Ambrož M, Boušová I, Skarka A, Hanušová V, Králová V, Matoušková P, Szotáková B, Skálová L. The influence of sesquiterpenes from Myrica rubra on the antiproliferative and pro-oxidative effects of doxorubicin and its accumulation in cancer cells. Molecules 2015; 20: 15343-15358
    CrossrefPubMedSuche in Google Scholar
  • 14 Su YC, Hsu KP, Wang EIC, Ho CL. Composition, in vitro cytotoxic, and antimicrobial activities of the flower essential oil of diospyros discolor from Taiwan. Nat Prod Commun 2015; 10: 1311-1314
    CrossrefPubMedSuche in Google Scholar
  • 15 Hadri A, Gómez del Río MA, Sanz J, González Coloma A, Idaomar M, Ribas Ozonas B, Benedí González J, Sánchez Reus MI. Cytotoxic activity of alpha-humulene and trans-caryophyllene from Salvia officinalis in animal and human tumor cells. An Real Acad Farm 2010; 76: 343-356
    PubMedSuche in Google Scholar
  • 16 Legault J, Dahl W, Debiton E, Pichette A, Madelmont JC. Antitumor activity of balsam fir oil: Production of reactive oxygen species induced by alpha-humulene as possible mechanism of action. Planta Med 2003; 69: 402-407
    Thieme ConnectPubMedSuche in Google Scholar
  • 17 Legault J, Pichette A. Potentiating effect of β-caryophyllene on anticancer activity of α-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol 2010; 59: 1643-1647
    CrossrefPubMedSuche in Google Scholar
  • 18 Cole RA, Bansal A, Moriarity DM, Haber WA, Setzer WN. Chemical composition and cytotoxic activity of the leaf essential oil of Eugenia zuchowskiae from Monteverde, Costa Rica. J Nat Med 2007; 61: 414-417
    CrossrefPubMedSuche in Google Scholar
  • 19 da Silva SL, Chaar JS, Figueiredo PMS, Yano T. Cytotoxic evaluation of essential oil from Casearia sylvestris Sw on human cancer cells and erythrocytes. Acta Amazon 2008; 38: 107-112
    CrossrefPubMedSuche in Google Scholar
  • 20 Loizzo MR, Tundis R, Saab AM, Statti GA, Menichini F. Antiproliferative effects of essential oils and their major constituents in human renal adenocarcinoma and amelanotic melanoma cells. Cell Prolif 2008; 41: 1002-1012
    CrossrefPubMedSuche in Google Scholar
  • 21 Fukuoka K, Sawabe A, Sugimoto T, Koga M, Okuda H, Kitayama T, Shirai M, Komai K, Komemushi S, Matsuda K. Inhibitory actions of several natural products on proliferation of rat vascular smooth muscle cells induced by Hsp60 from Chlamydia pneumoniae J138. J Agric Food Chem 2004; 52: 6326-6329
    CrossrefPubMedSuche in Google Scholar
  • 22 Viveiros MMH, Silva MG, da Costa JGM, de Oliveira AG, Rubio C, Padovani CR, Rainho CA, Schellini SA. Anti-inflammatory effects of α-humulene and β-caryophyllene on pterygium fibroblasts. Int J Ophthalmol 2022; 15: 1903-1907
    CrossrefPubMedSuche in Google Scholar
  • 23 Pichette A, Larouche PL, Lebrun M, Legault J. Composition and antibacterial activity of Abies balsamea essential oil. Phytother Res 2006; 20: 371-373
    CrossrefPubMedSuche in Google Scholar
  • 24 Azizan N, Mohd Said S, Zainal Abidin Z, Jantan I. Composition and antibacterial activity of the essential oils of Orthosiphon stamineus Benth and Ficus deltoidea Jack against pathogenic oral bacteria. Molecules 2017; 22: 2135
    CrossrefPubMedSuche in Google Scholar
  • 25 Jang HI, Rhee KJ, Eom YB. Antibacterial and antibiofilm effects of alpha-humulene against Bacteroides fragilis. Can J Microbiol 2020; 66: 389-399
    CrossrefPubMedSuche in Google Scholar
  • 26 Rossato TCA, Alves T, Cuevas-Suárez CE, Rosa WLO, Silva AF, Piva E, Zanchi CH, Lund RG. Effect of alpha-humulene incorporation on the properties of experimental light-cured periodontal dressings. Braz Oral Res 2022; 36: e091
    CrossrefPubMedSuche in Google Scholar
  • 27 de Oliveira RN, Dos Santos KR, Mendes TMF, Garcia VL, Santos Oliveira AS, de Lourdes Sierpe Jeraldo V, Allegretti SM. Sesquiterpenes evaluation on Schistosoma mansoni: Survival, excretory system and membrane integrity. Biomed Pharmacother 2017; 90: 813-820
    CrossrefPubMedSuche in Google Scholar
  • 28 Govindarajan M, Benelli G. α-Humulene and β-elemene from Syzygium zeylanicum (Myrtaceae) essential oil: Highly effective and eco-friendly larvicides against Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus (Diptera: Culicidae). Parasitol Res 2016; 115: 2771-2778
    CrossrefPubMedSuche in Google Scholar
  • 29 Huy Hung N, Ngoc Dai D, Satyal P, Thi Huong L, Thi Chinh B, Quang Hung D, Anh Tai T, Setzer WN. Lantana camara essential oils from Vietnam: Chemical composition, molluscicidal, and mosquito larvicidal activity. Chem Biodivers 2021; 18: e2100145
    CrossrefPubMedSuche in Google Scholar
  • 30 Andrade-Ochoa S, Correa-Basurto J, Rodríguez-Valdez LM, Sánchez-Torres LE, Nogueda-Torres B, Nevárez-Moorillón GV. In vitro and in silico studies of terpenes, terpenoids and related compounds with larvicidal and pupaecidal activity against Culex quinquefasciatus Say (Diptera: Culicidae). Chem Cent J 2018; 12: 53
    CrossrefPubMedSuche in Google Scholar
  • 31 Zheng GQ, Kenney PM, Lam LKT. Sesquiterpenes from clove (Eugenia caryophyllata) as potential anticarcinogenic agents. J Nat Prod 1992; 55: 999-1003
    CrossrefPubMedSuche in Google Scholar
  • 32 Fernandes ES, Passos GF, Medeiros R, da Cunha FM, Ferreira J, Campos MM, Pianowski LF, Calixto JB. Anti-inflammatory effects of compounds alpha-humulene and (−)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea. Eur J Pharmacol 2007; 569: 228-236
    CrossrefPubMedSuche in Google Scholar
  • 33 Basting RT, Spindola HM, Sousa IMO, Queiroz NCA, Trigo JR, de Carvalho JE, Foglio MA. Pterodon pubescens and Cordia verbenacea association promotes a synergistic response in antinociceptive model and improves the anti-inflammatory results in animal models. Biomed Pharmacother 2019; 112: 108693
    CrossrefPubMedSuche in Google Scholar
  • 34 Medeiros R, Passos GF, Vitor CE, Koepp J, Mazzuco TL, Pianowski LF, Campos MM, Calixto JB. Effect of two active compounds obtained from the essential oil of Cordia verbenacea on the acute inflammatory responses elicited by LPS in the rat paw. Br J Pharmacol 2007; 151: 618-627
    CrossrefPubMedSuche in Google Scholar
  • 35 Rogerio AP, Andrade EL, Leite DFP, Figueiredo CP, Calixto JB. Preventive and therapeutic anti-inflammatory properties of the sesquiterpene α-humulene in experimental airways allergic inflammation. Br J Pharmacol 2009; 158: 1074-1087
    CrossrefPubMedSuche in Google Scholar
  • 36 Tanaka S, Akimoto M, Tambe Y, Tabata M, Ikeshiro Y. Volatile antiallergic principles from a traditional herbal prescription of kampo medicine. Phytother Res 1996; 10: 238-241
    CrossrefPubMedSuche in Google Scholar
  • 37 Chen H, Yuan J, Hao J, Wen Y, Lv Y, Chen L, Yang X. α-Humulene inhibits hepatocellular carcinoma cell proliferation and induces apoptosis through the inhibition of Akt signaling. Food Chem Toxicol 2019; 134: 110830
    CrossrefPubMedSuche in Google Scholar
  • 38 Costa EV, Menezes LRA, Rocha SLA, Baliza IRS, Dias RB, Rocha CAG, Soares MBP, Bezerra DP. Antitumor properties of the leaf essential oil of Zornia brasiliensis. Planta Med 2015; 81: 563-567
    Thieme ConnectPubMedSuche in Google Scholar
  • 39 Passos GF, Fernandes ES, da Cunha FM, Ferreira J, Pianowski LF, Campos MM, Calixto JB. Anti-inflammatory and anti-allergic properties of the essential oil and active compounds from Cordia verbenacea. J Ethnopharmacol 2007; 110: 323-333
    CrossrefPubMedSuche in Google Scholar
  • 40 Xing M, Zheng L, Deng Y, Xu D, Xi P, Li M, Kong G, Jiang Z. Antifungal activity of natural volatile organic compounds against litchi downy blight pathogen Peronophythora litchii. Molecules 2018; 23: 358
    CrossrefPubMedSuche in Google Scholar
  • 41 Lemos M, Santin JR, Mizuno CS, Boeing T, De Sousa JPB, Nanayakkara D, Kenupp Bastos J, Faloni de Andrade S. Copaifera langsdorffii: Evaluation of potential gastroprotective of extract and isolated compounds obtained from leaves. Rev Bras Farmacogn 2015; 25: 238-245
    CrossrefPubMedSuche in Google Scholar
  • 42 LaVigne JE, Hecksel R, Keresztes A, Streicher JM. Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Sci Rep 2021; 11: 8232
    CrossrefPubMedSuche in Google Scholar
  • 43 Ilic N, Schmidt BM, Poulev A, Raskin I. Toxicological evaluation of grains of paradise (Aframomum melegueta) [Roscoe] K. Schum. J Ethnopharmacol 2010; 127: 352-356
    CrossrefPubMedSuche in Google Scholar
  • 44 Caputo L, Smeriglio A, Trombetta D, Cornara L, Trevena G, Valussi M, Fratianni F, De Feo V, Nazzaro F. Chemical composition and biological activities of the essential oils of Leptospermum petersonii and Eucalyptus gunnii. Front Microbiol 2020; 11: 409
    CrossrefPubMedSuche in Google Scholar
  • 45 Astray G, Gullón P, Gullón B, Munekata PES, Lorenzo JM. Humulus lupulus L. as a natural source of functional biomolecules. Appl Sci 2020; 10: 5074
    CrossrefPubMedSuche in Google Scholar
  • 46 Russo EB. Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163: 1344-1364
    CrossrefPubMedSuche in Google Scholar
  • 47 Sharmeen J, Mahomoodally F, Zengin G, Maggi F. Essential oils as natural sources of fragrance compounds for cosmetics and cosmeceuticals. Molecules 2021; 26: 666
    CrossrefPubMedSuche in Google Scholar
  • 48 Guzmán E, Lucia A. Essential oils and their individual components in cosmetic products. Cosmetics 2021; 8: 114
    CrossrefPubMedSuche in Google Scholar
  • 49 Tomko AM, Whynot EG, Ellis LD, Dupré DJ. Anti-cancer potential of cannabinoids, terpenes, and flavonoids present in cannabis. Cancers (Basel) 2020; 12: 1985
    CrossrefPubMedSuche in Google Scholar
  • 50 Elegbede JA, Maltzman TH, Elson CE, Gould MN. Effects of anticarcinogenic monoterpenes on phase II hepatic metabolizing enzymes. Carcinogenesis 1993; 14: 1221-1223
    CrossrefPubMedSuche in Google Scholar
  • 51 Singh RR, Reindl KM. Glutathione S-transferases in cancer. Antioxidants 2021; 10: 701
    CrossrefPubMedSuche in Google Scholar
  • 52 Putra IMH, Pratama IPAAC, Putra KDA, Pradnyaswari GAD, Laksmiani NPL. The potency of alpha-humulene as HER-2 inhibitor by molecular docking. Pharm Rep 2022; 2: 19
    CrossrefPubMedSuche in Google Scholar
  • 53 Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, Li Z, Pan CX. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol 2021; 14: 156
    CrossrefPubMedSuche in Google Scholar
  • 54 Blowman K, Magalhães M, Lemos MFL, Cabral C, Pires IM. Anticancer properties of essential oils and other natural products. Evid-Based Complementary Altern Med 2018; 2018: 1-12
    CrossrefPubMedSuche in Google Scholar
  • 55 Boshuizen J, Peeper DS. Rational cancer treatment combinations: An urgent clinical need. Mol Cell 2020; 78: 1002-1018
    CrossrefPubMedSuche in Google Scholar
  • 56 Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: Mechanism and clinical study. Signal Transduct Target Ther 2020; 5: 209
    CrossrefPubMedSuche in Google Scholar
  • 57 Liktor-Busa E, Keresztes A, LaVigne J, Streicher JM, Largent-Milnes TM. Analgesic potential of terpenes derived from Cannabis sativa. Pharmacol Rev 2021; 73: 1269-1297
    CrossrefPubMedSuche in Google Scholar
  • 58 Tai FWD, McAlindon ME. Non-steroidal anti-inflammatory drugs and the gastrointestinal tract. Clin Med (Northfield Il) 2021; 21: 131-134
    CrossrefPubMedSuche in Google Scholar
  • 59 Wu S, Zhu W, Thompson P, Hannun YA. Evaluating intrinsic and non-intrinsic cancer risk factors. Nat Commun 2018; 9: 3490
    CrossrefPubMedSuche in Google Scholar
  • 60 Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, Li Y. Inflammation and tumor progression: Signaling pathways and targeted intervention. Signal Transduct Target Ther 2021; 6: 263
    CrossrefPubMedSuche in Google Scholar
  • 61 Hashem S, Ali TA, Akhtar S, Nisar S, Sageena G, Ali S, Al-Mannai S, Therachiyil L, Mir R, Elfaki I, Mir MM, Jamal F, Masoodi T, Uddin S, Singh M, Haris M, Macha M, Bhat AA. Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents. Biomed Pharmacother 2022; 150: 113054
    CrossrefPubMedSuche in Google Scholar
  • 62 Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov 2022; 21: 141-162
    CrossrefPubMedSuche in Google Scholar
  • 63 Sharma D, Misba L, Khan AU. Antibiotics versus biofilm: An emerging battleground in microbial communities. Antimicrob Resist Infect Control 2019; 8: 76
    CrossrefPubMedSuche in Google Scholar
  • 64 Bowler P, Murphy C, Wolcott R. Biofilm exacerbates antibiotic resistance: Is this a current oversight in antimicrobial stewardship?. Antimicrob Resist Infect Control 2020; 9: 162
    CrossrefPubMedSuche in Google Scholar
  • 65 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. The Lancet 2022; 399: 629-655
    CrossrefPubMedSuche in Google Scholar
  • 66 Subbiah V. The next generation of evidence-based medicine. Nat Med 2023; 29: 49-58
    Suche in Google Scholar
  • 67 Prasanthi D, Lakshmi PK. Terpenes: Effect of lipophilicity in enhancing transdermal delivery of alfuzosin hydrochloride. J Adv Pharm Technol Res 2012; 3: 216-223
    CrossrefPubMedSuche in Google Scholar
  • 68 Palmer ME, Andrews LJ, Abbey TC, Dahlquist AE, Wenzler E. The importance of pharmacokinetics and pharmacodynamics in antimicrobial drug development and their influence on the success of agents developed to combat resistant gram negative pathogens: A review. Front Pharmacol 2022; 13: 888079
    CrossrefPubMedSuche in Google Scholar
  • 69 Palrasu M, Wright L, Patel M, Leech L, Branch S, Harrelson S, Khan S. Perspectives on challenges in cannabis drug delivery systems: Where are we?. Med Cannabis Cannabinoids 2022; 5: 102-119
    CrossrefPubMedSuche in Google Scholar
  • 70 University of Washington. Bratman G. Do terpenes play a role in the stress-reducing effects of a forest bathing intervention? ClinicalTrials.gov Identifier: NCT05316597 (2022 Nov 1).. Accessed 2023-12-23 at: https://clinicaltrials.gov/ct2/show/NCT05316597
    PubMed
  • 71 Sun D, Gao W, Hu H, Zhou S. Why 90 % of clinical drug development fails and how to improve it?. Acta Pharm Sin B 2022; 12: 3049-3062
    CrossrefPubMedSuche in Google Scholar
  • 72 Seyhan AA. Lost in translation: The valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Transl Med Commun 2019; 4: 18
    CrossrefPubMedSuche in Google Scholar
  • 73 Keefover-Ring K. The chemical biogeography of a widespread aromatic plant species shows both spatial and temporal variation. Ecol Evol 2022; 12: e9265
    CrossrefPubMedSuche in Google Scholar
  • 74 Arksey H, OʼMalley L. Scoping studies: Towards a methodological framework. Int J Soc Res Methodol 2005; 8: 19-32
    CrossrefPubMedSuche in Google Scholar
  • 75 Levac D, Colquhoun H, OʼBrien KK. Scoping studies: Advancing the methodology. Implement Sci 2010; 5: 69
    CrossrefPubMedSuche in Google Scholar
  • 76 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021; 372: 71
    CrossrefPubMedSuche in Google Scholar
  • 77 Ajaiyeoba EO, Ekundayo O. Essential oil constituents of Aframomum melegueta (Roscoe) K. Schum. seeds (alligator pepper) from Nigeria. Flavour Fragr J 1999; 14: 109-111
    CrossrefPubMedSuche in Google Scholar
  • 78 Brophy JJ, Goldsack RJ, Bean AR, Forster PI, Lepsch BJ. Leaf essential oils of the genus Leptospermum (Myrtaceae) in eastern Australia. Part 6. Leptospermum polygalifolium and allies. Flavour Fragr J 2000; 15: 271-277
    CrossrefPubMedSuche in Google Scholar
  • 79 Duarte PF, do Nascimento LH, Fischer B, Lohmann AM, Bandiera VJ, Fernandes IA, Magro JD, Valduga E, Cansian RL, Paroul N, Junges A. Effect of extraction time on the yield, chemical composition, and antibacterial activity of hop essential oil against lactic acid bacteria (Lactobacillus brevis and Lactobacillus casei) beer spoilage. Curr Microbiol 2023; 80: 237
    CrossrefPubMedSuche in Google Scholar
  • 80 Sakurai K, Tomiyama K, Yaguchi Y, Asakawa Y. The characteristic smell emitted from two scale insects, Ceroplastes japonicus and Ceroplastes rubens . Biosci Biotechnol Biochem 2020; 84: 1541-1545
    CrossrefPubMedSuche in Google Scholar
  • 81 Govindarajan M, Rajeswary M, Arivoli S, Tennyson S, Benelli G. Larvicidal and repellent potential of Zingiber nimmonii (J. Graham) Dalzell (Zingiberaceae) essential oil: an eco-friendly tool against malaria, dengue, and lymphatic filariasis mosquito vectors?. Parasitol Res 2016; 115: 1807-1816
    CrossrefPubMedSuche in Google Scholar