Abstract
Hydatid cysts occur in the larval stage of Echinococcus granulosus worms in vital organs such as the liver, lung, brain, kidney, heart and spleen. As a result, the formation of these cysts in humans and animals is considered one of the most catastrophic common infections in humans and animals. So far, there is no definitive effective treatment strategy for this disease in humans. Cyst eradication through surgery is the only treatment, which might be difficult or impossible in some cases. The most difficult aspect of cyst removal surgery is recurrence and anaphylactic shock. As a result, many scolicidal medications are ineffective at inactivating the content of hydatid cysts in vivo. Herbal medicines are now considered a potential treatment for the treatment of hydatid cysts due to their effective anti-cystic activities, minimal side effects, and ability to improve immunity. In the present review study, the anti-cystic role of carvacrol as one of the main constituents of the Lamiaceae family on hydatid cyst has been discussed. The results demonstrate that carvacrol-containing essential oils may be utilized as a hydatid cyst inhibitor. This study has also shown the synergistic activity of carvacrol, thymol and other active plant metabolites.
Keywords: Carvacrol, Hydatid cyst, Echinococcus granulosus, Herbal medicines
Introduction
Hydatidosis is a zoonotic disease caused by the larval stage of the parasitic Echinococcus granulosus being replaced in numerous organs such as the liver, lungs, and brain (Bhutani and Kajal 2018). Adult worms reside in the digestive tract of dogs and other carnivores. Cystic infection occurs in ruminants when grazing forage infected with parasitic eggs. The parasite has a worldwide distribution and primarily affects poor rural dairy farmers (Baumann et al. 2019). Over one million people with hydatid disease have been documented worldwide, indicating the condition is quite common.
Some of the most typical treatment modalities include surgery, PAIR (Puncture, Aspiration, Injection, and Respiration), and scolicidal medications (Adjerid et al. 2020). Meanwhile, surgery is the most effective treatment for cyst elimination, and in most instances, or when surgery is not possible, drug therapy with mebendazole and albendazole is administered (Dehkordi et al. 2019). Although surgery can efficiently remove hydatid cysts, there is a high risk of cyst rupture during surgery, which results in cyst fluid draining into the abdomen and disease recurrence. Subsequently, the possibility of anaphylactic shock occurs when the cyst fluid drains. As a result of the cyst fluid draining, anaphylactic shock is imminent. Therefore, scolicidal materials should be infused into the cysts during surgery to avoid hydatidosis recurrence (Jain et al. 2019).
Several chemical compounds are administered to inactivate protoscolices; however, most of the chemicals utilized in vivo are toxic to the host cell (Moazeni et al. 2019b). As a result, researchers are increasingly striving for new drugs with efficient scolicidal activity, indicating fewer adverse effects. In general, strong anti-cystic chemical drugs are often not suitable for in vivo administration. Therefore, an ideal drug should be most effective at low concentrations. On the other hand, drug stability in cyst fluid is one of the critical factors in vivo (Garedaghi et al. 2020; Siles-Lucas et al. 2018). Natural medicines have been deemed an efficient alternative due to the evident adverse effects of drugs. Herbal remedies are one of the most effective treatments for various diseases, including parasitic infections (Cheraghipour et al. 2021; Moazeni et al. 2019a). Over the last two decades, researchers have attempted to assess the efficacy of herbal medicines in treating infectious diseases. To treat parasitic infections, essential oils and their derivatives are employed as novel alternatives or combined with parasite drugs (Al-Abodi et al. 2019; Moazeni et al. 2019a).
Medicinal plants have bioactive chemicals with good biocompatibility and fewer adverse effects due to their natural origin. Plants with unique anti-protoscolices properties include thyme, garlic, olive, coriander, mint, onion, barberry, caper bush and ginger (Al-Abodi et al. 2019; Kohansal et al. 2017). Furthermore, essential oils, including thymol derivatives, caryophyllene, terpenoids, and fatty acids, have been demonstrated to have anti-parasitic properties (Amiri et al. 2019; Kohansal et al. 2017; Selles et al. 2020) (Fig. 1).
Fig. 1.
Studied plants with carvacrol- rich essential oils having scolicidal activity
Data collection and purification methodology
The systematic review investigated carvacrol usage and its combination with other medications against echinococcosis hydatid cyst. The most recent research on the utilization of carvacrol-rich plants against hydatid cysts was evaluated. From January 20, 2021, relevant literature was retrieved from five English databases, including Science Direct, PubMed, Scopus, Ovid and Cochrane. Furthermore, other studies were obtained from four Persian databases (Scientific Information Database (SID), Iran Medex, Iran Doc, and Magiran). The search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline (Moher et al. 2009). The scientific and general keywords for searching were used as follows: (Echinococcosis OR “hydatidosis”), (hydatid cyst OR “Cystic echinococcosis”), (protoscolices effect), (Botanical name), (Carvacrol), (Herbal medicine), (In vitro) and (In vivo). Two of the authors independently assessed the papers, and disagreements were addressed by discussion and consultation.
Data extraction and screening criteria
Two authors independently screened the preliminary information of the reviewed studies, which comprised the following: Year and Country, botanical name, Plant extract, carvacrol percent, Concentration, Exposure duration, Treatment Durations, In vitro, In vivo, and experimental output.
Inclusion criteria included the following: (I) Studies supporting the efficacy of carvacrol-containing medicinal plants against hydatid cyst. (II) Related studies have been published in Persian and English. (III) Study that has been published in peer-reviewed publications. (IV) Studies that provided clear information for evaluation. (V) Studies for which the full text was available.
Exclusion criteria included: (I) Studies for which the full text was unavailable. (II) Studies that were case-report, case-series and systematic review. (III) Paper abstracts from seminars and conferences. (IV) Studies with insufficient information for analysis.
Results
Selection of relevant studies
As seen in the PRISMA flowchart in Fig. 2, 150 documents were found in the initial search and imported to the Endnote X7 software. After removing the duplicates, screening was performed based on inclusion and exclusion criteria and the total number of studies was reduced to 95 cases. In the next step, 53 items were removed based on the inconsistency of the titles and content of the abstract with keywords. The remaining 42 documents were evaluated based on the data and context analyses in the full article. Finally, eight studies were fully consistent with the objectives of this review. The information contained in the purified studies was classified according to the main criteria in two main classes: in vitro and in vivo experiments. The only in vivo study was performed by Moazeni et al. (2017) in which hydatid-infected mice were treated with carvacrol-rich aromatic water from Z. multiflora for 8 months. The other treatments included 9 independent studies from 2012 to 2021 against hydatid in vitro by 7 medicinal plant essential oils containing the different doses of carvacrol. Figure 3 shows carvacrol-rich plants used in the studies for killing protoscolices in vitro.
Fig. 2.
PRISMA flowchart obtained from of the systematic search in the review study
Fig. 3.

Carvacrol contents in the essential oils of the studied plants in this review
Among the studied plants, S. khuzistanica had the greatest content of carvacrol (94.97%), whereas Nigella sativa essential oil had the lowest proportion of carvacrol (10.3%) (Fig. 3). As a result, most studies on the anti-cystic activity of herbs have focused on thyme essential oil, with the greatest carvacrol concentration estimated to be about 28%.
As shown in Table 1, eight studies of the effective role of carvacrol-rich plants against hydatid cysts have been retrieved. Data extracted from the research literature included the first author’s name, year and country, botanical name, treatment dose, treatment duration, and outcome. According to Table 1, the research performed on carvacrol-containing medicinal plants against hydatid cyst was 7 studies (87.5% of all studies) in Iran and 1 study (12.5% of all studies) in Turkey.
Table 1.
Characteristics of studies included in the systematic review, up to January 2021 in vitro
| Reference | Country | Botanical name | Treatment dose (µg/ml) | Exposure time | Result |
|---|---|---|---|---|---|
| (Sokmen et al. 2020) | Turkey | Origanum minutiflorum | 0.025%, 0.05% and 0.1% | 1, 3 and 5 min | At 0.1% concentration of the oil exhibited 100% death after 3 and 5 min of exposure time |
| (Moazeni et al. 2019c) | Iran | Satureja hortensis | 1 and 2 mg/mL | 10 and 20 min | The concentrations of 1 and 2 mg/mL showed 100% scolicidal power |
| (Mahmoudvand et al. 2017) | Iran | Zataria multiflora | 3.125, 6.25, 12.5 and 25 μl/mL | 5–30 min | The concentrations of 12.5 and 6.25 μL/mL killed 100% protoscoleces after 5 and 20 min |
| (Moazeni et al. 2015) | Iran | Zataria multiflora | 1 mL | 1, 2, 3, 4, and 5 min | The scolicidal power of Z. multiflora AW was 93.78, 96.33, 99.16, 99.48, and 100% after 1, 2, 3, 4, and 5 min |
| (Mahmoudvand et al. 2014) | Iran | Nigella sativa | 0.01, 0.1, 1 and 10 mg/ml | 5,10,20,30 and 60 min | The concentration of 1 mg/ml had potent scolicidal activities against protoscolices of protoscoleces after 10 min exposure |
| (Kavoosi and Purfard 2013) | Iran | Zataria multiflora | 1 -100 μg/mL | 10 min | Results indicated that all protoscolices were killed after 10 min of exposure to concentrations more than 17 μg/mL of essential oil from Z. multiflora |
| (Moazeni et al. 2012) | Iran | Satureja khuzistanica | 1, 3, 5 and 10 mg/ml | 10, 20, 30 and 60 min | The concentration of 10 mg/ml showed100% scolicidal power |
| (Soleimani et al. 2021) | Iran | Origanum vulgare | 0.6, 1, 10% | 1, 5, 10, 15, 20 or 25 min | Maximum protoscoleces were killed at 10% for 5 min exposure time |
| (Soleimani et al. 2021) | Iran | Zataria multiflora | 0.6, 1, 10% | 1, 5, 10, 15, 20 or 25 min | Maximum protoscoleces were killed at 10% for 10 min exposure time |
Figure 4 represents the effective dose of plant essential oils against hydatid cyst without considering dose exposure time. As can be seen, the most scolicidal potency has been determined for N. sativa and Z. multiflora to be about 10 and 17 µg/ml, respectively. Besides, those plants with high carvacrol contents, namely S. khuzistanica and S. hortensis, have indicated less scolicidal activity.
Fig. 4.
Scolicidal efficacy of carvacrol-rich essential oils from the studied plants
Discussion
Hydatidosis is still an important public health issue in many countries despite advances in echinococcosis control (Wen et al. 2019). The recurrence of the disease has not yet been resolved by the development of more effective medicine for treating hydatid cysts. However, plant metabolites, especially essential oils, are potential avenues for treating Hydatidosis (Moazeni et al. 2019a). A preferred treatment for killing protoscoleces in cyst fluid should have features such as stability, penetration, low viscosity, and fast action (Dehkordi et al. 2019). Benzimidazole derivatives are being utilized in treating hydatidosis (Cheng et al. 2020). These treatments are adversely affected by poor intestinal absorption, low hepatotoxicity and liver levels. Albendazole-resistant cysts have also been found in several investigations (Dehkordi et al. 2019). New medicines for treating hydatidosis thus seem inevitable. In contrast, a detailed understanding of all therapeutic products, particularly natural medicinal plants, is important (Moazeni et al. 2015). Resistance to chemical drugs has now spread to most parasitic diseases. Herbal medicines have the ability to break the drug resistance in a wide range of parasites due to their high diversity and synergistic effect of different metabolites. According to a study conducted by Sokmen et al. (2020), 0.1% of the essential oil of Origanum minutiflorum had a 100% lethal effect on hydatid cysts after 3–5 min of exposure. The carvacrol content of plant essential oils was determined to be 64.29% in this investigation. As a result, the concentration of carvacrol can be attributed to its scolicidal activity. Researchers have already demonstrated essential oils’ antifungal and antibacterial properties (Marinelli et al. 2018). Satureja hortensis nanoemulsion with 55.66% carvacrol in two doses of 1 and 2 mg/ml killed the scolexes after 20 and 10 min, respectively. As per studies, nano-formulations of plant compounds can dramatically boost their biological activity.
On the other hand, it was revealed that a nanoemulsion of carvacrol-rich essential oils might penetrate the cyst’s germinal layer, causing it to crumble and detach from other layers (Moazeni et al. 2019c). The results demonstrated that thymol and carvacrol in Z. multiflora essential oil interact with the protoscolex cell membrane, disrupting their vital activity. These molecules cause a breakdown of membrane integrity in the microorganism by binding to cations on the membrane’s surface. Although their combination is more effective than either alone, thymol or carvacrol are potent scolicidal agents. Surprisingly, N. sativa essential oil with carvacrol content exhibited around 94% less anti-parasitic efficacy than thyme with a carvacrol level of around 29%. It may be speculated that the synergistic actions of other chemicals, such as thymol and carvacrol, play a significant role in boosting anti-parasitic effectiveness in this case (Mahmoudvand et al. 2017). In a study conducted by Moazeni et al. (2015) to examine the effect of aromatic water of Z. multiflora, it was revealed that this extract contained carvacrol equivalent to 15.2 percent. In an in vitro experiment, hydatid cysts are eliminated after 5 min of treatment with 1 ml of aromatic water. According to their claim, the scolicidal effectiveness of this aromatic water was equivalent to that of the conventional anti-parasitic drug such as albendazole (Moazeni et al. 2015). In this study, in vivo trials in cyst-infected mice showed that aromatic water of Z. multiflora (20 ml/l) prevents cyst formation during 8 months of oral treatment (Moazeni et al. 2014). A study on the scolicidal activity of N. sativa essential oil found that the greatest scolicidal activity was at a 10 mg/ml concentration. According to GC–MS analysis, the essential oil contained 10% carvacrol (Mahmoudvand et al. 2014).
Furthermore, in the presence of 17.5 g/ml of EO, Z. multiflora essential oil with a carvacrol content of 28.5% demonstrated significant efficacy of scolicidal activity. When the components in different essential oils were compared, it was shown that chemicals such as thymol and other terpenoids caused synergy against hydatid cyst (Kavoosi and Purfard 2013). Compared to other studies, Moazeni et al. (2012) demonstrated that, although S. khuzestanica essential oil had a high carvacrol content, it had lesser scolicidal effectiveness than Z. multiflora and N. sativa. As a result, the synergistic effects of plant essential oil molecules can significantly increase their scolicidal potency (Moazeni et al. 2012).
Limitations and challenges of study
-
(I)
Lack of sufficient information regarding clinical and animal trials using medicinal plants containing carvacrol on hydatid cyst.
-
(II)
Lack of extensive in vitro and in vivo studies on the effective compounds of essential oils to study in detail their synergistic effects with carvacrol.
-
(III)
Lack of international studies and access to limited studies in Iran on the use of medicinal plants containing carvacrol.
Conclusion
According to the findings of this study, the essential oil of a medicinal plant containing carvacrol has a great potential for use as a hydatid cyst inhibition. This study also revealed a synergistic effect between carvacrol, thymol, and other active herbal components. According to these findings, the essential oils of these plants and their derivatives can be utilized to treat parasite diseases, albeit further research on laboratory animal specimens is required. However, due to the growing limitations of antimicrobial chemical use, such as side effects and drug resistance, it is necessary to substitute these natural substances, such as carvacrol-rich essential oils, to control hydatid cysts in animals and humans.
Acknowledgements
The authors thanked the Vice Chancellor for Research and Technology of Lorestan University of Medical Sciences and stated that this review article did not receive any financial support.
Declaration
Conflict of interest
The authors declare that there are no conflicts of interest.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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