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Synergy research: Approaching a new generation of phytopharmaceuticals
Abstract
The longstanding, successful use of herbal drug combinations in traditional medicine makes it necessary to find a rationale for the pharmacological and therapeutic superiority of many of them in comparison to isolated single constituents. This review describes many examples of how modern molecular-biological methods (including new genomic technologies) can enable us to understand the various synergistic mechanisms underlying these effects. Synergistic effects can be produced if the constituents of an extract affect different targets or interact with one another in order to improve the solubility and thereby enhance the bioavailability of one or several substances of an extract. A special synergy effect can occur when antibiotics are combined with an agent that antagonizes bacterial resistance mechanisms. The verification of real synergy effects can be achieved through detailed pharmacological investigations and by means of controlled clinical studies performed in comparison with synthetic reference drugs. All the new ongoing projects aim at the development of a new generation of phytopharmaceuticals which can be used alone or in combination with synthetic drugs or antibiotics. This new generation of phytopharmaceuticals could lend phytotherapy a new legitimacy and enable their use to treat diseases which have hitherto been treated using synthetic drugs alone.
... Locals have utilized Zanthoxylum armatum as "wood" as a chomping stick to cure mouth ulcers and dental diseases. According to some sources, the plant bark and fruits are also utilized cancer treatments and digestive disorders like dysentery and cholera [13][14][15]. ...
... Studies on phytochemistry reported the existence of many substances produced from capers (Capparis spp.) that have anti-bacterial, anti-viral, antioxidant and anti-inflammatory properties, including spermidine, carotenoids, quercetin, tocopherol, and rutin. The anti-bacterial, anti-fungal, and antileishmanial action of Capparis decidua seed-extracts is due to the presence of glucosinolate and quaternary ammonium [14][15][16][17][18][19]. Cranberry juice (Vaccinium macrocarpon) and b earberry (Arctostaphylos ura-ursi) juice is used urinary tract infections treatments, whereas broad spectrum anti-bacterial plants like tea tree (Melaleuca alternifolia), lemon balm (Melissa officinalis) and garlic, are also proven effective. ...
... and Salmonella Typhi are all susceptible to the anti-bacterial effects of methanol extracts of Artemisia vulgaris, Ageratina adenophora, Cinnamomum tamala, and Oxalis corniculata . Furthermore, high action against S. aureus, Enterobacter cloacae and Enterococcus faecalis, was shown by hydromethanolic extracts of Punica granatum, Cistus monspeliensis, and Berberis vulgaris[12][13][14][15][16][17].Hyperenone A, hyperphorin, emodin and hypercalin B were found in an endophytic fungus that was isolated from medicinal plant Hypericum acmosepalum. These compounds have been shown to have anti-bacterial activity against resistant S. aureus, The principal constituents of the Hypericum olympicum's essential oil components include E-anethole, spathulenol and β-farnesene.The growth of C. frundii, S. aureus, E. aerogenes, and E. coli is inhibited by the extracts of Polygonum persicaria, Rumex dentatus, Polygonum plebejum, Rumex nepalensis, Rumex hastatus, and Rheum australe [23]. ...
Infectious pathologic changes caused by pathogens, which are harmful that enter the body by bacteria, fungus, viruses, and parasites. Infectious-diseases can range in severity from very mild to very dangerous. Numerous human diseases are caused by bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris and Bacillus subtilis. Capparis spp. that have anti-bacterial, anti-oxidant and anti-inflammatory properties, including spermidine, carotenoids, quercetin, tocopherol, and rutin by the anti-bacterial, anti-fungal, and anti-leishmanial action. Carrot seed oil (Daucus carota) and tea tree oil (Melaleuca alternifolia) both exhibit antibacterial action respectively. Curcumin and its derivatives were found to have more potent anti-bacterial activity against several strains of S. pneumonia. Oregano oil and carvacrol has revealed that they have anti-viral properties against respiratory-syncytial-virus (RSV), that causes respiratory disease, rotavirus, a frequent condition of diarrhea in theng children, and herpes simplex virus type 1 (HSV-1). Sweet basil extract, which contain ingredients like ursolic acid and apigenin, have powerful antiviral properties against hepatitis B, herpes and enterovirus. Candida infections have fewer severe side effects and less cost load than chemical medications, can be treated with new pharmaceuticals, plant, and herbal items.
... The scientific search for medicinal plant extracts is challenging because of their huge complexity and variability. Since complex plant extracts and no single bioactive molecules are often used for medicinal purposes, understanding the interactions between the active compounds could be of great importance [10][11][12]. It was found that disease resistance is less likely to occur against a combination of bioactive compounds than against single active molecules [11][12][13]. ...
... Since complex plant extracts and no single bioactive molecules are often used for medicinal purposes, understanding the interactions between the active compounds could be of great importance [10][11][12]. It was found that disease resistance is less likely to occur against a combination of bioactive compounds than against single active molecules [11][12][13]. Medicinal plants are targeting microbes through the combined action of structurally and functionally diverse active compounds. Combined effects can vary based on the target microbial species [10,14]. ...
... Medicinal plant extracts may contain hundreds or even thousands of individual bioactive compounds in varying abundances and identifying the bioactive compounds responsible for a given biological activity is a significant challenge [15]. In fact, the overall activity of medicinal plant extracts is a result of the combined action of multiple compounds with synergistic, additive, or antagonistic activity [12,[16][17][18][19]. It is not acceptable to use bioactive compounds as medicines without understanding intra-extract interactions on a wider scale. ...
It is accepted that the medicinal use of complex mixtures of plant-derived bioactive compounds is more effective than purified bioactive compounds due to beneficial combination interactions. However, synergy and antagonism are very difficult to study in a meticulous fashion since most established methods were designed to reduce the complexity of mixtures and identify single bioactive compounds. This study represents a critical review of the current scientific literature on the combined effects of plant-derived extracts/bioactive compounds. A particular emphasis is provided on the identification of antimicrobial synergistic or antagonistic combinations using recent metabolomics methods and elucidation of approaches identifying potential mechanisms that underlie their interactions. Proven examples of synergistic/antagonistic antimicrobial activity of bioactive compounds are also discussed. The focus is also put on the current challenges, difficulties, and problems that need to be overcome and future perspectives surrounding combination effects. The utilization of bioactive compounds from medicinal plant extracts as appropriate antimicrobials is important and needs to be facilitated by means of new metabolomics technologies to discover the most effective combinations among them. Understanding the nature of the interactions between medicinal plant-derived bioactive compounds will result in the development of new combination antimicrobial therapies.
... Ví dụ, mặc dù artemisinin có hiệu quả lâm sàng tốt trong điều trị nhiễm ký sinh trùng trên người, cao chiết từ cây Thanh cao hoa vàng (Artemisia annua L.) tỏ ra hiệu quả hơn artemisinin trong việc làm chậm sự tiến triển của hiện tượng kháng thuốc bởi ký sinh trùng sốt rét và kháng kháng thuốc tốt [12]. Việc giảm hiệu quả điều trị liên quan mật thiết đến việc mất tác dụng hiệp đồng giữa các thành phần trong cao dược liệu sau khi cao được tinh chế thành đơn chất tinh khiết [13][14][15][16][17][18]. Vấn đề này sẽ được phân tích và bàn luận kỹ ở phần sau của nghiên cứu. ...
... Cao dược liệu có thể gồm các chất chuyển hóa sơ cấp (protein, lipid, acid amin và đường [27]) và các chất chuyển hóa thứ cấp (các chất phân tử nhỏ, hoạt chất hoặc các chất khác [28]) từ dược liệu. Tương tác giữa các thành phần trong cao là hiện tượng phổ biến và rất phức tạp, xảy ra dưới nhiều hình thức như hiệp đồng tăng cường, hiệp đồng cộng hoặc đối kháng, theo cơ chế dược động học, dược lực học hoặc các cơ chế khác [13,[15][16][17]. Xét về sinh dược học, trong nhiều trường hợp, toàn bộ cao dược liệu được xem là hoạt chất. ...
... Đồng thời, cơ chế và đích tác dụng của chúng cũng có thể giống hoặc khác nhau [20,25,34]. Ngoài ra, khác với các đơn chất tinh khiết, cao dược liệu thường tác dụng đa đích do bản chất nhiều thành phần [13,26,35,36]. Cơ chế hiệp đồng dược lực học giữa các hoạt chất trong cao dược liệu đã được ghi nhận ở nhiều nghiên cứu [13,[15][16][17]. ...
Herbal extracts are one of the herbal preparations obtained by the extraction method. There has been an increasing trend of application of herbal extracts to replace traditional medicinal herbs in using and manufacturing of drug dosage forms. The quality characteristics of herbal extracts roots from their multi-components nature, leading to multiple targets and mechanisms of action. Thus hindering the development of quality assessment systems and also the application of pharmaceutical technologies in the development of modern dosage forms, leading to a decrease in therapeutic efficacy in clinical practice. This review systematizes some information related to herbal extracts: the position and importance of herbal extracts in drug research and development, classification, characteristics, and quality control strategies. The purpose of this review is to consolidate and expand the general understanding of the “pharmaceutical nature” of herbal extracts and to provide some quality control strategies using markers and reference materials Keywords Herbal extracts, quality characteristics, classification, quality control, pharmaceutical nature.
... A combination can be made of different natural compounds or a natural compound combined with standard antimicrobial drugs. The rationale for combination therapy is to prevent the emergence of resistant strains and encourage the use of lower doses of drugs to minimize toxicity [5]. Andrographolide is a diterpene lactone, the predominant constituent of Andrographis paniculata (Burm. ...
... The synergistic effect observed showed a greater effect than the combined effects of each constituent. Combinations of antimicrobial agents provide many benefits such as enhancing antibacterial activity, minimizing dose-dependent side effects, reducing the time needed for long-term antimicrobial therapy and preventing the emergence of resistant microorganisms [5]. Although combination therapy could enhance antimicrobial efficacy, the use of andrographolide with antimicrobials should be done with caution as not all the antimicrobial drugs displayed synergic combination effects. ...
Background and objectives: The resistance of infectious pathogens to antimicrobial drugs is an underestimated threat to public health. This rapidly developing phenomenon necessitates the discovery of new treatment strategies. Combining natural compounds with first-line antimicrobials is one treatment strategy to mitigate the emergence of resistant pathogens. Andrographolide, a diterpene lactone isolated from Andrographis paniculata has been reported to possess potent anti-infective activity. This study was conducted to evaluate the combination effect of andrographolide with first-line antimicrobial drugs to fight emerging resistance. Method: The minimum inhibitory concentration (MIC), fold increase in antimicrobial efficacy and fractional inhibitory concentrations (FIC) of andrographolide and ceftriaxone, ciprofloxacin, amoxicillin, metronidazole, amikacin, clindamycin and fluconazole were determined using the high throughput spot culture growth inhibition (HT-SPOTi) assay against ten isolated clinical strains; Streptococcus pyogenes, Escherichia coli, Vibrio cholerae, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae, Enterococcus faecalis, Salmonella paratyphi B and Candida albicans. Results: Combination of andrographolide and the first-line antimicrobials showed various degrees of susceptibility and efficacy against the tested microorganisms with the highest MIC, 0.85 μg/mL recorded. The FICI (Fractional Inhibitory Concentration Indices) for synergy ranged between 0.00 to 0.28 depending on the microorganism and antimicrobial drug. Conclusion: Use of andrographolide with first-line antimicrobials could aid in combating the menace of resistance pathogens. However, this should be done with caution as some of the antimicrobials tested exhibited antagonistic effects.
... In the parasite, there was abnormal lipid accumulation after exposure to lupenone, suggesting that this compound affects the lipid biosynthesis pathways of the parasites, resulting in apoptosis. One of the strategies adopted by research groups in drug development is the combination of two or more compounds to achieve a better therapeutic effect [66]. With this strategy in mind, Polanco-Hernández and co-workers reported their work on the effect of different mixtures and concentrations of lupenone and βcaryophyllene oxide on leishmanicidal activity and immunomodulatory effects [67]. ...
... In high concentrations, they also inhibit mouse liver arginase (ARG-1), however, they are more active against the parasite enzyme. It was observed by the enzymatic kinetics that (65) and (66) are competitive inhibitors of ARG-L, whereas EGCG is a mixed inhibitor and gallic acid (67) is a non-competitive inhibitor. The most potent arginase inhibitor is (65) (IC50 = 0.8 μM) followed by (66) (IC50 =1,8 µM), (67) (IC50 = 2,2 µM) and (64) (IC50 = 3,8 µM). ...
Neglected Tropical Diseases (NTD) are a group of endemic diseases that cause up to one million deaths annually. Leishmaniasis and Chagas Disease are classified as NTD whose current treatments are of limited access. There is an urgent need to develop new agents to combat or alleviate the symptoms of these pathologies. The present work highlights the activities of several natural products and their derivatives which have been tested against the causative parasites of both diseases. The activities of natural products illustrate their potential to assist in the combat against NTD. Research in this area could provide an opportunity to advance medical research and to provide treatments to low- and middle-income countries.
... This effect is reached when components contained in plant extract minimize the negative effects by destroying toxic-acting compound or inhibiting its negative activity and thus providing better activity when added to the original raw drug. Using one of four known methods for preparation of Radix Aconiti, the level of toxicity can be reduced to 0.2% [86]. Rhus hirta extract, when combined with 5-fluorouracil (chemotherapeutic drug), reduced the toxicity of the drug in vitro, possibly due to presence of antioxidants in the extract [33]. ...
... Juniperus communis and Solanum xanthocarpum when combined in lower doses noticeably reduced hepatotoxicity in vivo studies [34]. The abovementioned interaction is achieved when the compounds affect different target sites or increase the solubility of one another, thus enhancing their bioavailability [33,34,[84][85][86]. ...
Plant-based natural products have been used as a source for therapeutics since the dawn of civilization. According to the World Health Organization (WHO), more than 80% of the world’s population relies on traditional medicine for their primary healthcare. Numerous natural extracts, widely known in Traditional Chinese Medicine, Indian Ayurveda medicine and other practices, have led to the modern discovery and development of new drugs. Plants continuously interact with their environment, producing new compounds and ever-changing combinations of existing ones. Interestingly, some of the compounds have shown lower therapeutic activity in comparison to the extract they were isolated from. These findings suggest that the higher therapeutic activity of the source extract was due to the synergistic effect of several compounds. In other words, the total therapeutic potential of the extract cannot be explained only by the sum of its parts alone. In traditional medicine, most herbal remedies are based on a mixture of plants, and it is the interaction between different constituents that amplifies their therapeutic potential. Considering the significant influence traditional medicine has on human healthcare, knowing and studying the synergistic effect of compounds is paramount in designing smart therapeutic agents.
... Contrariwise, others have repeatedly found that the total EO is more effective than its single constituents (Tak and Isman, 2016;Feng et al., 2020), meaning that the bioactivities of the single molecules do not refer to the whole oil (Nelson and Kursar, 1999;Kim et al., 2016;Pandiyan et al., 2019;Brito et al., 2021). In this respect, many hypotheses have been prompted, including the most intensely studied, the one which demonstrates that interactions between their individual chemicals can create different effects, namely additive, once the sum of the activities of the single molecules is equivalent to the activity of their mixture; antagonistic, when the activity of the pooled chemicals is considerably lower than that resulting from an additive effect; or synergistic, if the activity of the coupled molecules is significantly greater than that resulting from an additive effect (Nelson and Kursar, 1999;Harris, 2002;Wagner and Ulrich-Merzenich, 2009;Kim et al., 2016;Pandiyan et al., 2019;Feng et al., 2020;Olszowy-Tomczyk, 2020;Brito et al., 2021). ...
... Although some literature reported the synergistic effect of EOs as insecticides but the mechanism of synergy was frequently unclear. Based on recent reports, the effectiveness of EOs combinations as insecticides may be attributed to their high content of monoterpenes that have a high potential for penetration through the cuticle, respiratory and digestive systems of insects (Lee et al., 2004;Rozman et al., 2007;Wagner and Ulrich-Merzenich, 2009;Gnankiné and Bassolé, 2017;Brito et al., 2021). Furthermore, the synergistic effect of EO mixtures on insects can be related to the mutual action of their major and minor ingredients in the tested samples since some principal ingredients have the ability to facilitate the absorption of minor bioactive ones (Tak and Isman, 2015, 2017aMessaoudi Moussii et al., 2020). ...
Using essential oil (EO) mixtures to improve their single effectiveness aids to minimize insect resistance to synthetic insecticides and reduce the amounts of the applied bio-products. This study seeks to identify the chemical compositions of nine binary combinations of EOs of Artemisia herba alba Asso (A), Juniperus phoenicea L (B), and Rosmarinus officinalis L (C), by Gas Chromatography coupled to Mass Spectrometry (GC-MS) side to side with the evaluation of their toxicity and repellency effectiveness against adults of Tribolium castaneum Herbst by fumigation and repellent tests. GC-MS results revealed that each mixture was dominated by one of the following compounds: Car-3-en-5-one, α-pinene, exo-2,7,7-trimethylbicyclo[2.2.1]heptan-, and Camphor. After 24 h of treatment, the most toxic mixtures were H (3C:1A), L (1B:1C), with K (1B:3C) (LD50 = 64.99, 68.98, and 74.76 μL/L air, respectively). After 96 h, synergistic mixtures K, I (1C:1A), and L seemed to be the most potent (LD50 = 55.6, 57.63, and 58.46 μL/L air, respectively) throughout the period of treatment. LT90 values at the concentration of 83.66 μL/L air did not exceed the limit of 19.20 h for the less potent blend. The most repellent mixtures were F, D, E, and H, showing RD90 values of 1.25, 2.99, 3.46, and 3.83 nL/cm2, respectively. All samples showed synergistic effects, except the combinations I and G (1C:3A). The synergistic mixtures might be suitable as alternatives to chemical treatments for the control of T. castaneum, but tests at a larger scale are necessary to confirm our results.
... Synergistic multi-target effects refer to the synergistic effect of multiple phytochemicals on different targets, which is considered as a mechanism of synergistic effect [141]. Combined phytochemicals can target different biomarkers, resulting in synergistic hypolipidemic effects, such as direct interactions with different target proteins in the same metabolic pathway [22]. ...
... The hypolipidemic interactions between different phytochemicals may increase their bioavailability in vivo [26]. Therefore, synergistic effects based on improved solubility and absorptivity to enhance the bioavailability of phytochemicals have drawn the interest of researchers [141]. The bioavailability of phytochemicals is a critical factor for functional foods and health claims related to food ingredients, leading to an understanding of the mechanisms of action associated with benefits [21]. ...
Hyperlipidemia, a chronic disorder of abnormal lipid metabolism, can induce obesity, diabetes, and cardiovascular and cerebrovascular diseases such as coronary heart disease, atherosclerosis, and hypertension. Increasing evidence indicates that phytochemicals may serve as a promising strategy for the prevention and management of hyperlipidemia and its complications. At the same time, the concept of synergistic hypolipidemic and its application in the food industry is rapidly increasing as a practical approach to preserve and improve the health-promoting effects of functional ingredients. The current review focuses on the effects of single phytochemicals on hyperlipidemia and its mechanisms. Due to the complexity of the lipid metabolism regulatory network, the synergistic regulation of different metabolic pathways or targets may be more effective than single pathways or targets in the treatment of hyperlipidemia. This review summarizes for the first time the synergistic hypolipidemic effects of different combinations of phytochemicals such as combinations of the same category of phytochemicals and combinations of different categories of phytochemicals. In addition, based on the different metabolic pathways or targets involved in synergistic effects, the possible mechanisms of synergistic hypolipidemic effects of the phytochemical combination are illustrated in this review. Hence, this review provides clues to boost more phytochemical synergistic hypolipidemic research and provides a theoretical basis for the development of phytochemicals with synergistic effects on hyperlipidemia and its complications.
... On the contrary, the "mainstream" pharmacodynamic effect in classical pharmacology is based on an isolated, single active compound. A synergistic effect is defined as an effect produced by a combination of substances that is greater than would be expected if the combined action of the individual components were considered [15,91,92]. A complementary concept is the theory of the polyvalent action of phytopharmacological ingredients, which assumes that herbal extracts can exert a wide range of biological activity due to the variety of chemical compounds present in herbs, each of which produces different effects [15,93]. ...
Depression is a mental health disorder that develops as a result of complex psycho-neuro-immuno-endocrinological disturbances. This disease presents with mood disturbances, persistent sadness, loss of interest and impaired cognition, which causes distress to the patient and significantly affects the ability to function and have a satisfying family, social and professional life. Depression requires comprehensive management, including pharmacological treatment. Because pharmacotherapy of depression is a long-term process associated with the risk of numerous adverse drug effects, much attention is paid to alternative therapy methods, including phytopharmacotherapy, especially in treating mild or moderate depression. Preclinical studies and previous clinical studies confirm the antidepressant activity of active compounds in plants, such as St. John’s wort, saffron crocus, lemon balm and lavender, or less known in European ethnopharmacology, roseroot, ginkgo, Korean ginseng, borage, brahmi, mimosa tree and magnolia bark. The active compounds in these plants exert antidepressive effects in similar mechanisms to those found in synthetic antidepressants. The description of phytopharmacodynamics includes inhibiting monoamine reuptake and monoamine oxidase activity and complex, agonistic or antagonistic effects on multiple central nervous system (CNS) receptors. Moreover, it is noteworthy that the anti-inflammatory effect is also important to the antidepressant activity of the plants mentioned above in light of the hypothesis that immunological disorders of the CNS are a significant pathogenetic factor of depression. This narrative review results from a traditional, non-systematic literature review. It briefly discusses the pathophysiology, symptomatology and treatment of depression, with a particular focus on the role of phytopharmacology in its treatment. It provides the mechanisms of action revealed in experimental studies of active ingredients isolated from herbal antidepressants and presents the results of selected clinical studies confirming their antidepressant effectiveness.
... If one agent enhances the effect of the other agent and together they act more efficiently than as individually, interaction between two agents has identified as "synergy". So, synergistic interactions between antibiotics and plant products motivate many scientists to evaluate of synergistic interactions and mechanisms of two agents [4]. Many plant products have shown antibacterial properties for a long time. ...
Antibiotic misuse or overuse leads antibiotic resistance. Antibiotic resistant bacteria infections cause significant clinical problem. Recently, antibiotic resistant bacteria numbers have increased, this situation has become a global public health treat. To achieve these problems, development of new antibacterial compounds is still popular among researchers. The focus on natural compounds/plant extracts in combination with antibiotics increase their activities and decrease the doses of antibiotics and their side effects. Despite known as poisonous, Arum italicum Miller is used as food and/or is used for the treatment such ailments as furuncle, eczema, peptic ulcer, wounds, etc. This interesting species was found as anticancer, cytotoxic, apoptotic agent against some human cancers. In the present study, the fractions of A. italicum tuber extract against human pathogens (Pseudomonas aeruginosa ATCC 27853, Bacillus cereus NRRL B-3711, Staphylococcus aureus ATCC 6538) were evaluated for their antibacterial activities by microdilution method. Each fraction was combined with ciprofloxacin and their synergistic activities were tested by checkerboard method. The MIC (minimum inhibitory concentrations) and FICI (fractional inhibitory concentration indexes) values were calculated. Totally, seven synergic interactions, ten additive interactions, and four indifferent interactions of tested fractions with ciprofloxacin were found.
... A powerful synergistic impact is achieved when the current AB and a resistance-antagonizer are utilized in combination. This is due to the fact that the majority of chemicals generated in response to pathogen infection are not AML [105]. Several studies have revealed that these phytochemicals have the ability to reestablish the effectiveness of AB when utilized in conjunction with other medications [81]. ...
Controlling microorganism outbreaks is a critical challenge in preventing the spread of infectious diseases. In addition, an increase in drug-resistant bacterial strains came from cross-contamination and medication overuse, making the problem much more difficult to control. One of the most humongous obstacles to the efficient treatment of a wide range of common infections is antimicrobial resistance (AML-R). Currently, antibiotics are being used hugely to treat such infectious conditions. However, because of their synthetic nature, the development of resistance to them when used over a long period of time or in low doses prompts us to seek alternative treatments. Phytoactives or bioactives from plant sources are the natural solutions to these conditions, as Mother Nature has already provided the answer to every ailment that mankind has faced. The most effective therapies for AML-R have been derived from natural Phytoactives. Because of the abundance of biologically active molecules found in nature, it is by far the best alternative to treat any infections. However, the bioavailability, pharmacokinetic characteristics, low solubility, poor gastrointestinal absorption, low hydrophilicity, and delayed intrinsic dissolution are the major physicochemical barriers that hinder the utilization of these natural actives as AML treatments. These problems can be overcome through the application of novel drug-delivery technologies. This review provides a comprehensive study of AML Phytoactives-based drug delivery, leveraging the potential of nanotechnology to address and overcome the delivery problems associated with them, resulting in a successful approach toward antimicrobial therapy.
... Although technological development has enabled improved extraction and characterization techniques of natural compounds [16,17], screening strategies are not always capable of unwrapping the mechanism of the isolated compounds responsible for the combinatory effect [18]. Sometimes the active compound operates at a lower degree compared with the whole extract [19]. It is important to consider ...
Natural extracts have been and continue to be used to treat a wide range of medical conditions, from infectious diseases to cancer, based on their convenience and therapeutic potential. Natural products derived from microbes, plants, and animals offer a broad variety of molecules and chemical compounds. Natural products are not only one of the most important sources for innovative drug development for animal and human health, but they are also an inspiration for synthetic biology and chemistry scientists towards the discovery of new bioactive compounds and pharmaceuticals. This is particularly relevant in the current context, where antimicrobial resistance has risen as a global health problem. Thus, efforts are being directed toward studying natural compounds’ chemical composition and bioactive potential to generate drugs with better efficacy and lower toxicity than existing molecules. Currently, a wide range of methodologies are used to analyze the in vitro activity of natural extracts to determine their suitability as antimicrobial agents. Despite traditional technologies being the most employed, technological advances have contributed to the implementation of methods able to circumvent issues related to analysis capacity, time, sensitivity, and reproducibility. This review produces an updated analysis of the conventional and current methods to evaluate the antimicrobial activity of natural compounds.
... The green and ripe fruit extracts of M.azedarach were tested qualitatively for steroids, alkaloids, phenols, flavonoids, saponins, tannins, and terpenoids as characterised by characteristic colour change, (Harborne, 1998;Wagner and Ulrich-Merzenich (2009);Malar et al., 2020). Each plant extract was examined independently using a specialised chemical reagent and following precise techniques as shown in Table ( ...
... The rationale is that the bioactive principles present in the medicinal plant act synergistically and modulate the activity of other constituents from the same plant or other plant species [248,249]. Numerous plants and their constituents are reputed in traditional practices of medicine to enhance cognitive function [246,247,250,251]. This approach has been used in Ayurveda, traditional Chinese medicine (TCM), and the Native American system of medicine, where a single herb or a combination of two or more herbs is commonly prescribed [249,[252][253][254][255]. ...
Alzheimer’s disease (AD) is a multifactorial, progressive, neurodegenerative disease typically characterized by memory loss, personality changes, and a decline in overall cognitive function. Usually manifesting in individuals over the age of 60, this is the most prevalent type of dementia and remains the fifth leading cause of death among Americans aged 65 and older. While the development of effective treatment and prevention for AD is a major healthcare goal, unfortunately, therapeutic approaches to date have yet to find a treatment plan that produces long-term cognitive improvement. Drugs that may be able to slow down the progression rate of AD are being introduced to the market; however, there has been no previous solution for preventing or reversing the disease-associated cognitive decline. Recent studies have identified several factors that contribute to the progression and severity of the disease: diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, and toxins. Thus, increasing evidence supports dietary and other lifestyle changes as potentially effective ways to prevent, slow, or reverse AD progression. Studies also have demonstrated that a personalized, multi-therapeutic approach is needed to improve metabolic abnormalities and AD-associated cognitive decline. These studies suggest the effects of abnormalities, such as insulin resistance, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, in the AD process. Therefore a personalized, multi-therapeutic program based on an individual’s genetics and biochemistry may be preferable over a single-drug/mono-therapeutic approach. This article reviews these multi-therapeutic strategies that identify and attenuate all the risk factors specific to each affected individual. This article systematically reviews studies that have incorporated multiple strategies that target numerous factors simultaneously to reverse or treat cognitive decline. We included high-quality clinical trials and observational studies that focused on the cognitive effects of programs comprising lifestyle, physical, and mental activity, as well as nutritional aspects. Articles from PubMed Central, Scopus, and Google Scholar databases were collected, and abstracts were reviewed for relevance to the subject matter. Epidemiological, pathological, toxicological, genetic, and biochemical studies have all concluded that AD represents a complex network insufficiency. The research studies explored in this manuscript confirm the need for a multifactorial approach to target the various risk factors of AD. A single-drug approach may delay the progression of memory loss but, to date, has not prevented or reversed it. Diet, physical activity, sleep, stress, and environment all contribute to the progression of the disease, and, therefore, a multi-factorial optimization of network support and function offers a rational therapeutic strategy. Thus, a multi-therapeutic program that simultaneously targets multiple factors underlying the AD network may be more effective than a mono-therapeutic approach.
... However, the combination between essential oil and conventional antimicrobial drugs has been referred to as a strategy to bring about maximum of therapeutic efficacy by additive or synergistic effect. 17 It will be a good idea if this plant endowed with a lot of compound which have antibacterial activity could have applied to address the resistant bacteria against the modern medicine. ...
Objective: The study aimed to identify the phytochemical composition of Leucaena leococephala leaf and evaluate the antimicrobial potential of the essential oil from the leaf. Material and Methods: The sample was subjected to Clevenger apparatus to extract the oil. The essential oil was characterized by chromatography method (GC-MS). The GC-MS was performed on Perkin Elmer gas chromatography model Clarus 680 equipped with HP-5 fused capillary column (5%) phenylmethyl polysiloxane stationary phase with 30m length, 0.25µm of film thickness and 0.25oc and 280oc respectively. Antibacterial activity using Agar Disc Method. Result: The result obtained from the GC-MS presented thirty phytochemicals of which Neophytadiene (9.48%), Octadecane (3.15%), 1-Octadecyne (3.85%), Phytol (52.51%) and Hexacosane (7.26%) are major. The antibacterial potential activities were observed in various ways with zone of inhibition diameters ranging from 0.70±0.00mm to1.27±0.06mm for staphylococcus aureus and Klebsielia pneumonia respectively among the six-concentration selected (25, 50, 100, 250, 500, and 1000ppm). Conclusion: It is investigated in this present studies that Leucaena leococephala essential oil can be utilized against the management of antibacterial diseases particularly Klebsielia pneumonia and Staphylococcus aureusas well as used in the Pharmaceutical and Cosmetics industry.
... The concept of combined therapeutics has resulted in development of several types of new cancer drugs with higher efficacy, lower therapeutic dosage, and less drug resistance emergence. Furthermore, combining plant derivate compounds may result in compositions with higher chemopreventive effects (Wagner, 2011;Lotfi-Attari et al., 2017;Bagheri et al., 2018;Adlravan et al., 2021;Lin et al., 2022). ...
Objective:
The incidence of breast cancer continues to rise despite decades of laboratory, epidemiological and clinical research. Breast cancer is still the leading cause of cancer death in women. Cyclin D1 is one of the most important oncoproteins associated with cancer cell proliferation and is overexpressed in more than 50% of cases. Curcumin and chrysin are plant-derived components that are believed to assist in inhibiting the viability of breast cancer cells. These agents are involved in cancer cells' growth and reducing cyclin D1 expression. In this study, the hypothesis of combining curcumin and chrysin is applied to analyze the potential synergistic effect in inhibiting cancer cell proliferation and down-regulation of cyclin D1. Furthermore, applying PLGA-PEG NPs could improve the bioavailability of free curcumin and chrysin components and at the same time increases the anti-cancer potential of this compound.
Methods:
PLGA-PEG NPs were synthesized via the ring-opening polymerization technique and characterized with FT-IR and FE-SEM for chemical structure and morphological characteristics, respectively. Next, curcumin and chrysin were loaded in PLGA-PEG NPs and MTT assay was performed to assess the cytotoxic effect of these agents. T-47D cells were treated with appropriate concentrations of these agents and cyclin D1 expression level was evaluated by real-time PCR.
Results:
The obtained results from FT-IR and FE-SEM techniques illustrated that curcumin and chrysin were efficiently encapsulated into PLGA-PEG NPs. Curcumin, chrysin, and curcumin-chrysin in free and nano-encapsulated forms exhibited an anti-cancer effect on T-47D cells in a time- and dose-dependent manner, especially in a combination of free and encapsulated forms demonstrated synergistic anti-cancer effects. Compared to free form, Nano-curcumin, Nano-chrysin, and Nano-combination remarkably down-regulated cyclin D1 gene expression. (p-value < 0.05).
Conclusion:
Our results revealed that the curcumin-chrysin combination has a synergistic effect and the encapsulated form of this nano-component has more inhibition on cyclin D1 expression.
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... On the other hand, the blend of natural metabolites with commercial drugs might regain the effectiveness of existing medicine that is lost due to over exploitation. Thus, the interaction of new antimicrobials and the synthetic drugs that produce synergistic and additive outcomes could ease the process and duration of treatment [35]. ...
... Furthermore, the increasing demand for innovative and functional food products with clear and clean labeling requires natural, safe, and simple ingredients that can be used conventionally [2]. Plant origin materials contain bodies of specialized metabolites that, when present in the extracts, exert health-promoting or pharmacological effects, as well as synergistic and additive effects [3]. In addition to the well-known plant materials with long ethnopharmacological histories, there are certain underutilized and neglected plants that can provide various raw materials that are extremely rich in particular groups of compounds of interest [4][5][6]. ...
The leaves and fruits of various Sorbus L. genotypes have long ethnopharmacological and food-usage histories, but inflorescences are still underutilized and neglected materials with scarce phytochemical scientific evidence. The aim of this study was to determine the phenolic profiles of inflorescence extracts of 26 Sorbus species, genotypes, and cultivars. HPLC and UPLS with MS detection were applied, and coupled data revealed unique phytochemical phenolic profiles. Neochlorogenic and chlorogenic acids were the key compounds, reaching up to 5.8 mg/g of dw. Rutin, isoquercitrin, quercetin 3-O-malonylglucoside, isorhamnetin 3-O-rutinoside, sexangularetin derivative, and kaempferol acetyl hexoside were detected in all Sorbus inflorescence samples. Overall, high quantitative heterogeneity across the various Sorbus genotypes was found by profiling. Phenolic fingerprint profiles and sexangularetin derivatives could serve as markers in authenticity studies and quality control schemes. The species S. amurensis, S. arranensis, S. commixta, and S. discolor and the cultivars ‘Chamsis Louing’, ‘Coral Beauty’, and ‘Edulis’ could be used as target genotypes for production of smart and innovative inflorescence matrix-based ingredients.
... In botanical samples, mixtures of phytochemicals are often more effective than their individual constituents in isolation due to additive or synergistic interactions among compounds. Indeed, many chronic and infectious diseases are not regulated by a single cellular target, but often have multiple regulating pathways [24,25]. As organisms in a complex and dynamic ecological environment, plants have evolved to address this multifactorial disease etiology through the synthesis of structurally and functionally diverse phytochemicals. ...
Cannabis is a complex biosynthetic plant, with a long history of medicinal use. While cannabinoids have received the majority of the attention for their psychoactive and pharmacological activities, cannabis produces a diverse array of phytochemicals, such as terpenes. These compounds are known to play a role in the aroma and flavor of cannabis but are potent biologically active molecules that exert effects on infectious as well as chronic diseases. Furthermore, terpenes have the potential to play important roles, such as synergistic and/or entourage compounds that modulate the activity of the cannabinoids. This review highlights the diversity and bioactivities of terpenes in cannabis, especially minor or secondary terpenes that are less concentrated in cannabis on a by-mass basis. We also explore the question of the entourage effect in cannabis, which studies to date have supported or refuted the concept of synergy in cannabis, and where synergy experimentation is headed, to better understand the interplay between phytochemicals within Cannabis sativa L.
... Therefore, the pure compound identification strategy very commonly ends in poor reproducibility and translatability [10]. Therefore, identifying the bioactive compounds of interest in a plant extract and understanding their targeted pathways responsible for the observed health benefits need to be well understood to exploit their full potential [38]. In our previous study, we reported that STEE exerts beneficial effects on aging-related cognitive health by promoting neuronal differentiation and neuronal energy metabolism and extending the length of the astrocytic process in vitro [19]. ...
Sugarcane (Saccharum officinarum L.) is a tropical plant grown for sugar production. We recently showed that sugarcane top (ST) ameliorates cognitive decline in a mouse model of accelerated aging via promoting neuronal differentiation and neuronal energy metabolism and extending the length of the astrocytic process in vitro. Since the crude extract consists of multicomponent mixtures, it is crucial to identify bioactive compounds of interest and the affected molecular targets. In the present study, we investigated the bioactivities of major polyphenols of ST, namely 3-O-caffeoylquinic acid (3CQA), 5-O-caffeoylquinic acid (5CQA), 3-O-feruloylquinic acid (3FQA), and Isoorientin (ISO), in human fetal neural stem cells (hNSCs)- an in vitro model system for studying neural development. We found that multiple polyphenols of ST contributed synergistically to stimulate neuronal differentiation of hNSCs and induce mitochondrial activity in immature astrocytes. Mono-CQAs (3CQA and 5CQA) regulated the expression of cyclins related to G1 cell cycle arrest, whereas ISO regulated basic helix-loop-helix transcription factors related to cell fate determination. Additionally, mono-CQAs activated p38 and ISO inactivated GSK3β. In hNSC-derived immature astrocytes, the compounds upregulated mRNA expression of PGC-1α, a master regulator of astrocytic mitochondrial biogenesis. Altogether, our findings suggest that synergistic interactions between major polyphenols of ST contribute to its potential for neuronal differentiation and astrocytic maturation.
... Several plant components have been shown to act synergistically with antifungal agents and to exert therapeutic effects against fungal infections with the bene ts of broad e cacy, safety, reduced toxicity, and reduced antifungal resistance (Augostine and Avery 2022; Ogidi et al. 2021). The use of two antifungal agents that act synergistically is particularly useful and effective because they can increase both the rate and the degree of sterilization (Mukherjee et al. 2005), while each agent may also have a different mechanism of antifungal activity (Johnson et al. 2004;Wagner and Ulrich-Merzenich 2009). ...
Many skin diseases are caused by microbial infections. Representative pathogenic fungus and bacterium that cause skin diseases are Candida albicans and Staphylococcus aureus , respectively. In this study, among methanol extracts of 240 edible plants, C. albicans , S. aureus , and Malassezia pachydermatis , a fungus that causes animal skin diseases, were killed by extracts of 10 plants: Acori Gramineri Rhizoma, Angelicae Tenuissimae Radix, Cinnamomi Cortex, Cinnamomi Ramulus, Impatientis Semen, Magnoliae Cortex, Moutan Cortex Radicis, Phellodendri Cortex, Scutellariae Radix, and Syzygii Flos. By evaluating the synergistic antifungal activities against C . albicans using all 45 possible combinations of these 10 extracts, five new synergistic antifungal combinations were identified. By utilizing the selected extracts and five combinations with synergistic antifungal effects, this work provides materials and methods to develop new and safe methods for treating candidiasis using natural products.
... However, more future work should be performed to evaluate the aphicidal activity of other minor compounds in PSO and the synergistic effects among them. Numerous previous studies have demonstrated that the overall biological effects of botanical extracts can be the result of combinations of substances with synergistic, additive, or antagonistic activity (Stermitz et al., 2000;Wagner and Ulrich-Merzenich, 2009;Junio et al., 2011). ...
Cowpea aphid ( Aphis craccivora Koch) is a plant pest that causes serious damage to vegetable crops. Extensive use of synthetic chemical pesticides causes deleterious effects on consumers as well as the environment. Hence, the search for environmentally friendly insecticides in the management of cowpea aphids is required. The present work aims to investigate the aphicidal activity of pomelo seed oil (PSO) on cowpea aphids, the possible insecticidal mechanisms, its chemical constituent profile, as well as the toxicity of its primary compounds. The results of the toxicity assay showed that PSO had significant insecticidal activity against aphids with a 72-hour LC 50 value of 0.09 μg/aphid and 3.96 mg/mL in the contact and residual toxicity assay, respectively. The enzymatic activity of both glutathione S-transferase (GST) and acetyl cholinesterase (AChE) significantly decreased, as well as the total protein content, after PSO treatment, which suggested that the reduction of AChE, GST, and the total protein content in aphids treated with PSO might be responsible for the mortality of A. craccivora . The GC-MS analysis revealed that PSO contained limonene (22.86%), (9Z,12 Z )-9,12-octadecadienoic acid (20.21%), n -hexadecanoic acid (15.79%), (2 E ,4 E )-2,4-decadienal (12.40%), and (2 E ,4 Z )-2,4-decadienal (7.77%) as its five major compounds. Furthermore, (9Z,12 Z )-9,12-octadecadienoic acid showed higher toxicity to aphids than both PSO and thiamethoxam (positive control). This study emphasized the potential of PSO as a natural plant-derived insecticide in controlling cowpea aphids and also provided a novel approach for the value-added utilization of pomelo seed.
... HSV-2 belongs to the Herpesviridae family and Alphaherpesvirinae subfamily. It is a sexually transmitted contagious viral disease responsible for skin and nervous system affections (Wagner and Ulrich-Merzenich 2009). After primary infection, HSV-2 established in sensory dorsal root ganglia. ...
The methanolic extracts of cypress (Cupressus sempervirens L.) collected at three phenological stages were evaluated for their cytotoxicity on Vero cells by MTT test as well as on Herpes simplex (HSV-2) and coxsackie (CVB-3) viruses by plaque reduction assay. The methanolic extract exhibited the highest cytotoxicity against HSV-2 (IC50 = 20.40 µg/mL) and CVB-3 (IC50 = 47.50 µg/mL) at the flowering stage. This extract also exhibited a virucidal action both during the entry of viruses and the release of newly formed virions. The methanolic extract bioguided purification showed that the ethyl-acetate fraction was responsible for virucidal activity. This fraction was endowed with more important selectivity index of 8.15 for HSV-2 and 4.40 for CVB-3. The ethyl acetate fraction was subjected to thin layer chromatography fractionation and identification by HPLC-DAD-ESI-MSⁿ. Results showed that the condensed tannin procyanidin B2 was identified for the first time responsible of the antiviral activity of cypress.
... These findings could be related to EO components' potential to promise pharmacokinetics or physicochemical effects of antibiotics across bacterial membranes (e.g., improved solubility or bioavailability). Moreover, the combination of EOs and antibiotics could produce a multi-target effect in which constituents target several sites in the bacterial cell or targeting a specific resistance mechanism of bacteria 15 . This new strategy has been established to overcome drug resistance 16 . ...
The development of pathogenic Salmonella typhi strains resistant to several classes of antibiotics has become a worldwide main health care concern. Combinations of plant essential oils and drugs provide a promising approach to overcome drug resistance. This study investigates the potential antibacterial activity of EOs extracted from Rosmarinus officinalis, Salvia officinalis, and Thymus satureioides, individually and in combination with conventional antibiotics against S. typhi. The screening of 27 antibiotics was performed by the disc diffusion method, and the minimum inhibitory concentration of the selected antibiotics and EOs were determined by the broth microdilution method. At the same time, the interactions between EO and drugs were assessed by determining the fractional inhibitory concentration (FIC) using the diagonal measurement of n-way drug interactions method. The mechanism of antibacterial effect against S. typhi was evaluated by measuring the product of lipid peroxidation (MDA), potassium leakage from the bacteria cells, and scanning electron microscopy. Antibacterial screening indicated that nine antibiotics induced strong antibacterial activity against S. typhi with MIC values ranging from 2 to 85 µg/mL. Moreover, the EOs revealed an interesting effect against S. typhi, with MIC values ranging between 0.068 and 1.25 mg/mL. The combination of R. officinalis, T. satureioides EOs, and piperacillin/tazobactam provided a strong and reproducible synergistic effect against S. typhi. This combination seemed to amplify the antibacterial activity of EOs and antibiotics against S. typhi by increasing their potency in disrupting bacterial cell membrane integrity. These findings suggest that this combination could be a promising option for controlling the emergence of multidrug-resistant S. typhi.
... Moreover, their interaction may underlie the observed effects in additive or even synergistic ways, rather than one single compound. This assumption is supported by several studies, reviewed in [126][127][128]. Thus, further studies on bioactivities of single constituents, and especially their combinations, are necessary to find the underlying cause for healthspan benefits. ...
We examined the effects of the extracts from two traditional Chinese medicine plants, Cuscuta chinensis and Eucommia ulmoides, on the healthspan of the model organism Caenorhabditis elegans. C. chinensis increased the short-term memory and the mechanosensory response of aged C. elegans. Furthermore, both extracts improved the resistance towards oxidative stress, and decreased the intracellular level of reactive oxygen species. Chemical analyses of the extracts revealed the presence of several bioactive compounds such as chlorogenic acid, cinnamic acid, and quercetin. A fraction from the C. chinensis extract enriched in zingibroside R1 improved the lifespan, the survival after heat stress, and the locomotion in a manner similar to the full C. chinensis extract. Thus, zingibroside R1 could be (partly) responsible for the observed health benefits of C. chinensis. Furthermore, a hydroxygallic acid derivative and the sterol lipid 4-alpha-formyl-stigmasta-7,24(241)-dien-3-beta-ol are abundantly present in the C. chinensis extract and its most bioactive fraction, but hardly in E. ulmoides, making them good candidates to explain the overall healthspan benefits of C. chinensis compared to the specific positive effects on stress resistance by E. ulmoides. Our findings highlight the overall anti-aging effects of C. chinensis in C. elegans and provide first hints about the components responsible for these effects.
... Although discovering an active compound and describing its effects on pharmacological targets is useful in identifying lead compounds for drug discovery, investigating the effects of multiple compounds together and their synergistic effects may be more valuable. Multiple active ingredients of a single plant can simultaneously act on different cellular targets and together show a beneficial cumulative effect on a specific disease that may be superior to using each isolated component separately (111,112). In other words, these compounds can potentially act as a "polypill, " a concept in modern medicine that was first introduced by Wald and Low in 2003 as a single pill combining several drugs with fixed doses for the prevention of CVDs (113). ...
Cardiac arrhythmias, characterized by an irregular heartbeat, are associated with high mortality and morbidity. Because of the narrow therapeutic window of antiarrhythmic drugs (AADs), the management of arrhythmia is still challenging. Therefore, searching for new safe, and effective therapeutic options is unavoidable. In this study, the antiarrhythmic effects of medicinal plants and their active constituents were systematically reviewed to introduce some possible candidates for mechanism-based targeting of cardiac arrhythmias. PubMed, Embase, and Cochrane library were searched from inception to June 2021 to find the plant extracts, phytochemicals, and multi-component herbal preparations with antiarrhythmic activities. From 7337 identified results, 57 original studies consisting of 49 preclinical and eight clinical studies were finally included. Three plant extracts, eight multi-component herbal preparations, and 26 phytochemicals were found to have antiarrhythmic effects mostly mediated by affecting K+ channels, followed by modulating Ca2+ channels, upstream target pathways, Nav channels, gap junction channels, and autonomic receptors. The most investigated medicinal plants were Rhodiola crenulata and Vitis vinifera. Resveratrol, Oxymatrine, and Curcumin were the most studied phytochemicals found to have multiple mechanisms of antiarrhythmic action. This review emphasized the importance of research on the cardioprotective effect of medicinal plants and their bioactive compounds to guide the future development of new AADs. The most prevalent limitation of the studies was their unqualified methodology. Thus, future well-designed experimental and clinical studies are necessary to provide more reliable evidence.
... Thus, the presence of different compounds of Morchella extracts in varying amounts might be responsible for the anticancer effect on colon cancer cells. It is well established by numerous studies that the overall activity of natural extracts are due to additive and synergistic effects of different compounds [53][54][55][56]. In short, medicinal mushrooms produce several compounds that can act synergistically on cancer cells [57]. ...
In search of new anticancer agents, natural products including fungal compounds had been used as potential anticancer agents. The aim of this study was to investigate the anticancer activity of Morchella extracts against colon cancer cell line and UPLC-DAD-MS/MS analysis for the identification of compounds. The cytotoxic activity of the three Morchella species was examined for their anti-carcinogenic properties against the colon cancer cell lines. Phytochemical analyses were performed to screen Morchella for the presence of anti-cancerous compounds. All the fungal extracts inhibited the viability of colon cancer cells in a dose-dependent manner. Major compounds identified in Morchella included amino acid, fatty acid, sterol, flavonoid, peptide, glutamic acid, alkaloid, terpenoid, cyclopyrrolones, and coumarin. Several new compounds were detected among all the three Morchella extracts. In conclusion, all the fungal extracts showed potential inhibition of colon cancer cells and actively arrested the cell viability. It was concluded that the identified bioactive compounds might be the main constituents contributing to the anticancer activity of Morchella against human colon cancer cell lines. Thus, Morchella extracts are a potential source of bioactive compounds with cytotoxicity and could potentially be used as functional food supplements. Due to the nature of impressive findings, this investigation should be undertaken further to allow the studies to explore and develop a potential cytotoxic agents against colon cancer.
... Until a few years ago, the monotherapy has been the typical approach to address the infective diseases, but currently, there is enough evidence that combined antimicrobials or multitherapy are more effective than single-drug-based treatments [3]. ...
Resistance or multi-resistance to antibiotics by microorganisms has generated one of the most emerging problems of public health due to the loss of susceptibility to drugs. The World Health Organization (WHO) publishes the groups of bacteria considered antibiotic-resistant "priority pathogens", and for these microbes new antimicrobials or strategic combinations are urgently needed. A novel strategy to control resistance is the application of combined antimicrobials with synergistic effect to destroy priority pathogens, but also against parasites, fungi, even viral particles. Therefore, it is important to expand the scientific knowledge regarding to antimicrobial combinations and the pharmacological treatments to preserve human health because paradoxically, the former solution to the spread of infectious diseases found in antibiotics, is now the main cause of a new problem: antimicrobial resistance.
... The management of both clinical conditions involves non-pharmacological approaches like diet, physical activity, and smoke cessation, in addition to pharmacological approaches using different drugs. Low adherence to pharmacological treatment has been reported in many cases and may be ascribed to the appearance of adverse effects, as well as to the inadequate restoring of glycaemia and blood pressure, thus demanding the development of new agents (Wagner and Ulrich-Merzenich, 2009). Interestingly, 88% and 65% of the new chemical entities introduced in the therapy of diabetes and hypertension, respectively, in the last three decades are, somehow, attached to natural sources (Newman and Cragg, 2020). ...
Ethnopharmacological relevance
Hancornia speciosa Gomes (Apocynaceae) is a tree found in the Brazilian savannah, traditionally used to treat several diseases, including diabetes and hypertension. The anti-hypertensive activity of H. speciosa leaves (HSL) has been demonstrated in different models and is credited to the vasodilator effect and ACE (angiotensin-converting-enzyme) inhibition. The hypoglycemic effect of HSL has been also reported.
Aim of the study
To establish correlations between the biological activities elicited by H. speciosa extracts and the contents of their major compounds, aiming to define chemical markers related to the potential antihypertensive and antidiabetic effects of the species. Additionally, it aimed to isolate and characterize the chemical structure of a marker related to the α-glucosidase inhibitory effect.
Materials and methods
Extracts of a single batch of H. speciosa leaves were prepared by extraction with distinct solvents (ethanol/water in different proportions; methanol/ethyl acetate), employing percolation or static maceration as extraction techniques, at different time intervals. The contents of chlorogenic acid, rutin and FlavHS (a tri-O-glycoside of quercetin) were quantified by a developed and validated HPLC-PDA method. Bornesitol was determined by HPLC-PDA after derivatization with tosyl chloride, whereas total flavonoids were measured spectrophotometrically. Identification of other constituents in the extracts was performed by UPLC-DAD-ESI-MS/MS analysis. The vasorelaxant activity was assayed in rat aortic rings precontracted with phenylephrine, and α-glucosidase inhibition was tested in vitro. Principal component analysis (PCA) was employed to evaluate the contribution of each marker to the biological responses. Isolation of compound 1 was carried out by column chromatography and structure characterization was accomplished by NMR and UPLC-DAD-ESI-MS/MS analyses.
Results
The contents of the chemical markers (mean ± s.d. % w/w) varied significantly among the extracts, including total flavonoids (2.68 ± 0.14 to 5.28 ± 0.29), bornesitol (5.11 ± 0.26 to 7.75 ± 0.78), rutin (1.46 ± 0.06 to 1.97 ± 0.02), FlavHS (0.72 ± 0.05 to 0.94 ± 0.14) and chlorogenic acid (0.67 ± 0.09 to 0.91 ± 0.02). All extracts elicited vasorelaxant effect (pIC50 between 4.97 ± 0.22 to 6.48 ± 0.10) and α-glucosidase inhibition (pIC50 between 3.49 ± 0.21 to 4.03 ± 0.10). PCA disclosed positive correlations between the vasorelaxant effect and the contents of chlorogenic acid, rutin, total flavonoids, and FlavHS, whereas a negative correlation was found with bornesitol concentration. No significant correlation between α-glucosidase inhibition and the contents of the above-mentioned compounds was found. On the other hand, PCA carried out with the areas of the ten major peaks from the chromatograms disclosed positive correlations between a peak ascribed to co-eluted triterpenes and α-glucosidase inhibition. A triterpene was isolated and identified as 3-O-β-(3′-R-hydroxy)-hexadecanoil-lupeol.
Conclusion
According to PCA results, the vasorelaxant activity of H. speciosa extracts is related to flavonoids and chlorogenic acid, whereas the α-glucosidase inhibition is associated with lipophilic compounds, including esters of lupeol like 3-O-β-(3′-R-hydroxy)-hexadecanoil-lupeol, described for the first time for the species. These compounds can be selected as chemical markers for the quality control of H. speciosa plant drug and derived extracts.
... Plant extracts may contain many individual components that elicit a biological effect [66]. The physiological activity of plant extracts may be synergistic, additive, or antagonistic due to the mixture of various compounds [67][68][69]. Therefore, further studies are needed on the potential of 2-furoic acid to affect the bone health efficacy of HR1901-W. ...
Owing to global population aging, instances of bone metabolic diseases have increased. Consequently, interest in natural and functional plant food products for the prevention and treatment of osteoporosis is also increasing. In this study, we determine the potential therapeutic effects of Benincasa hispida extract (HR1901-W) on osteoblast and osteoclast differentiation. The potential preventive effects of Benincasa hispida in osteoporosis have not previously been reported. We identified and analyzed 2-furoic acid, a chemical component of HR1901-W. We evaluated whether HR1901-W promoted osteogenesis in the MC3T3-E1 cell line and whether it inhibited the differentiation of RAW 264.7 macrophage cells (osteoblast precursors). We observed that HR1901-W promoted significantly high dose-dependent proliferation and extracellular matrix mineralization in MC3T3-E1 cells. In fact, increased cell proliferation was found to be associated with increased protein expression of factors related to osteoblast differentiation, including alkaline phosphatase, osteocalcin, and runt-related transcription factor 2. On the other hand, macrophage colony-stimulating factor (10 ng/mL) and nuclear factor-κB ligand (100 ng/mL) treated differentiated RAW264.7 macrophages exhibited a significant reduction in tartrate-resistant acid phosphatase activity. Taken together, our results indicate that HR1901-W is a promising candidate of functional materials that regulate the balance between bone-forming osteoblasts and bone-resorbing osteoclasts to prevent osteoporosis.
... Unlike antibiotics or NSAIDs, herbal treatment options usually do not target specific pathogens or signaling-pathways. Rather, their efficacy is based on a multi-targeted approach [75][76][77]. For many common and recurring infections, such as urogenital infections [78,79] or infections of the upper and lower respiratory tract [80,81], effective and safe herbal treatment options are available. ...
Epithelial surfaces in humans are home to symbiotic microbes (i.e., microbiota) that influence the defensive function against pathogens depending on the health of the microbiota. Healthy microbiota contribute to the well-being of their host in general (e.g., via the gut-brain-axis), and their respective anatomical site in particular (e.g., oral, urogenital, skin or respiratory microbiota). Despite efforts towards a more responsible use of antibiotics, they are often prescribed for uncomplicated, self-limiting infections and can have a substantial negative impact on the gut microbiota. Treatment alternatives such as non-steroidal anti-inflammatory drugs may also influence the microbiota and thus can have lasting adverse effects. Herbal drugs offer a generally safe treatment option for uncomplicated infections of the urinary or respiratory tract. Additionally, their microbiota preserving properties allow for a more appropriate therapy of uncomplicated infections without contributing to an increase in antibiotic resistance or disturbing the gut microbiota. Here, herbal treatments may be a more appropriate therapy with a generally favorable safety profile.
... Alternatively, there may be pharmacokinetic or physicochemical interactions, such as enhancement of solubility or bioavailability. The most commonly reported test method for assessing interactions with antibiotics is the checkerboard assay with calculation of the FIC (fractional inhibitory concentration) index (Hemaiswarya et al., 2008;Wagner and Ulrich-Merzenich, 2009). ...
Essential oils (EOs) and their individual volatile organic constituents have been an inherent part of our civilization for thousands of years. They are widely used as fragrances in perfumes and cosmetics and contribute to a healthy diet, but also act as active ingredients of pharmaceutical products. Their antibacterial, antiviral, and anti-inflammatory properties have qualified EOs early on for both, the causal and symptomatic therapy of a number of diseases, but also for prevention. Obtained from natural, mostly plant materials, EOs constitute a typical example of a multicomponent mixture (more than one constituent substances, MOCS) with up to several hundreds of individual compounds, which in a sophisticated composition make up the property of a particular complete EO. The integrative use of EOs as MOCS will play a major role in human and veterinary medicine now and in the future and is already widely used in some cases, e.g. , in aromatherapy for the treatment of psychosomatic complaints, for inhalation in the treatment of respiratory diseases, or topically administered to manage adverse skin diseases. The diversity of molecules with different functionalities exhibits a broad range of multiple physical and chemical properties, which are the base of their multi-target activity as opposed to single isolated compounds. Whether and how such a broad-spectrum effect is reflected in natural mixtures and which kind of pharmacological potential they provide will be considered in the context of ONE Health in more detail in this review.
... The activity of plant extracts is due to the presence of secondary plant metabolites, as they play a role in both cell signaling and defense [123]. Single plant extract can act on multiple targets due to the presence of different constituents, which act by showing synergistic action [124]. In Table 1, we have summarized the plants and its active constituents responsible for antibacterial effects with the mechanism. ...
Bacteria cause various infectious diseases and cause millions of deaths each year. Bacteria are broadly classified based on the phenotypic and genotypic systems. Bacteria cause resistance mainly by Plasmids, Inactivation of antibiotics, Target site modification, Prevent drug uptake, Efflux pumps, and Biofilm. Plants have been used for thousands of years for their medicinal uses to treat various diseases. Secondary metabolites like terpenes, alkaloids, phenolic compounds, tannins, quinones, steroids, polyketides, aromatics, and, peptides are plant-derived compounds that possess antibacterial activity and decrease resistance by inhibition of biofilm formation, Efflux pump [EP] inhibitors, attenuating bacterial virulence, Immunomodulation activity. Use of phytoconstituents synergism, combination therapy (Bio-enhancers), herbal preparation benefit in antibacterial potential and decrease resistance.
... Using the disk-diffusion method, the interaction between two agents can be qualitatively checked, most often for antagonism. On the other hand, the broth microdilution checkerboard method is a two-dimensional, two-agent broth microdilution assay for testing the effect of chemical agents against a given microorganism [7][8][9][10][11]. With prior knowledge of the MIC values of the given agents, the checkerboard method is set up in order to check the bacteriostatic and/or bactericidal activity of antimicrobial agents. ...
Phage-antibiotic synergy is a promising therapeutic strategy, but there is no reliable method for synergism estimation. Although the time-kill curve assay is a gold standard, the method is not appropriate for fast and extensive screening of the synergy. The aim is to optimize the checkerboard method to determine phage-chemical agent interactions, to check its applicability by the time-kill curve method, and to examine whether the synergy can be obtained with both simultaneous and successive applications of these agents. In addition, the aim is to determine interactions of the Pseudomonas phage JG024 with ciprofloxacin, gentamicin, or ceftriaxone, as well as the Staphylococcus phage MSA6 and SES43300 with ciprofloxacin, gentamicin, and oxacillin. The results show that the optimized checkerboard method is reliable and that results correspond to those obtained by the time-kill curve. The synergy is detected with the phage JG024 and ciprofloxacin or ceftriaxone against Pseudomonas aeruginosa, and the phage SES43300 with ciprofloxacin against MRSA. The synergy was obtained after simultaneous applications, and in the case of P. aeruginosa, after application of the second agent with delay of one hour, indicating that simultaneous application is the best mode of synergy exploitation for therapy. The checkerboard method can be used for thorough clinical studies on synergy and in the future for personalized therapy when infections are caused by multiple resistant bacteria.
The health knowledge of indigenous/tribal peoples, developed globally over centuries through their intimate relationship with nature, is a highly understudied component of the present health system by health systems research or health policy research. While in practice, it is a living and dynamic stream in almost all parts of the world, the disciplines of public health and health systems research have tended to ignore it as a valuable resource. Ethnobotany and anthropology, as well as pharmacology and the pharmaceutical industry, have studied it and drawn upon it for both academic knowledge development and product development, for academic and commercial purposes. This paper will examine the contemporary relevance of indigenous health knowledge in India and argue its importance from a health systems perspective. Drawing from national and international debates and approaches adopted by various countries, it will examine the challenges to its continuing use and the various options available to protect and promote it.
Saikosaponin A (SSA) is an active ingredient of the Asian medicinal herb, Bupleurum falcatum L. When administered via the intraperitoneal (i.p.) route, SSA suppressed multiple addictive-like behaviours, including operant alcohol self-administration, in rodents. It is unknown whether these effects are retained after intragastric (i.g.) administration, a desirable prerequisite for a compound with therapeutic potential. To fill this gap, i.g. SSA (0, 50, and 100 mg/kg) was tested in Sardinian alcohol-preferring (sP) rats trained to lever-respond for oral alcohol. SSA reduced lever-responding and amount of self-administered alcohol. However, when compared to i.p. SSA, i.g. SSA resulted to be markedly less potent and effective, suggestive of reduced bioavailability after i.g. treatment. Finally, and in agreement with previous data on the suppressing effect of i.p. SSA on behaviours motivated by highly palatable foods, i.g. SSA (0, 50, and 100 mg/kg) reduced oral sucrose self-administration in a separate set of sP rats.
Resistant bacteria are emerging as a critical problem in the treatment of bacterial infections by neutralizing antibiotic activity. The development of new traditional mechanisms of antibiotics is not the optimal solution. A more reasonable approach may be to use relatively safe, plant-based compounds in combination with conventional antibiotics in an effort to increase their efficacy or restore their activity against resistant bacteria. We present our study of mixing Ricini Semen extract, or its constituent fatty acids, with oxacillin and testing the effects of each on the growth of methicillin-resistant Staphylococcus aureus. Changes in the cell membrane fluidity of methicillin-resistant S. aureus were found to be a major component of the mechanism of synergistic antibiotic activity of Ricini Semen extract and its constituent fatty acids. In our model, changes in cellular membrane fluidity disrupted the normal function of bacterial signaling membrane proteins BlaR1 and MecR1, which are known to detect oxacillin, and resulted in the incomplete expression of penicillin-binding proteins 2a and β-lactamase. Utilizing the mechanism presented in this study presents the possibility of developing a method for treating antibiotic-resistant bacteria using traditional antibiotics with plant-based compounds.
Antimicrobial research into the use of Melaleuca alternifolia essential oil has demonstrated broad-spectrum activity; however, much of the research published focuses on identifying the potential of this essential oil individually, rather than in combination for an enhanced antimicrobial effect. This study aimed to determine the antimicrobial activity of four essential oil combinations, all inclusive of M. alternifolia, against nine pathogens associated with the respiratory tract. The minimum inhibitory concentration assay was used to determine the antimicrobial activity of four essential oil combinations, M. alternifolia in combination with Cupressus sempervirens, Origanum majorana, Myrtus communis, and Origanum vulgare essential oils. The interactions between essential oil combinations were analyzed using isobolograms and SynergyFinder 2.0 software to visualize the synergistic potential at varied ratios. The antimicrobial activity of the different combinations of essential oils all demonstrated the ability to produce an enhanced antimicrobial effect compared to the essential oils when investigated independently. The findings of this study determined that isobolograms provide a more in-depth analysis of an essential oil combination interaction; however, the value of that interaction should be further quantified using computational modelling such as SynergyFinder. This study further supports the need for more studies where varied ratios of essential oils are investigated for antimicrobial potential.
Aedes aegypti L. (Diptera: Culicidae) is a vector for serious diseases in tropical regions. This pest is mainly controlled by commercial larvicides but the application of such products has led to environmental problems. Essential oils (EO) have been consistently reported as molecules with insecticidal activity and can be used to produce more environmentally friendly larvicides in the control of A. aegypti. In this study, the larvicidal effect of essential oils (EO) from the leaves of three Artemisia species was evaluated against A. aegypti. The oils were obtained from steam distillation and their chemical composition was determined by gas chromatography–mass spectrometry. The EO of Artemisia camphorata was the most active in the screening bioassay and presented LC50 and LC95 of 64.95 and 74.18 μg ml−1, respectively. In addition, we found that germacrene D‐4‐ol was the constituent responsible for the toxicity of this EO. Artemisia camphorata EO and its major constituent, germacrene D‐4‐ol, are promising for the development of natural larvicides against A. aegypti.
Since time immemorial, the Indian medical system, particularly Ayurveda and Siddha, has prioritised prevention and health over symptoms and drugs. Siddha, an Indian system of medicine, originated in ancient Thamilakam (currently Tamil Nadu, India). The combination of Inji (Zingiber officinale Roscoe), Sukku (Zingiber officinale Roscoe) and Kadukkai (Terminalia chebula Retz) as herbal therapy with numerous chemical constituents can be considered a better pharmacological approach than consuming individual ingredients and/or chemical constituents. This review is an attempt to summarize the evidence related to the anti-obesity and weight-lowering effects of ginger and T. chebula. The overall view shows an anti-hyperlipidemic effect of Zingiber officinale and Terminalia chebula.
Introduction and purpose: Nowadays, with the increase of resistance of bacteria against a wide range of chemical antibiotics, it has caused the failure of the treatment process and the use of medicinal plants has been welcomed. The purpose of this study is to determine the antibacterial properties of the ethanolic extract of Rosemary on standard
Nowadays, oral oil extracts of Cannabis represent the most relevant galenic plant-derived formulations employed in clinics. Nevertheless, the low and variable Δ9-tetrahydrocannabinol (THC) oral bioavailability due to hepatic first-pass metabolism and low solubility in biological fluids makes Cannabis pharmacological response highly unpredictable. In this scenario, new formulation strategies appear crucial to improve cannabinoids bioavailability and stability, administration comfort and patient compliance. Here, we present a nanoemulsion (NE) for the buccal administration of olive oil extract from a Cannabis sativa L. variety (Bedrocan®). A preliminary study was carried out on olive oil-based NE to identify the optimal formulation conditions to achieve a stable system. The Bedrocan®-loaded NE were then prepared and characterized for size, polydispersity index, stability upon delivery by the common buccal nebulizers.
THC content and release in simulated buccal fluids and permeation studies across porcine buccal mucosa. The Bedrocan® NEs ensured THC stability and solubility in the buccal medium as compared with the Cannabis oil extract. Furthermore, the nanoemulsification process led to a THC diffusion and absorption on buccal mucosa 20-folds and 2-folds higher than olive oil extract, respectively. Overall, the results suggest that Bedrocan® NE represents a novel formulation strategy for the buccal administration of Cannabis extracts that can overcome the limits associated with conventional oily formulations.
Pueraria lobatae (Willd) Ohwi is a traditional Chinese medicine used to treat alcohol intoxication, diabetes, cerebrovascular and cardiovascular diseases. Some of its active components include the flavonoids puerarin, daidzin, daidzein, and genistin. The therapeutic efficacy of these agents is hampered by their poor pharmacokinetic profiles (rapid systemic clearance, low oral bioavailability, short half-life) and physicochemical properties (such as poor aqueous solubility and stability). In the current study, chitosan/xanthan gum-based (hydroxypropyl methylcellulose-co-2-acrylamido-2-methylpropane sulfonic acid) hydrogels for the controlled release of Pueraria lobata-solid dispersion (SD) were successfully prepared and characterized. A total of 61 compounds were identified in the Pueraria lobatae-SD using UHPLC-Q-TOF-MS analysis. Hydrogel structure was confirmed by FTIR, XRD, TGA, DSC, and SEM showed a porous structure. Correlations between hydrogels structural properties was also investigated. The hydrogels showed higher swelling after 48 h at pH 1.2 (21.15 %) than pH 7.4 (15.91 %). In vitro drug release study demonstrated that drug release was maximum at pH 1.2 (63 %) compared to pH 7.4 (49 %) after 48 h. The gel fraction of the synthesized hydrogel was increased with the increase in the polymer and crosslinker concentrations. Furthermore, in vitro studies demonstrated that the developed hydrogels possess good antioxidant and antimicrobial properties.
Ethnopharmacological relevance
Lagenaria siceraria Stand. (Family: Cucurbitaceae), popularly known as bottle gourd, is traditionally used in Ayurvedic medicine as a food plant, especially in hypertension and obesity.
Aim of the study
Investigations were undertaken to assign novel lead combinations from this common food plant to multi-molecular modes of actions in the complex disease networks of obesity and hypertension. LC–MS/MS based metabolite screening, in-vivo high fat diet induced hyperlipidemia animal study and network pharmacology explorations of the mechanism of action for lipid lowering effects including a neighbourhood community approach for molecular combinations were performed.
Material and methods
Major chemical constituents of the fruits of LS (LSFE) were analysed by HPLC-DAD-MS/MS-QTOF. Wistar albino rats (n = 36), divided into 6 groups (n = 6) received either no treatment or a high-fat diet along with LSFE or Atorvastatin. Lipid profiles and biochemical parameters were evaluated. In silico cross-validated network analyses using different databases and Cytospace were applied.
Results
Profiling of LSFE revealed 18 major constituents: phenolic acids like p-Coumaric acid and Ferulic acid, the monolignolconferyl alcohol, the flavonoid glycosides hesperidin and apigenin-7-glucoside. Hyperlipidemic animals treated with LSFE (200 mg/kg, 400 mg/kg, 600 mg/kg) showed a significant improvement of their lipid profiles after 30 days of treatment. Network pharmacology analyses for the major 18 compounds revealed enrichment of the insulin and the ErbB signalling pathway. Novel target node combinations (e.g. AKR1C1, AGXT) including their connection to different pathways were identified in silico.
Conclusions
The combined in vivo and bioinformatics analyses propose that lead compounds of LSFE act in combination on relevant targets of hyperlipidemia. Perturbations of the IRS→Akt→Foxo1 cascade are predicted which suggest further clinical investigation towards development of safe natural alternative to manage hyperlipidemia.
Nootropics, also known as “smart drugs” are a diverse group of medicinal substances whose action improves human thinking, learning, and memory, especially in cases where these functions are impaired. This review provides an up-to-date overview of the potential effectiveness and importance of nootropics. Based on their nature and their effects, this heterogeneous group of drugs has been divided into four subgroups: classical nootropic compounds, substances increasing brain metabolism, cholinergic, and plants and their extracts with nootropic effects. Each subgroup of nootropics contains several main representatives, and for each one, its uses, indications, experimental treatments, dosage, and possible side effects and contraindications are discussed. For the nootropic plant extracts, there is also a brief description of each plant representative, its occurrence, history, and chemical composition of the medicinal part. Lastly, specific recommendations regarding the use of nootropics by both ill and healthy individuals are summarized.
Herbal medicines are botanical mixtures which present synergies of poly-pharmacological phyto-combinations are more prevalent in developing countries. They modulate the activity of target networks of underlying disease phenotypes are efficient than purified compounds due to favorable “synergistic” interactions. This chapter emphasis on methodical, systems pharmacology, network analysis and machine learning approaches for identifying elucidating the mechanisms that underlie their synergistic or antagonistic combinations and interactions. Different studies of synergistic interactions are considered along with various strategies based on network pharmacology approach. The chapter present a comprehensive account of evaluation strategies accelerate innovation in botanical research.
Natural products as antibiofilm agents have been increasingly reported for their promising application in different clinical and environmental settings. However, present crises are mainly dealing with pathogenic biofilms and its control strategy in clinical settings. Medicinal plants are traditionally used in the treatment of various ailments including fungal infections, and many phytocompounds find application in the treatment of pathogenic biofilms in oral and systemic infections. Since biofilms development is associated with enhanced protection of fungi against stress conditions, resistance to antifungal drug treatments as well as contributing in increase protection from the host defense system. In addition, biofilm associated chronic infections are difficult to treat because of the preseinse of multi-drug resistant bacteria. Further, limited efficacy against biofilms and their host toxicity has compelled the researchers for improved formulation and discovery of new natural antibiofilm agents. It is believed that natural product-based antibiofilm agents are safer than synthetic drugs. The present review mainly focuses on various antibiofilm agents from natural sources, i.e., phytochemicals, microbial origin, bio-surfactant, and natural peptide with special reference phytocompounds and its application against the most common fungal pathogen, Candida spp. This information could be exploited to improve the existing therapies using antibiofilm agents possessing different applications in health care and in the food industry, etc. in preventing pathogenic biofilms.
We previously reported that tea catechin shows bactericidal activity against various bacteria including methicillin resistant Staphylococcus aureus (MRSA) and that bactericidal catechin damages the lipid bilayer of bacterial cell membranes. Here we describe that oxacillin (MPIPC) shows antibacterial activity against MRSA in the presence of catechin below MIC. Twenty clinical isolates of MRSA were examined by a cup method. In the absence of catechin, MPIPC even at a concentration of 40 micrograms/ml did not show antibacterial activity against all isolates of MRSA. However, when catechin below MIC (25-100 micrograms/ml) was mixed with the agar medium, MPIPC (5-12.5 micrograms/ml) showed antibacterial activity against all MRSA isolates. By counting the numbers of viable bacteria in a broth culture, only MPIPC (5 micrograms/ml) or catechin (100 micrograms/ml) showed similar growth curves to the control. But addition of both MPIPC and catechin reduced the number of viable bacteria to 1/100-1/10000 after 24 hours of cultures. Besides MPIPC, in the presence of catechin below MIC methicillin (12.5 micrograms/ml), aminobenzylpenicillin (32 micrograms/ml), tetracycline (2.5 micrograms/ml), and chloramphenicol (12.5 micrograms/ml) showed antibacterial activities against multiple drug resistant MRSA to antibiotics mentioned above. These findings suggest a possible use of catechin in the treatment of MRSA infection.
The effects of components of aqueous licorice root extract (LE) on the pharmacokinetics of glycyrrhizin (G) and glycyrrhetic acid (GA) were investigated in rats and humans. The aim of this work was to define the role of pharmacokinetics in G toxicity. In the procedure, G and GA were detected in biological fluids by means of recently improved HPLC methods. Significantly lower G and GA plasma levels were found in rats and humans treated with LE compared to the levels obtained with those in which G alone was administered. The pharmacokinetic curves showed significant differences in the areas under the plasma-time curve (AUC), Cmax, and Tmax parameters. The data obtained from urine samples are in agreement with the above results and confirm a reduced bioavailability of G present in LE compared to pure G. This should be attributed to the interaction during intestinal absorption between the G constituent and the several components in LE. The modified bioavailability could explain the various clinical adverse effects resulting from the chronic oral administration of G alone as opposed to LE.
A commercially available extract of the aerial parts of Hypericum perforatum, LI 160, showed pronounced activity in selected animal bioassays. These include the forced swimming test (FST) and the tail suspension test, used to determine antidepressant activity, and tests indicating activity on the central nervous system, such as body temperature and ketamine induced sleeping time. The counteracting effects of drugs known to interfere with the central dopaminergic system strongly suggested that dopamine mediated activity is important for the activity of the extract. Dose-response experiments of the total extract and of fractions rich in flavonoids and napthodianthrones produced inverted U-shaped dose response curves.
Extracts of tea (Camellia sinensis) can reverse methicillin resistance in methicillin-resistant Staphylococcus aureus (MRSA) and also, to some extent, penicillin resistance in beta-lactamase-producing S. aureus. These phenomena are explained by prevention of PBP2' synthesis and inhibition of secretion of beta-lactamase, respectively. Synergy between beta-lactams and tea extracts were demonstrated by disc diffusion, chequerboard titration and growth curves. Partition chromatography of an extract of green tea on Sephadex LH-20 yielded several fractions, one of which contained a virtually pure compound that showed the above-mentioned activities, at concentrations above about 2 mg/L. The observed activities are novel and distinct from the previously reported direct antibacterial activity of tea extracts. Prevention of PBP2' synthesis offers an interesting possible new approach for the treatment of infections caused by MRSA.
In Staphylococcus aureus, in addition to mutations in the grl and gyr gene loci, multidrug efflux pumps like NorA contribute to decreased fluoroquinolone susceptibility. Efflux pumps can be inhibited by the plant alkaloid reserpine, which, at 20 mg/L, reduced sparfloxacin, moxifloxacin and ciprofloxacin IC50s and MICs by up to four-fold in 11, 21 and 48 of the 102 unrelated clinical isolates tested, respectively. The effect was less pronounced with the hydrophobic drugs sparfloxacin and moxifloxacin than with the hydrophilic drug ciprofloxacin and was stable in all 25 clonally related isolates tested.
Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5'-methoxyhydnocarpin (5'-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5'-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5'-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5'-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5'-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.
As part of a screening programme to identify modulators of multidrug efflux in methicillin resistant Staphyloccocus aureus (MRSA), we have validated our assays using the antihypertensive plant alkaloid reserpine. Clinical isolates of MRSA were resistant to tetracycline and shown to possess the tet(K) determinant which encodes for the Tet(K) efflux protein, which conferred high level resistance to tetracycline (MIC = 128 microg/mL). In the presence of reserpine, a known inhibitor of multidrug resistance (mdr) efflux pumps, this MIC was significantly reduced (MIC = 32 microg/mL).
It has been shown recently that a flavonoid fraction (fraction II) obtained from a crude extract of Hypericum perforatum (St. John's Wort) was remarkably active in the forced swimming test (FST). Fraction II was further separated using MLCCC to give fractions IIa and IIb. Both fractions proved to be active in the FST at different dosages. Further separation of fraction IIa by preparative HPLC yielded fraction IIa1 which mainly was composed of hyperoside, isoquercitrin, miquelianin and quercitrin, and fraction IIa2 which contained small amounts of hyperoside and astilbin, while most compounds were not known. Both fractions were active after acute treatment in the FST. Isolates obtained from these fractions including hyperoside, isoquercitrin, quercitrin, miquelianin, the aglycone quercetin and astilbin, were tested for activity in the FST. Except for quercetin, quercitrin and astilbin all compounds were active. To exclude false positive results in the FST the validity was checked in open field experiments and in the FST after 12 days of daily treatment.
The popularity of herbal medicines is high and continues to increase. At the same time, the safety issues related to herbal drugs continue to be ignored by the public, neglected by manufacturers and legislative bodies as well as under-researched by the medical professions. This is particularly true for the potential of interactions between herbal and synthetic medicines. This article represents an attempt to summarise anecdotal and experimental evidence regarding such interactions. Four independent literature searches were carried out to identify case reports and systematic clinical investigations of herb/drug interactions. Numerous case reports of herb/drug interactions were found. Several of these relate to interactions of herbal remedies with synthetic anticoagulants. Such anecdotal evidence, however, has its obvious limitations. Systematic investigations, which might overcome these limitations, are still extremely sparse. It is concluded that interactions between herbal medicines and synthetic drugs undoubtedly exist. Yet, at present, our knowledge of the subject is incomplete. In the interest of consumer safety, this area deserves more rigorous research.
The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6′,7′-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
In a multicentre, double-blind comparative study 132 patients with NYHA stage II stable heart failure were treated with 3 x 300 mg of the Crataegus extract LI 132 or 3 x 12.5 mg Captopril for 8 weeks. The confirmatory parameter was exercise tolerance at sitting bicycle ergometry on the days -7, 28 and 56. Secondary criteria were the pressure-rate product and a score for 5 typical symptoms. Exercise tolerance increased statistically significantly during the course of treatment in both treatment groups from 83 to 97 watts (LI 132) and from 83 to 99 watts (Captopril), respectively. The pressure-rate product was reduced in both groups. The incidence and severity of the symptoms also decreased by around 50% in both groups. None of the target parameters showed any significant difference between the Crataegus preparation and the reference drug. One patient treated with Captopril had to discontinue therapy on account of adverse effects. No serious adverse events were reported unter treatment with LI 132.
During the screening of compounds that potentiate the effect of antimicrobial agents against methicillin‐resistant Staphylococcus aureus (MRSA), we found that an extract of thyme (Thymus vulgaris L) leaves greatly reduced the minimum inhibitory concentration (MIC) of tetracycline against MRSA. We isolated the effective compound and identified it as baicalein (5, 6, 7‐trihydroxyflavone). One of the clinically isolated MRSA strains possessed tetK, a gene encoding active efflux pump for tetracycline. We examined the effect of baicalein on the efflux of tetracycline, using Escherichia coli KAM32/pTZ1252 carrying the tetK. The E. coli KAM32/pTZ1252 showed 8 to 16 times higher MIC than E. coli KAM32. We observed strong inhibition of transport of tetracycline by baicalein with membrane vesicles prepared from E. coli KAM32/pTZ1252. Baicalein also showed synergy with tetracycline in a MRSA strain that doesn't possess tetK, or with β‐lactams. Thus, mechanisms of the synergies seem to be versatile.
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
The effect of extracts and constituents of St. John's wort, Hypericum perforatum, at various CNS receptors were studied by radioligand binding techniques in order to determine a profile of pharmacological activity in vitro. Binding inhibition was examined for the G-protein coupled opioid, serotonin (5-HT), histamine, neurokinin and corticotropin releasing factor (CRF) receptors, for the steroid estrogen-a receptor and for the ligand-gated ionchannel GABA A receptor. Hypericin showed the most potent binding inhibiton of all tested constituents to human CRF 1 receptor with an IC 50 value of 300 nM. Preliminary GTPγ 35 S binding studies to CRF 1 coupled G-protein indicated an antagonistic action for hypericin. The acylphloroglucinole hyperforin failed to inhibit 125 I-astressin binding to hCRF 1 receptor up to 10 μM. Hyperforin inhibited binding to opioid and serotonin (5-HT) receptors at IC 50 values between 0.4 and 3 μM, while hypericin and pseu-dohypericin inhibited with weaker potency. The biflavonoid 13,118-biapigenin inhibited 3 H-estradiol binding to the estrogen-a receptor with an IC 50 value of 1 μM. The inhibition of 3H-muscimol binding to the GABA A receptor is likely to be exclusively due to GABA present in the extract. We therefore hypothesize that additive or synergistic actions of several ditsinct compounds may be responsible for the beneficial antidepressant effect of St. John's wort.
Der pflanzliche Extrakt stellt ein komplex zusammengesetztes Vielkomponentengemisch dar, das in Hauptwirkstoffe und Begleitstoffe unterteilt werden kann. Da pflanzliche Begleitstoffe die physikochemischen Eigenschaften und somit biopharmazeutische Parameter beeinflussen, werden sie als Koeffektoren bezeichnet. An zahlreichen Beispielen wird die Beeinflussung des Lösungsverhaltens und der Resorption von pflanzlichen Wirkstoffen durch Begleitstoffe und damit deren Bedeutung aufgezeigt.
The study of drug interactions presents investigators with questions about both experimental design and interpretation of results that easily can become complex and confusing. Among the advantages of the isobolographic method is that it leads to rational experimental design and renders both the descriptive and analytical considerations of results obtained relatively simple and straightforward. In particular, the descriptive use of the method is such that it permits experimenters to express compactly and unambiguously the salient features of the observed interaction.
The gradual transition from the long-standing use of monodrug therapy in classical medicine to the new concept of a multidrug and multitarget therapy has great implications for the research strategies of natural products chemistry and phytomedicine. The rationalization of the new strategies, however, requires great efforts in: standardization of mono- and multi- phytopreparations using all available high-tech methods; screening of extracts and their con- stituents by integration of modern molecular biological bioassays; and controlled, clinical studies, inclusive of pharmacokinetic and bioavailability investigations, aimed at evidence- based phytotherapy. The first results obtained in recent years are explained using several ex- amples of phytopharmacological and clinical studies. These show the therapeutic superiority of many plant extracts over single isolated constituents, as well as the bioequivalence of many phytopharmaceuticals with synthetic chemotherapeutics.
This study was undertaken to evaluate a possible effect of the extracts PY102 of Pygeum africanum (Hook), and UR 102 of Urtica dioica L. as well as their combination PHL-00801 (Prostatonin®) on the enzymes 5 α-reductase (5 α-RE) and aromatase (AR): Inhibition of 5 α-RE: Pygeum africanum extract PY 102, and Urtica dioica extract UR 102, inhibited the 5 α-RE activity in a concentration dependent manner. Whereas UR102 extract was only able to influence the enzyme activity at high concentrations (≥ 12mg/ml) and its ED(50) being calculated as 14.7mg/ml, the PY102 extract showed a much higher activity starting with low concentrations (0.1 mg/ml) its ED(50) being calculated as 0.78 mg/ml. When compared with the effects of UR 102, the combination of both extracts, PHL-00801 (Prostatonin®), led to a similar inhibition of the enzyme (ED(50) 14.15 mg/ml). Inhibition of AR: The PY 102 extract showed a concentration dependent and strong activity (ED(50) = 0.98 mg/ml). The activity of the UR 102 extract was also concentration dependent (ED(50) = 3.58 mg/ml). The combination of both extracts, PHL-00801 (Prostatonin®) showed a synergistic action and significantly (p = 0.05) increased the AR-inhibitory activity in concentrations as low as 0.1 mg/ml (ED(50) 0.24 mg/ml). These observations are an explanation for the beneficial effects of PHL-00801 (Prostatonin®) observed in the clinical studies on BPH.
Observational studies with preparations of St. John's wort have recorded an incidence of adverse events (AE) among those treated of between 1 and 3%. This is some ten times less than with synthetic antidepressants. The most common adverse events (1 per 300000 treated cases) among the spontaneous reports in the official register concern reactions of the skin exposed to light. Investigations in volunteers have shown that the threshold dose for an increased risk of photosensitisation is about 2-4 g/day of a usual commercial extract (equivalent to approximately 5-10 mg of the hypericin that causes the phenomenon). In view of the newly observed side effects and interactions, the following additional restrictions on use appear justified: as with all preparations in this group of indications, hypericum preparations must not be taken at the same time as other antidepressants. If co-medication with coumarin-type anticoagulants is unavoidable, it must only be undertaken provided the physician closely monitors clotting parameters. Co-medication with ciclosporin and indinavir, and for the time being, other protease inhibitors used in anti-HIV treatment, is absolutely contraindicated. Without exception, all preparations of St. John's wort must only be available through pharmacies.
Die Ergebnisse von 36 kontrollierten Studien zur Wirksamkeit von Johanniskrautextrakten wurden bis zum Herbst 2002 publiziert. Etwa 3.000 Patienten, fast ausschließlich solche mit leichten und mittelschweren depressiven Episoden, waren eingeschlossen. Die Studien ab 1990 werden zusammenfassend dargestellt. Die konfirmatorischen Prüfkriterien waren meistens die Score-Werte bzw. Response-Quoten der Hamilton-Depressions-Skala (HAMD).
Bei 10 Studien, basierend auf Extrakten, hergestellt mit Ethanol 50 % oder 60 % in Wasser (V/V), reichten die Dosierungen von 300 mg bis 1.050 mg Extrakt pro Tag. Bei 5 der 10 Studien wurde im Vergleich mit Placebo geprüft und in allen 5 Fällen die signifikante Überlegenheit der Hypericum-Extrakte nachgewiesen. Im Vergleich mit Imipramin oder Fluoxetin waren die Erfolge mit Hypericum gleichwertig oder sogar besser. Mit einem Extrakt, hergestellt mit 80 % Methanol in Wasser (V/V), wurden im Zeitraum nach 1990 die Ergebnisse von insgesamt 14 kontrollierten Studien publiziert, davon 7 im Vergleich mit Placebo, je 2 gegen Imipramin und Sertralin und je eine im Vergleich mit Maprotilin, Amitriptylin oder Lichttherapie. Die Dosierungen lagen im Bereich von 450 bis 1.200 mg Extrakt pro Tag. Die statistische Auswertung der Hamilton-Gesamt-Scores zeigte bei 5 von 7 Placebokontrollierten Studien signifikante Unterschiede zwischen dem Hypericum-Extrakt und Placebo. Bei 6 der 7 Vergleichs-Studien gegen insgesamt 4 synthetische Antidepressiva ergaben sich keine signifikanten Unterschiede im Behandlungserfolg.
Diese Ergebnisse der bisher vorliegenden Studien lassen keine wesentlichen Unterschiede in der Wirksamkeit der alkoholischen Extrakte erkennen. Bei Berücksichtigung aller Studienergebnisse ist somit davon auszugehen, dass die Schwelle der Wirksamkeit für einzelne Symptome und Beschwerden, die im Rahmen der depressiven Erkrankung auftreten, bei etwa 300 mg Extrakt pro Tag liegen könnte. In der Dosierung von etwa 500 bis 1.000 mg Extrakt pro Tag sind diese Johanniskraut-Präparate im Rahmen der ärztlich gestützten Therapie vergleichbar wirksam wie synthetische Antidepressiva. Diese Aussage gilt nur für leichte und mittelschwere depressive Episoden; bei schweren Depressionen sind Johanniskrautextrakte nicht ausreichend geprüft
Kakkon-to-ka-senkyu-shin'i (KSS), a Japanese-Sino medicine consists of nine crude drugs: pueraria, ephedra, cnidium, magnolia, cassia, peony, liquorice, ginger and jujube. It has long been used clinically in the treatment of nasal inflammation. The antiinflammatory effects of KSS, its related combinations, and component crude drugs were investigated on adjuvant-induced air pouch granuloma in mice. KSS was effective in inhibiting the inflammatory process of pouch fluid exudation, inflammatory cell migration and angiogenesis. Antiangiogenic effects were additive between (1) Keishi-to and the combination of pueraria + ephedra + cnidium + magnolia in KSS, (2) Keishi-to and the combination of pueraria + ephedra in Kakkon-to, and (3) cnidium and magnolia in the combination of cnidium + magnolia. Inhibitory effects on inflammatory cell migration were also additive between (4) cnidium and magnolia in the combination of cnidium + magnolia, and were potentiative between (5) Kakkon-to and the combination of cnidium + magnolia in KSS, (6) (pueraria+ephedra) and (cnidium + magnolia) in the combination of pueraria + ephedra + cnidium + magnolia, and (7) pueraria and ephedra in the combination of pueraria + ephedra. The main component crude drugs and combination in KSS for antiinflammation were magnolia and pueraria for angiogenesis, magnolia and ephedra for pouch fluid exudation, and pueraria + ephedra + cnidium + magnolia for inflammatory cell migration.
Carvacrol, (+)-carvone, thymol, and trans-cinnamaldehyde were tested for their inhibitory activity against Escherichia coli O157:H7 and Salmonella typhimurium. In addition, their toxicity to Photobacterium leiognathi was determined, utilizing a bioluminescence assay. Their effects on the cell surface were investigated by measuring the uptake of 1-N-phenylnaphthylamine (NPN), by measuring their sensitization of bacterial suspensions toward detergents and lysozyme, and by analyzing material released from cells upon treatment by these agents. Carvacrol, thymol, and trans-cinnamaldehyde inhibited E. coli and S. typhimurium at 1-3 mM, whereas (+)-carvone was less inhibitory. trans-Cinnamaldehyde was the most inhibitory component toward P. leiognathi. Carvacrol and thymol disintegrated the outer membrane and released outer membrane-associated material from the cells to the external medium; such release by (+)-carvone or trans-cinnamaldehyde was negligible. Of the tested components, carvacrol and thymol decreased the intracellular ATP pool off. coli and also increased extracellular ATP, indicating disruptive action on the cytoplasmic membrane.
In 30 physically and mentally healthy volunteers, 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-2H-1,4-benzodiazepin-2-one (temazepam, K 3917) was tested for its sleep inducing action, the subjective quality of sleep and any post-medication effects. Temazepam was orally administered at doses of 15, 20 or 30 mg in hard gelatin capsules or 20 mg in soft gelatin capsules. Nitrazepam (5 mg) and amylobarbitone sodium (100 mg) were used for comparison as well as a placebo. Temazepam showed very much the same effects as they are known from conventional 1,4-benzodiazepines except for its lack of impairment in early morning behavior following night time medication.
Severe and widespread atopic eczema often fails to respond adequately to currently available therapies. Following the observation of substantial benefit in patients receiving oral treatment with daily decoctions of traditional Chinese medicinal plants, we undertook a placebo-controlled double-blind trial of a specific prescription formulated for widespread non-exudative atopic eczema. Forty-seven children were given active treatment and placebo in random order, each for 8 weeks, with an intervening 4-week wash-out period. Thirty-seven children tolerated the treatment and completed the study. Response to active treatment was superior to response to placebo, and was clinically valuable. There was no evidence of haematological, renal or hepatic toxicity. These findings anticipate a wider therapeutic potential for traditional Chinese medicinal plants in this disease, and other skin diseases.
We examined tea extract, (-) epigallocatechin gallate (EGCg) and theaflavin digallate (TF3) for their antifungal and fungicidal activities against Trichophyton mentagrophytes, T. rubrum, Candida albicans and Cryptococcus neoformans. Tea extract (2.5%) inhibited completely the growth of both T. mentagrophytes and T. rubrum. EGCg at 2.5 mg/ml failed to inhibit their growth, whereas TF3 at 0.5 mg/ml inhibited the growth. EGCg (1mg/ml) showed no fungicidal activity against Trichophyton. TF3 (1mg/ml) killed Trichophyton by a long time contact (72-96 hrs). Tea extract showed a fungicidal activity against Trichophyton in a dose- and contact time-dependent manner. It did not inhibit the growth of C. albicans, but at a high concentration, inhibited slightly the growth of C. neoformans. It had no fungicidal activity against C. albicans or C. neoformans.
Antagonism of the effects of platelet activating factor (PAF) by the ginkgolide mixture BN 52063 was assessed in a double-blind, placebo-controlled, crossover study in 6 normal subjects. Weal and flare responses to 400 ng PAF, examined 2 h after ingestion of BN 52063 (80 mg, 120 mg) were inhibited in a dose-related manner. After 120 mg the flare area was reduced by a mean 62.4% (p less than 0.005) and the weal volume by a mean 60% (p less than 0.05). Bot