Metagenics Bactrex Technical Data

Metagenics Bactrex Technical Data

This Information is intended as an information resource for Practitioners, and should not be substituted for medical advice, diagnosis or treatment.

See Small Intestinal Bacterial Control

Herbs and Nutrients That May Assist

Phellodendron - Phellodendron amurense, bark, dry

Oregano - Origanum vulgare, essential oil

Clove - Syzygium aromaticum, essential oil

Thyme - Thymus vulgaris, essential oil

Actions

• Maintain upper digestive health
• Antimicrobial

Clinical Applications

• Small intestinal bacterial overgrowth (SIBO)
• Small intestinal fungal overgrowth (SIFO)

Dosing Considerations*

• Pregnancy
• Breastfeeding

*Dosing regimens should be determined by appropriate assessment and monitoring.

Potent antimicrobial herbs such as phellodendron and the essential oils of oregano, thyme and clove have shown specificity against both bacterial and fungal overgrowth. These ingredients are highly efficacious in infectious conditions not only for their antimicrobial actions, but also due to their ability to penetrate biofilms to overcome microbial resistance. Biofilms provide a haven for potentially pathogenic bacterial species (Figure 1), therefore a mechanism able to bypass their defences is key to efficacious antimicrobial activity.

The use of antimicrobial herbs for bacterial infections has other advantages. A major one is that herbal antimicrobials contain multiple compounds, therefore are able to deliver a range of actions that target pathogens.1 In addition, bitter compounds, also found in herbal antimicrobials, have been shown to strengthen digestion and motility, simultaneously supporting digestion, whilst eliminating pathogens.2 In this way antimicrobial herbs help maintain intestinal integrity and function.3 Moreover, these herbs exert anti-inflammatory and antioxidant properties,4 further supporting both the health and integrity of the gastrointestinal tract (GIT).

Medicinal herbs, such as phellodendron, along with the essential oils of oregano, thyme and clove provide a therapeutic alternative for patients with suspected or confirmed fungal (e.g. Candidiasis) or bacterial infections, including small intestinal bacterial overgrowth (SIBO), and other infections.

Figure 1: The stages of biofilm development.

Key: A. Initial attachment - free floating organisms attach to a biomaterial surface; B. Irreversible attachment - cells multiply, forming micro-colonies and excrete extracellular polymeric substances; C. Maturation I - biofilm is formed and bacteria form multi-layered clusters; D. Maturation II - three-dimensional growth and further maturation of the biofilm; E. Dispersion – the biofilm reaches critical mass and disperses bacteria to colonise other areas.

Background Technical Information

There are times when direct action to manipulate the composition of the intestinal microbiome is indicated, such as presentations signifying a fungal and/or bacterial infection. It is in these cases herbal medicine offers a range of very effective antimicrobials.

Phellodendron has also been found to be effective against bacteria that are commonly found in high numbers in cases of small intestinal bacterial overgrowth (SIBO).

Within the genus of Candida there are approximately 150- 200 species recognised.5 Being an invasive opportunistic microorganism, Candida albicans is able to transform from a harmless commensal to a pathobiont. This opportunistic fungus possesses many putative virulent traits that contribute to its survival and persistence within the host.6 Candida accounts for 75% of fungal infections in humans and has been found to commonly colonise the human GIT as a component of the resident microbiota.7,8 Whilst the presence of Candida is generally benign in most healthy individuals, recent studies show that a high level of Candida colonisation is associated with several diseases of the GIT. Further, results from animal models note that Candida colonisation delays the healing of inflammatory lesions and that inflammation promotes further colonisation. These effects create a vicious cycle in which low-level inflammation promotes fungal colonisation and fungal colonisation promotes further inflammation.9

Fungal and/or bacterial associated GIT disorders have been fraught with controversy due to the various symptoms and associated differential diagnoses. One such medically recognised condition is SIBO, which is predominantly defined according to the number and often type of culturable bacteria located within the small intestine.10 A consensus on the exact definition of SIBO has been difficult to establish, however SIBO can be broadly defined as excessive bacteria in the small intestine.11 What has been noted is that SIBO is a challenge to diagnose as it is associated with a myriad of GIT symptoms, including altered anatomical function, motility, intestinal pH and immunity, through to more systemic inflammatory presentations. Similarly, testing is not entirely clear-cut as the current ‘gold standard’ for diagnosis involves an invasive endoscopic collection of duodenal fluid. Even then, elevated bacterial counts cannot rule out other gastrointestinal disease.12

Some of the characteristic presentations of SIBO include steatorrhea, abdominal bloating and weight loss, however this trilogy is, in fact, an infrequent clinical presentation. More commonly, patients with SIBO report bloating, flatulence, abdominal pain and diarrhoea. This non-specific presentation makes for a broad differential diagnosis and difficulty in deciding a clinical verdict. Therefore, it can prove advantageous to consider antimicrobial therapy in suspected cases of:

• Gut pathogen detection (e.g. parasites, yeasts);
• “Never been well since” gastroenteritis;
• A positive SIBO test;
• Symptoms indicative of SIBO, including irritable bowel syndrome (IBS), fibromyalgia and fatigue;
• Symptoms of bloating and/or constipation (worse for fibre);
• Symptoms exacerbated with clinically-proven probiotics;
• Stubborn, plateaued gut cases; and/or
• Structural issues affecting normal motility (e.g. adhesions, endometriosis, and post-gastric surgery).

Actions

Maintain Upper Digestive Health

Herbs and their essential oils have been renowned for their ability to attenuate a conglomerate of digestive symptoms via their beneficial actions upon the digestive system and their valued anti-bacterial actions. Phellodendron, one of the fundamental herbs of traditional Chinese medicine (TCM) for the treatment of diarrhoea and dysentery,13 attenuates ion transport via the intestinal epithelium, supporting symptom relief.14 More recently modern pharmacological research has specified that phellodendron has the ability to eliminate pathogenic microorganisms from within the GIT.15 To date numerous studies have been conducted around the world with the aim of confirming the antimicrobial efficiency and/or the properties of antimicrobial preparations. In fact, antimicrobials used to treat bacterial infections caused by multiple drug resistant strains are becoming more common in the clinical setting.16

Current scientific findings reveal the biochemical activities of phellodendron can, in fact, be attributed to three key medicinal components: berberine, phellodendrine and palmatine.

Some research has accredited berberine as the single biologically active constituent of phellodendron.17 However, current scientific findings reveal the biochemical activities of phellodendron can, in fact, be attributed to three key medicinal components: berberine, phellodendrine and palmatine.18 These constituents have shown efficacy in the treatment of inflammation, gastroenteritis, abdominal pain, and diarrhoea. These effects are due to fungicidal, bactericidal and antimicrobial activity against unicellular pathogenic agents.19 Furthermore, phellodendron has been shown to exhibit minimal toxicity in normal tissues.20 With such a wide and efficient array of effects, it comes as no surprise that phellodendron is one of the most therapeutically indicated herbal formulations for GIT health.

Oregano essential oil (OEO) is concentrated from natural plant products containing volatile aromatic compounds. Therapeutically, these volatile compounds exert biological actions including antimicrobial, anti-inflammatory, and antioxidant activities,21 which work to support healthy digestion, assisting in loss of appetite and reducing the effects of gaseous abdominal bloating.22,23

Of note is that the composition of intestinal microbiota influences the function and integrity of the GIT,24 including gut barrier integrity. OEO supplementation offers not only a positive impact upon endotoxin concentrations,25 but anti-inflammatory and antioxidant qualities.26 These latter actions help moderate gut barrier defects by supporting the tight junction (TJ) proteins occludin and zonulin occlidens-1,27 evidence signifying the dual healing approach OEO offers the intestinal barrier,28 which can become disrupted in the presence of upper intestinal microbiome imbalance.

Similarly, bitter principles present in Thymus vulgaris (thyme) also support digestive health.29 Used remedially, thyme provides relief from dyspepsia, gastritis, diarrhoea and flatulence, as well as offering anthelmintic activity.30 Thymol (a monoterpene) is an active constituent of thyme. It has shown clinical promise as an immunostimulant, antispasmodic and digestive stimulant; the latter of which is helpful where there is a ‘sluggish’ digestion.31 Clove provides additional GIT support via its carminative and antispasmodic actions, which helps to relieve flatulence and supports healthy gastrointestinal function.32 The traditional uses of clove includes intestinal parasites, as well as for dyspepsia, diarrhoea, intestinal spasm and flatulence.33,34

Eugenol (from clove) has exhibited a wide spectrum of antimicrobial activity, inhibiting the growth of selected GIT pathogens, notably Salmonella enterica, Clostridicum difficile, Escherichia coli and Candida albicans.

Antimicrobial

Due to the ever-increasing resistance of GIT pathogens to conventional treatment strategies, such as antibiotics, alternative microbial agents are clinically required. It has been shown that antimicrobials offer six potential mechanisms of action:

1. Disintegration of the cytoplasmic membrane;
2. Interaction with membrane proteins (ATPases);
3. Disturbance of the outer membrane of gram negative bacteria, leading to apoptosis;
4. Destabilisation of the proton motive force with leakage of ions, resulting in cellular disintegration;
5. Coagulation of the cell content; and
6. Inhibition of enzyme synthesis.35

Phellodendron and the essential oils oregano, clove and thyme have all been found to be potential sources of novel antimicrobial compounds able to act against bacterial pathogens. The latter three essential oils are able to do this due to constituents containing phenolic structures: carvacrol, eugenol and thymol respectively.36 Amongst these constituents, thymol was found to be the most efficacious, (followed by carvacrol) at disrupting cell wall membranes.37 In addition, eugenol (from clove) has exhibited a wide spectrum of antimicrobial activity,38 inhibiting the growth of selected GIT pathogens, notably Salmonella enterica, Clostridium difficile, Escherichia coli and Candida albicans.39

[Phellodendron’s] ability to interrupt microbial metabolism also accounts for the inhibition of biofilm formation, helping to break the cycle of bacterial persistence in chronic infections.

Phellodendron has been shown to have potent antimicrobial and anti-inflammatory activity, due to berberine’s activity against stealth pathogens; inhibiting bacterial protein and DNA synthesis of cell wall deficient microbes.40,41 This ability to interrupt microbial metabolism also accounts for the inhibition of biofilm formation,42 helping to break the cycle of bacterial persistence in chronic infections. Furthermore, phellodendron provokes growth inhibitory effects in vitro on specific bacteria found within the human intestinal tract, including C. perfringens, E. coli and S. mutans.43 In addition to phellodendrons antimicrobial effects, berberine has shown other beneficial activity against filamentous fungi, as well as yeasts such as Candida strains.44,45,46 These mechanisms include the inhibition of sterol and cell wall biosynthesis.47

OEO has been shown to inhibit the growth of several pathogenic bacteria and yeast,48 with in vitro research observing oregano’s antimicrobial activity against strains of Escherichia coli (including enterotoxigenic E. coli) and Salmonella spp. (including S. enteritidis and S. typhimurium).49 The enhanced inhibitory capacity demonstrated by OEO was attributed to the higher percentage of its phenolic components: carvacrol and thymol,50 which disrupted the cell membrane, causing cell wall permeability and disintegration.51 Further to this, oregano has been shown to inhibit the growth of preformed biofilms against a variety of pathogens, helping to eradicate persistent, recurrent infections, specifically those that are resistant to antibiotics.52

Eugenol works to denature cellular proteins and react with cell membrane phospholipids via rapid ATPase inhibition and release, changing cellular permeability and inhibiting replication.

The essential oil of clove has well established antiseptic properties due to a high percentage of eugenol.53 Clove has shown strong antibacterial activity against a range of gram positive and gram negative bacterial strains, including E. coli, Staphylococcus aureus, Klebsiella pnuemoniae and Proteus vulgaris.54 Eugenol denatures cellular proteins, and reacts with cell membrane phospholipids via rapid ATPase inhibition and release,55 changing their permeability and inhibiting replication.56 These actions have proven effective in combating several fungal and microbial pathogens including C. albicans (Figure 2).57 Collectively demonstrating clove’s broad-spectrum antimicrobial capabilities.

Figure 2: Graph of growth curve presented as log10 CFU/ml vs. incubation time for Candida albicans treated with different concentrations of eugenol.58

Both the extract and essential oils of thyme exhibit antibacterial activity against a wide range of bacteria. Thymol and carvacrol constituents provide therapeutic efficacy against clinically relevant bacterial strains of Staphylococcus, Enterococcus, Escherichia and Pseudomonas genera, Clostridium botulinum, Haemophilus influenza, Klebsiella pneumonia, S. typhi, Brochothrix thermosphacta and P. acnes.59

Herbal antimicrobials, taken for four weeks, were found to be more effective for SIBO (resolving 46% of cases), than two weeks of antibiotics (resolving only 34% of cases).

Thyme’s ability to also penetrate the extracellular matrix, cell membrane or cell wall of bacterial biofilms60 provides a useful mechanism when the goal is pathogenic eradication. Another traditional use of thyme is in the treatment of intestinal parasitic infections; including roundworm, threadworm, hookworm and tapeworm.61

Clinical Applications

Small Intestinal Fungal Overgrowth

Multiple studies have reported upon the significant antifungal effects of phellodendron extracts to reduce the growth rate of Candida albican strains.62,63One such study exposed eleven Candida strains (isolated from blood samples) to increasing berberine concentrations for 24 hours (the minimum inhibitory concentration ranged from 8 to 16 μg/ml). Results revealed all eleven Candida strains were inhibited by berberine.64 Subsequent cytometeric analysis established that berberine administration caused alterations to the integrity of the plasma, mitochondrial membrane and DNA of Candida cells, which led to cell membrane instability and cell death. In addition, assessment of biofilm-forming isolates following berberine treatment showed statistically significant reductions in Candida biofilm cell activity.65 Evidence such as this highlights berberines ability to induce cell membrane damage and impair cellular function in resistant Candida stains; mechanism that resulted in increased cell membrane permeability and cell death.

Further to this, OEO and its constituent carvacrol, have demonstrated positive antifungal effects against C. albicans, both in vitro and in an animal Candidiasis model.66,67 In addition, the antifungal constituents of thyme show specific activity against Candida spp in vitro.68,69

Small Intestinal Bacterial Overgrowth

Medical consensus agrees that non-absorbable antibiotic therapy is an effective way to resolve gut symptoms and reverse the positive test results potentially produced by SIBO.

Controversially, a 2014 comparative trial revealed interesting results. In this trial, herbal antimicrobials, taken for four weeks, were found to be more effective for SIBO (resolving 46% of cases), than two weeks of antibiotics (resolving only 34% of cases). Furthermore, the antibiotic non-responders went on to achieve similar benefits of 57% to 60% using either herbal antimicrobials or triple antibiotic therapy. Interestingly, some of the patients experienced significant adverse effects when receiving triple antibiotic therapy, whilst patients receiving herbal therapy experienced no noteworthy adverse effects.70 These results support the use of herbal therapy as an innovative approach in the management of SIBO.

Testing for SIBO

Digestive microbes can significantly influence gut motility due to fermentation gases they produce. Methane is a gaseous by-product of intestinal bacteria, and has the ability to slow small intestinal transit time and appears to do so by augmenting small bowel contractile activity.* To date, most research has focused on the effects of hydrogen and methane production, which can be measured using breath testing. Whilst not the gold standard, a reliable diagnosis of SIBO can be made by consuming either a lactulose or glucose solution, then measuring the presence of fermentation gases on the breath after set timeframes; a positive hydrogen breath test indicating SIBO.*

 

Phellodendron has also been found to be effective against bacteria that are commonly found in high numbers in cases of SIBO. One in vitro study found berberine strongly inhibited the growth of Clostridium perfringens, and moderately inhibited the growth of Escherichia coli and Streptococcus mutans.71 These results infer that the growth inhibiting activity of phellodendron can be useful as a preventative agent against diseases caused by potentially pathogenic intestinal bacteria.

In another trial, Oregano was administered orally to 14 adult patients whose stools tested positive for enteric parasites: Blastocystis hominis, Entamoeba hartmanni and Endolimax nana. After six weeks of supplementation with 600 mg/day of oregano, participants were found to have a complete disappearance of Entamoeba hartmanni (n=4), Endolimax nana (n=1), and Blastocystis hominis (n=8). In addition, Blastocystis hominis scores declined in an additional three cases. Patients further reported an amelioration of symptoms including bloating, abdominal pain, diarrhoea, constipation and fatigue.72 This study offers support for therapeutic use of oregano in humans for parasites.

Another investigation focusing on the antibacterial potential of an infusion and essential oil of oregano against 11 gram-positive bacterial isolates (belonging to 23 different species) also returned positive results. This study confirmed that both an infusion and the essential oil of oregano exhibit antibacterial activity against Staphylococcus saprophyticus, S. aureus, Micrococcus roseus, M. kristinae, M. nishinomiyaensis, M. lylae, M. luteus, M. sedentarius, M. varians, Bacillus megaterium, B. thuringiensis, B. alvei, B. circulans, B. brevis, B. coagulans, B. pumilus, B. laterosporus, B. polymyxa, B. macerans, B. subtilis, B. firmus, B. cereus and B. lichiniformis. The oregano infusion exhibited maximum activity against B. laterosporus (17.5 mm mean zone of inhibition ± 1.5 Standard deviation[SD]) followed by B. polymyxa (17.0 mm ± 2.0 SD). Additionally, the essential oil exhibited maximum activity against S. saprophyticus (16.8 mm ± 1.8 SD) followed by B. circulans (14.5 mm ± 0.5 SD).73 This research notes positive results for the use of oregano as an antibacterial.

Enteric-coated capsules

In situations of small intestinal microbial imbalance, using an enteric coated capsule may enhance efficacy. Enteric coatings resist digestion in the stomach, releasing their contents after approximately 2 to 3 hours, enabling delivery of active ingredients directly into the small intestine.

These studies help substantiate the use of herbal antimicrobials as a viable option in cases of bacterial overgrowth, noting they can be as effective as conventional approaches. That said, the use of herbal antimicrobials may require a longer prescription time (four weeks herbal therapy compared to two weeks of antibiotic therapy). Due to their safety profile, tolerability and efficacy, they are particularly indicated for presentations of SIBO and C. albicans infection, as well as for use in other pathogen elimination treatment plans.74

 

Clinical Focus/Additional Information

• Medications metabolised by cytochrome P450 3A4, may be inhibited by Phellodendron amurense. This could mean that the drug serum levels increase. This combination may allow a reduction in the dosage of drug, under supervision.
• Long-term use: Clove leaf oil may irritate mucous membranes if taken long-term,75 therefore it is not recommended for long-term use.

Cautions and Contraindications

Contraindications

Allergy or hypersensitivity:

• Avoid if allergic or sensitive to Phellodendron amurense.76 There has been one case of a rash from ingestion of the herb.77,78,79
• Avoid if allergic or sensitive to any plants in the Lamiaceae family. Oregano can cause reactions in people allergic to other plants in the Lamiaceae family, including thyme, basil, hyssop, lavender, marjoram, mint, and sage.80,81,82
• Avoid if allergic or sensitive to any plants in the Myrtaceae family.83
• Avoid if allergic or sensitive to any plants in the Lamiaceae family. Cross-reactivity to oregano and other Lamiaceae species has been reported in an individual allergic to thyme.84,85

Moderate Level Cautions    

Anticoagulant/Antiplatelet Drugs:

• The eugenol content of clove oil has antiplatelet effects. Concomitant use alongside anticoagulant or antiplatelet agents such as aspirin and warfarin might increase the risk of bleeding.86,87,88 Use with caution and monitor INR in patients taking warfarin.
• Warfarin: This anticoagulant medication is metabolised by cytochrome P450 3A4,89,90 and has a narrow therapeutic range.91,92,93 Phellodendron amurense inhibits the activity of this enzyme,94 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor INR levels.
• Thyme oil has a potential antiplatelet effect. Concomitant use alongside anticoagulant or antiplatelet agents such as aspirin and warfarin might increase the risk of bleeding.95,96 Use with caution and monitor INR in patients taking warfarin.
• Bleeding disorders: Due to the anticoagulant properties of thyme oil,97,98 and clove oil,99,100,101 there have been safety concerns with regards to the risk of increased bleeding tendency in patients with bleeding disorders. Although this theoretical possibility is not reflected functionally in human studies, it still warrants caution in situations which carry a high risk of bleeding, such as haemorrhagic stroke and postoperative events.102,103,104

Low Level Cautions

• Amiodarone: This class III anti-arrhythmic drug is metabolised by cytochrome P450 3A4,105,106 and has a narrow therapeutic range.107,108 Phellodendron amurense inhibits the activity of this enzyme,109 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Atazanavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.110,111 Phellodendron amurense inhibits the activity of this enzyme,112 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Carbamazepine: This anti-epileptic, neurotropic and psychotropic drug is metabolised by cytochrome P450 3A4,113,114 and has a narrow therapeutic range.115,116 Phellodendron amurense inhibits the activity of this enzyme,117 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Cyclosporine (ciclosporin): This potent immunosuppressant anti-rejection drug is metabolised by cytochrome P450 3A4,118,119 and has a narrow therapeutic range.120,121 Phellodendron amurense inhibits the activity of this enzyme,122 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and consult the patient’s specialist if prescribed to manage organ transplant.
• Darunavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.123,124 Phellodendron amurense inhibits the activity of this enzyme,125 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Delavirdine: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.126,127 Phellodendron amurense inhibits the activity of this enzyme,128 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Digoxin: This cardiac glycoside drug is metabolised by cytochrome P450 3A4,129,130 and has a narrow therapeutic range.131,132 Phellodendron amurense inhibits the activity of this enzyme,133 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and only under medical supervision.
• Disopyramide: This class IA anti-arrhythmic drug is metabolised by cytochrome P450 3A4,134,135 and has a narrow therapeutic range.136,137,138 Phellodendron amurense inhibits the activity of this enzyme,139 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Efavirenz: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.140,141 Phellodendron amurense inhibits the activity of this enzyme,142 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Ethosuximide: This anticonvulsant drug is metabolised by cytochrome P450 3A4,143,144 and has a narrow therapeutic range.145,146 Phellodendron amurense inhibits the activity of this enzyme,147 which theoretically may affect the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Etravirine: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.148,149 Phellodendron amurense inhibits the activity of this enzyme,150 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Fosamprenavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.151,152 Phellodendron amurense inhibits the activity of this enzyme,153 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Indinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.154,155 Phellodendron amurense inhibits the activity of this enzyme,156 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Levothyroxine: This thyroid hormone is a substrate for cytochrome P450 3A4,157,158 and has a narrow therapeutic range.159,160 Phellodendron amurense inhibits the activity of this enzyme,161 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Lopinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.162,163 Phellodendron amurense inhibits the activity of this enzyme,164 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Mucous membrane irritant: Clove leaf165 and thyme166 may irritate mucous membranes if taken long-term. These oils are therefore not recommended to be taken long-term.
• Nelfinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.167,168 Phellodendron amurense inhibits the activity of this enzyme,169 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Nevirapine: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.170,171 Phellodendron amurense inhibits the activity of this enzyme,172 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Phenobarbital (phenobarbitone): This barbiturate is a widely used anti-seizure medication that is metabolised by cytochrome P450 3A4,173,174 and has a narrow therapeutic range.175,176 Phellodendron amurense inhibits the activity of this enzyme,177 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Phenytoin: This anti-epileptic, anticonvulsant and anti-seizure drug is metabolised by cytochrome P450 3A4,178,179 and has a narrow therapeutic range.180,181,182 Phellodendron amurense inhibits the activity of this enzyme,183 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Propafenone: This class IC anti-arrhythmic drug is metabolised by cytochrome P450 3A4,184,185 and has a narrow therapeutic range.186,187 Phellodendron amurense inhibits the activity of this enzyme,188 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and only under medical supervision.
• Quinidine: This anti-malarial and class IA anti-arrhythmic drug is metabolised by cytochrome P450 3A4,189,190 and has a narrow therapeutic range.191,192 Phellodendron amurense inhibits the activity of this enzyme,193 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Rifampicin (rifampin): This antibiotic drug is metabolised by cytochrome P450 3A4,194,195 and has a narrow therapeutic range.196,197 Phellodendron amurense inhibits the activity of this enzyme,198 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Ritonavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.199,200 Phellodendron amurense inhibits the activity of this enzyme,201 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Saquinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.202,203 Phellodendron amurense inhibits the activity of this enzyme,204 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Sirolimus (rapamycin): This immunosuppressant anti-rejection drug is metabolised by cytochrome P450 3A4,205,206 and has a narrow therapeutic range.207,208 Phellodendron amurense inhibits the activity of this enzyme,209 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and consult the patient’s specialist if prescribed to manage organ transplantation.
• Tacrolimus: This potent immunosuppressant anti-rejection drug is metabolised by cytochrome P450 3A4,210,211 and has a narrow therapeutic range.212,213 Phellodendron amurense inhibits the activity of this enzyme,214 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and consult the patient’s specialist if prescribed to manage organ transplant.
• Theophylline: This methylxanthine drug is used for acute relief in respiratory diseases such as COPD and asthma. This drug is metabolised by cytochrome P450 3A4,215,216 and has a narrow therapeutic range.217,218 Phellodendron amurense inhibits the activity of this enzyme,219 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for any adverse effects.
• Tipranavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.220,221 Phellodendron amurense inhibits the activity of this enzyme,222 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
• Valproate (sodium valproate): This anti-epileptic, anticonvulsant and anti-seizure drug is metabolised by cytochrome P450 3A4,223,224 and has a narrow therapeutic range.225 Phellodendron amurense inhibits the activity of this enzyme,226 which theoretically may change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for any adverse effects.

Pregnancy and Breastfeeding

Contraindicated in pregnancy.

• While the use of Phellodendron amurens during pregnancy is not contraindicated in traditional text, there is some concern due to its berberine content. This constituent is thought to inhibit biliary conjugation in the fetus or newborn and thus lead to hyperbilirubinaemia.227 Kernicterus, a rare type of brain damage that occurs in a newborn with severe jaundice, has developed in newborn infants exposed to berberine.228 Berberine has also shown uterine stimulant activity in animal studies,229 further supporting the avoidance of its use in pregnancy.

Contraindicated in breastfeeding.

• This is due to the berberine content in Phellodendron amurens, which may inhibit biliary conjugation in the newborn and thus lead to hyperbilirubinaemia.230,231
• Do not use in children.

Clove oil is not appropriate for use in children.232

References

1 Xu J, Chen HB, Li SL. Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota. Med Res Rev.2017 Jan 4.

2 Xu J, Chen HB, Li SL. Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota. Med Res Rev.2017 Jan 4.

3 Xu J, Chen HB, Li SL. Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota. Med Res Rev.2017 Jan 4.

4 Chedid V, Dhalla S, Clarke JO, Roland BC, Dunbar KB, Koh J, et. al. Herbal therapy is equivalent to rifaximin for the treatment of small intestinal bacterial overgrowth. Global advances in health and medicine. 2014 May;3(3):16-24.

5 Latifah-Munirah B, Himratul-Aznita WH, Mohd Zain N. Eugenol, an essential oil of clove, causes disruption to the cell wall of Candida albicans (ATCC 14053). Frontiers in Life Science. 2015 Jul 3;8(3):231-40.

6 Latifah-Munirah B, Himratul-Aznita WH, Mohd Zain N. Eugenol, an essential oil of clove, causes disruption to the cell wall of Candida albicans (ATCC 14053). Frontiers in Life Science. 2015 Jul 3;8(3):231-40.

7 Latifah-Munirah B, Himratul-Aznita WH, Mohd Zain N. Eugenol, an essential oil of clove, causes disruption to the cell wall of Candida albicans (ATCC 14053). Frontiers in Life Science. 2015 Jul 3;8(3):231-40.

8 Kumamoto CA. Inflammation and gastrointestinal Candida colonization. Current opinion in microbiology. 2011 Aug 31;14(4):386-91.

9 Kumamoto CA. Inflammation and gastrointestinal Candida colonization. Current opinion in microbiology. 2011 Aug 31;14(4):386-91.

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161 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

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163 Justesen US. Therapeutic drug monitoring and human immunodeficiency virus (HIV) antiretroviral therapy. Basic Clin Pharmacol Toxicol. 2006;98(1):20-31.

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165 Tisserand R, Balacs T. Essential Oil Safety. A Guide for Health Care Professionals. UK: Elsevier/ Churchill Livingstone; 1995. p 131.

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167 Stolbach A, Paziana K, Heverling H, Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products. J Med Toxicol. 2015;11:326-341.

168 Justesen US. Therapeutic drug monitoring and human immunodeficiency virus (HIV) antiretroviral therapy. Basic Clin Pharmacol Toxicol. 2006;98(1):20-31.

169 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

170 Stolbach A, Paziana K, Heverling H, Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products. J Med Toxicol. 2015;11:326-341.

171 Justesen US. Therapeutic drug monitoring and human immunodeficiency virus (HIV) antiretroviral therapy. Basic Clin Pharmacol Toxicol. 2006;98(1):20-31.

172 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

173 Prescribers’ Digital Reference. Phenobarbital – drug summary. 2017 [cited 2017 Oct 24]. Available from: http://www.pdr.net/drug-summary/Phenobarbital-Tablets--15-mg--30-mg--60-mg--100-mg--phenobarbital-861.

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175 Yu L. Quality and bioequivalence standards for narrow therapeutic index drugs. 2011 [cited 2017 May 18]. Available from: https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm292676.pdf.

176 Liang BA, Mackey TK, Lovett KM. Illegal “no prescription” internet access to narrow therapeutic index drugs. Clinical Therapeutics. 2013 May 31;35(5):694-700.

177 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

178 Prescribers’ Digital Reference. Phenytoin – drug summary [Internet]. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/Dilantin-Capsules-phenytoin-sodium-1813.

179 Drugbank. Phenytoin [Internet]. 2017 [cited Oct 26]. Available from: https://www.drugbank.ca/drugs/DB00252.

180 Yu L. Quality and bioequivalence standards for narrow therapeutic index drugs. 2011 [cited 2017 May 18]. Available from: https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm292676.pdf.

181 Snyder BD, Polasek TM, Doogue MP. Drug interactions: principles and practice. Aust Prescr. 2012 Jun 1;35(3):85.

182 Liang BA, Mackey TK, Lovett KM. Illegal “no prescription” internet access to narrow therapeutic index drugs. Clinical Therapeutics. 2013 May 31;35(5):694-700.

183 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

184 Drugbank. Propafenone [Internet]. 2017 [cited Oct 20]. Available from: https://www.drugbank.ca/drugs/DB01182.

185 Prescribers’ Digital Reference. Propafenone hydrochloride – drug summary. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/rythmol?druglabelid=223.

186 Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015 May;71(5):549-67.

187 Prescribers’ Digital Reference. Propafenone hydrochloride – drug summary [Internet]. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/rythmol?druglabelid=223.

188 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

189 Prescribers’ Digital Reference. Quinidine sulfate – drug summary. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/Quinidine-Sulfate-Tablets-quinidine-sulfate-3103.3451.

190 MIMS Australia. CYP450 drug interactions [Internet]. 2016 [cited 2017 Oct 26]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.

191 Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015 May;71(5):549-67.

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194 Prescribers’ Digital Reference. Rifampin – drug summary. 2017 [cited 2017 Oct 26]. Available from: https://www.drugbank.ca/drugs/DB01045.

195 Drugbank. Rifampicin [Internet]. 2017 [cited 2017 Oct 26]. Available from: https://www.drugbank.ca/drugs/DB01182.

196 Lucas C, Donovan P. Medications: 'Just a repeat': When drug monitoring is indicated. Australian Family Physician. 2013 Jan;42(1/2):18.

197 Liang BA, Mackey TK, Lovett KM. Illegal “no prescription” internet access to narrow therapeutic index drugs. Clinical Therapeutics. 2013 May 31;35(5):694-700.

198 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

199 Stolbach A, Paziana K, Heverling H, Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products. J Med Toxicol. 2015;11:326-341.

200 Justesen US. Therapeutic drug monitoring and human immunodeficiency virus (HIV) antiretroviral therapy. Basic Clin Pharmacol Toxicol. 2006;98(1):20-31.

201 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

202 Stolbach A, Paziana K, Heverling H, Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products. J Med Toxicol. 2015;11:326-341.

203 Justesen US. Therapeutic drug monitoring and human immunodeficiency virus (HIV) antiretroviral therapy. Basic Clin Pharmacol Toxicol. 2006;98(1):20-31.

204 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

205 MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. Sirolimus – Full PI. [2017 Oct 1; cited 2017 Oct 19]. Available from: http://www.emims.com.au/Australia/drug/info/Rapamune/Rapamune?type=full. Subscription required to view.

206 Prescribers’ digital reference. Sirolimus – drug summary. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/Rapamune-sirolimus-2097.4085.

207 Drugs.com. Sirolimus dosage [Internet]. 2017 [Cited 2017 Oct 19]. Available from: https://www.drugs.com/dosage/sirolimus.html.

208 NPS Medicinewise. Therapeutic drug monitoring: which drugs, why, when and how to do it [Internet]. 2008 [cited 2017 Oct 19]. Available from: https://www.nps.org.au/australian-prescriber/articles/therapeutic-drug-monitoring-which-drugs-why-when-and-how-to-do-it.

209 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

210 MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. Tacrolimus – Full PI. [2016 Nov 1; cited 2017 Oct 19]. Available from: http://www.emims.com.au/Australia/drug/info/Advagraf%20XL/Advagraf%20XL?type=full#Interactions. Subscription required to view.

211 Prescribers’ Digital Reference. Tacrolimus – drug summary. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/Prograf-tacrolimus-1331.3795.

212 Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015 May;71(5):549-67.

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214 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

215 Prescribers’ Digital Reference. Theophylline – drug summary [Internet]. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/Theophylline-Extended-Release-Tablets--100-mg--200-mg--300-mg--450-mg--theophylline-3337.

216 Drugbank. Theophylline [Internet]. 2017 [cited 2017 Oct 20]. Available from: https://www.drugbank.ca/drugs/DB00277.

217 Lucas C, Donovan P. Medications: 'Just a repeat': When drug monitoring is indicated. Australian Family Physician. 2013 Jan;42(1/2):18.

218 Liang BA, Mackey TK, Lovett KM. Illegal “no prescription” internet access to narrow therapeutic index drugs. Clinical Therapeutics. 2013 May 31;35(5):694-700.

219 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

220 Stolbach A, Paziana K, Heverling H, Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products. J Med Toxicol. 2015;11:326-341.

221 Justesen US. Therapeutic drug monitoring and human immunodeficiency virus (HIV) antiretroviral therapy. Basic Clin Pharmacol Toxicol. 2006;98(1):20-31.

222 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

223 MIMS Australia. CYP450 drug interactions [Internet]. 2016 [cited 2017 Oct 4]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.

224 Prescribers’ Digital Reference. Valproate sodium – drug summary [Internet]. 2017 [cited 2017 Oct 20]. Available from: http://www.pdr.net/drug-summary/Depacon-valproate-sodium-2015.

225 Pharmacists Pharma Journal. List of narrow therapeutic range drugs [Internet]. 2010 [cited 2017 Sep 4]. Available from: http://www.pharmacistspharmajournal.org/2010/12/list-of-narrow-therapeutic-range-drugs.html.

226 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

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229 Gardner Z, McGuffin M. Botanical safety handbook. 2nd ed. Botan Raton (FL): CRC Press; 2013. p 130.

230 Hempen CH, Fischer T. A materia medica for Chinese medicine: plants, minerals and animal products. Edinburgh (UK): Elsevier/Churchill Livingstone; 2009. p. 180-1.

231 Phellodendron. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Nov 8]. Available from: http://www.naturaldatabase.com. Subscription required to view.

232 Skidmore-Roth L. Mosby’s handbook of herbs & natural supplements. 4th ed. St Louis (MO): Mosby Elsevier; 2010. p. 186-187.