Intestinal epithelial injury from herbal products has rarely been reported, despite the gut being... more Intestinal epithelial injury from herbal products has rarely been reported, despite the gut being the first point of contact for oral preparations. These products often consist of multiple herbs, thereby potentially exposing consumers to higher levels of reactive phytochemicals than predicted due to pharmacokinetic interactions. The phytochemical coumarin, found in many herbal products, may be taken in combination with herbal medicines containing astragalosides and atractylenolides, purported cytochrome P450 (CYP) modulators. As herbal use increases, the need to predict interactions in multiple at-risk organ systems is becoming critical. Hence, to determine whether certain herbal preparations containing coumarin may cause damage to the intestinal epithelium, Caco2 cells were exposed to common phytochemicals. Coumarin, astragaloside IV (AST-IV) or atractylenolide I (ATR-I) solutions were exposed to Caco2 cultures in increasing concentrations, individually or combined. Coumarin produced a significant concentration-dependant fall in cell viability that was potentiated when CYP enzymes were induced with rifampicin and incubated with CYP3A4 inhibitor econazole, suggesting a role for other CYP enzymes generating toxic metabolites. ATR-I alone produced no toxicity in uninduced cells but showed significant toxicity in rifampicin-induced cells. ATR-I had no effect on coumarin-induced toxicity. AST-IV was nontoxic alone but produced significant toxicity when combined with nontoxic concentrations of coumarin. The combination of coumarin, ATR-I and AST-IV was significantly toxic, but no synergistic interaction was seen. This investigation was conducted to determine the likelihood for intestinal-based interactions, with the results demonstrating coumarin is potentially toxic to intestinal epithelium, and combinations with other phytochemicals can potentiate this toxicity.
Pharmacological Research - Modern Chinese Medicine
Herbal traditional Chinese medicines (TCMs) are an increasingly popular alternative therapy globa... more Herbal traditional Chinese medicines (TCMs) are an increasingly popular alternative therapy globally. Due to the complex chemical composition of herbal products, and with research showing that consumers from Western countries are more likely to take multiple herbal products at one time, the lack of understanding of the potential side effects of herbal TCM may pose a significant risk to health and wellbeing. This may be particularly so now that herbal preparations are being promoted for the prevention and treatment of COVID-19 symptoms, often in association with Western medicines such as paracetamol. Of interest are the potential adverse effects of herbal TCMs on the kidney. Many factors can lead to the development of renal injury including intrinsic toxicity, plant misidentification, adulteration, contamination, and of increasing importance, interactions with conventional drugs and other herbs. This review evaluates and summarises some of the key aspects of TCM-induced nephrotoxicity and the current scope of herb-drug and herb-herb interaction that may cause adverse effects.
A recent series of deaths in previously healthy dogs in Victoria, Australia associated with the i... more A recent series of deaths in previously healthy dogs in Victoria, Australia associated with the ingestion of raw meat contaminated by indospicine derived from native Australian plants of the Indigofera species draws attention to the potential that exists for herbal toxicity in domestic animals. Although the efficacy of herbal remedies generally remains unproven in domestic animals, herbal preparations are being increasingly used as supplements and treatments. Issues with incorrect ingredients, inadequate processing, faulty, incomplete or inaccurate product labelling, contamination with toxins, adulteration with undeclared pharmaceutical agents and herb-herb interactions are well recognized as causes of adverse effects in humans. However, apart from of the effects of noxious weed species, the literature on herbal toxicity in domestic animals is sparse. Thus, the forensic evaluation of cases of suspected poisoning in domestic animals should also encompass an accurate description the type and dose of any herbal preparations that may have been recently administered.
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary tre... more 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary treatment for hyperlipidemic cardiovascular diseases which are a leading global cause of death. Statin therapy is life saving and discontinuation due to adverse events such as myotoxicity may lead to unfavourable outcomes. There is no known mechanism for statin-induced myotoxicity although it is theorized that it is due to inhibition of downstream products of the HMG-CoA pathway. It is known that drug-drug interactions with conventional medicines exacerbate the risk of statin-induced myotoxicity, though little attention has been paid to herb-drug interactions with complementary medicines. Flavonoids are a class of phytochemicals which can be purchased as high dose supplements. There is evidence that flavonoids can raise statin plasma levels, increasing the risk of statin-induced myopathy. This could be due to pharmacokinetic interactions involving hepatic cytochrome 450 (CYP450) metabolism and organic anion transporter (OATP) absorption. There is also the potential for flavonoids to directly and indirectly inhibit HMG-CoA reductase which could contraindicate statin-therapy. This review aims to discuss what is currently known about the potential for high dose flavonoids to interact with the hepatic CYP450 metabolism, OATP uptake of statins or their ability to interact with HMG-CoA reductase. Flavonoids of particular interest will be covered and the difficulties of examining herbal products will be discussed throughout.
The non-linear polypyridylruthenium(ii) complex (Rubb7-TNL) exhibited good antimicrobial activity... more The non-linear polypyridylruthenium(ii) complex (Rubb7-TNL) exhibited good antimicrobial activity, but surprisingly was also highly active against cancer cells. The results suggestRubb7-TNLmay have potential as a new anticancer agent.
Intestinal epithelial injury from herbal products has rarely been reported, despite the gut being... more Intestinal epithelial injury from herbal products has rarely been reported, despite the gut being the first point of contact for oral preparations. These products often consist of multiple herbs, thereby potentially exposing consumers to higher levels of reactive phytochemicals than predicted due to pharmacokinetic interactions. The phytochemical coumarin, found in many herbal products, may be taken in combination with herbal medicines containing astragalosides and atractylenolides, purported cytochrome P450 (CYP) modulators. As herbal use increases, the need to predict interactions in multiple at-risk organ systems is becoming critical. Hence, to determine whether certain herbal preparations containing coumarin may cause damage to the intestinal epithelium, Caco2 cells were exposed to common phytochemicals. Coumarin, astragaloside IV (AST-IV) or atractylenolide I (ATR-I) solutions were exposed to Caco2 cultures in increasing concentrations, individually or combined. Coumarin produced a significant concentration-dependant fall in cell viability that was potentiated when CYP enzymes were induced with rifampicin and incubated with CYP3A4 inhibitor econazole, suggesting a role for other CYP enzymes generating toxic metabolites. ATR-I alone produced no toxicity in uninduced cells but showed significant toxicity in rifampicin-induced cells. ATR-I had no effect on coumarin-induced toxicity. AST-IV was nontoxic alone but produced significant toxicity when combined with nontoxic concentrations of coumarin. The combination of coumarin, ATR-I and AST-IV was significantly toxic, but no synergistic interaction was seen. This investigation was conducted to determine the likelihood for intestinal-based interactions, with the results demonstrating coumarin is potentially toxic to intestinal epithelium, and combinations with other phytochemicals can potentiate this toxicity.
Pharmacological Research - Modern Chinese Medicine
Herbal traditional Chinese medicines (TCMs) are an increasingly popular alternative therapy globa... more Herbal traditional Chinese medicines (TCMs) are an increasingly popular alternative therapy globally. Due to the complex chemical composition of herbal products, and with research showing that consumers from Western countries are more likely to take multiple herbal products at one time, the lack of understanding of the potential side effects of herbal TCM may pose a significant risk to health and wellbeing. This may be particularly so now that herbal preparations are being promoted for the prevention and treatment of COVID-19 symptoms, often in association with Western medicines such as paracetamol. Of interest are the potential adverse effects of herbal TCMs on the kidney. Many factors can lead to the development of renal injury including intrinsic toxicity, plant misidentification, adulteration, contamination, and of increasing importance, interactions with conventional drugs and other herbs. This review evaluates and summarises some of the key aspects of TCM-induced nephrotoxicity and the current scope of herb-drug and herb-herb interaction that may cause adverse effects.
A recent series of deaths in previously healthy dogs in Victoria, Australia associated with the i... more A recent series of deaths in previously healthy dogs in Victoria, Australia associated with the ingestion of raw meat contaminated by indospicine derived from native Australian plants of the Indigofera species draws attention to the potential that exists for herbal toxicity in domestic animals. Although the efficacy of herbal remedies generally remains unproven in domestic animals, herbal preparations are being increasingly used as supplements and treatments. Issues with incorrect ingredients, inadequate processing, faulty, incomplete or inaccurate product labelling, contamination with toxins, adulteration with undeclared pharmaceutical agents and herb-herb interactions are well recognized as causes of adverse effects in humans. However, apart from of the effects of noxious weed species, the literature on herbal toxicity in domestic animals is sparse. Thus, the forensic evaluation of cases of suspected poisoning in domestic animals should also encompass an accurate description the type and dose of any herbal preparations that may have been recently administered.
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary tre... more 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary treatment for hyperlipidemic cardiovascular diseases which are a leading global cause of death. Statin therapy is life saving and discontinuation due to adverse events such as myotoxicity may lead to unfavourable outcomes. There is no known mechanism for statin-induced myotoxicity although it is theorized that it is due to inhibition of downstream products of the HMG-CoA pathway. It is known that drug-drug interactions with conventional medicines exacerbate the risk of statin-induced myotoxicity, though little attention has been paid to herb-drug interactions with complementary medicines. Flavonoids are a class of phytochemicals which can be purchased as high dose supplements. There is evidence that flavonoids can raise statin plasma levels, increasing the risk of statin-induced myopathy. This could be due to pharmacokinetic interactions involving hepatic cytochrome 450 (CYP450) metabolism and organic anion transporter (OATP) absorption. There is also the potential for flavonoids to directly and indirectly inhibit HMG-CoA reductase which could contraindicate statin-therapy. This review aims to discuss what is currently known about the potential for high dose flavonoids to interact with the hepatic CYP450 metabolism, OATP uptake of statins or their ability to interact with HMG-CoA reductase. Flavonoids of particular interest will be covered and the difficulties of examining herbal products will be discussed throughout.
The non-linear polypyridylruthenium(ii) complex (Rubb7-TNL) exhibited good antimicrobial activity... more The non-linear polypyridylruthenium(ii) complex (Rubb7-TNL) exhibited good antimicrobial activity, but surprisingly was also highly active against cancer cells. The results suggestRubb7-TNLmay have potential as a new anticancer agent.
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Papers by Ian Musgrave