Hwee-Ling Koh

Herb-drug interactions: a literature review.

AbstractHerbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients. Piper methysticum (kava) increased the ‘off’ periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John’s wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Herbal bioactivation: The good, the bad and the ugly

Abstract It has been well established that the formation of reactive metabolites of drugs is associated with drug toxicity. Similarly, there are accumulating data suggesting the role of the formation of reactive metabolites/intermediates through bioactivation in herbal toxicity and carcinogenicity. It has been hypothesized that the resultant reactive metabolites following herbal bioactivation covalently bind to cellular proteins and DNA, leading to toxicity via multiple mechanisms such as direct cytotoxicity, oncogene activation, and hypersensitivity reactions. This is exemplified by aristolochic acids present in Aristolochia spp, undergoing reduction of the nitro group by hepatic cytochrome P450 (CYP1A1/2) or peroxidases in extrahepatic tissues to reactive cyclic nitrenium ion. The latter was capable of reacting with DNA and proteins, resulting in activation of H-ras oncogene, gene mutation and finally carcinogenesis. Other examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming diets. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, and the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which reacts with proteins such as CYP3A and epoxide hydrolase. On the other hand, some herbal/dietary constituents were shown to form reactive intermediates capable of irreversibly inhibiting various CYPs. The resultant metabolites lead to CYP inactivation by chemical modification of the heme, the apoprotein, or both as a result of covalent binding of modified heme to the apoprotein. Some examples include bergamottin, a furanocoumarin of grapefruit juice; capsaicin from chili peppers; glabridin, an isoflavan from licorice root; isothiocyanates found in all cruciferous vegetables; oleuropein rich in olive oil; dially sulfone found in garlic; and resveratrol, a constituent of red wine. CYPs have been known to metabolize more than 95% therapeutic drugs and activate a number of procarcinogens as well. Therefore, mechanism-based inhibition of CYPs may provide an explanation for some reported herb-drug interactions and chemopreventive activity of herbs. Due to the wide use and easy availability of herbal medicines, there is increasing concern about herbal toxicity. The safety and quality of herbal medicine should be ensured through greater research, pharmacovigilance, greater regulatory control and better communication between patients and health professionals.

Chinese proprietary medicine in Singapore : Regulatory control of toxic heavy metals and undeclared drugs

Traditional Chinese medicine (TCM) is gaining popularity as a form of complementary and alternative medicine. Reports of efficacy of TCM are increasing in numbers. TCM includes both crude Chinese medicinal materials (plants, animal parts and minerals) and Chinese proprietary medicine (CPM) [final dosage forms]. Despite the belief that CPM and herbal remedies are of natural origin, unlike Western medicine, and are hence safe and without many adverse effects, there have been numerous reports of adverse effects associated with herbal remedies. Factors affecting the safety of herbal medicines include intrinsic toxicity, adulteration, substitution, contamination, misidentification, lack of standardisation, incorrect preparation and/or dosage and inappropriate labelling and/or advertising. Hence, new regulations on the control of CPM were enforced in Singapore with effect from 1 September 1999. These include licensing and labelling requirements, as well as control of microbial contamination. This article also reviews reports of excessive toxic heavy metals and undeclared drugs in CPM in Singapore between 1990 and 1997. The names, uses, toxic heavy metal or drug detected and the year of detection are tabulated. Information on the brand or manufacturer’s name are provided whenever available. The public and healthcare professionals should be better informed of the basic concept of TCM and its usefulness, as well as the potential adverse effects associated with its use. Greater control over the safety and quality of CPM could be achieved through good manufacturing practice, regulatory control, research, education, reporting usage of Chinese medicine (as in drug history) as well as reporting of adverse events.

Analysis of saponins in raw and steamed Panax notoginseng using high-performance liquid chromatography with diode array detection.

A reversed-phase high-performance liquid chromatography-diode array detection method was developed and validated for the simultaneous determination of six saponins (notoginsenoside R1, ginsenosides Rg1, Re, Rb1, Rc, Rd) in raw and steamed Panax notoginseng. Linearity (r2 > 0.9988), intra- and inter-day precision (RSD < 4%), limit of detection (0.008-0.013 mg/ml), limit of quantification (0.027-0.042 mg/ml) of the saponins were determined. The method was successfully applied to 11 pairs of raw and steamed P. notoginseng products. Three products showed discrepancies between theirlabelled claims (raw or steamed) and the results of analysis. This new, simple and reliable method could be used in the quality control of raw and steamed P. notoginseng.

Antiplatelet and anticoagulant effects of Panax notoginseng: Comparison of raw and steamed Panax notoginseng with Panax ginseng and Panax quinquefolium

ETHNOPHARMACOLOGICAL SIGNIFICANCE Panax notoginseng (Burk.) F. H. Chen (Araliacea) is traditionally used for its hemostatic and cardiovascular effects when raw and as a tonic when steamed. AIM OF THE STUDY This study aims to compare the effects of raw and steamed Panax notoginseng, Panax ginseng C. A. Meyer and Panax quinquefolium Linn. on platelet aggregation and plasma coagulation. MATERIALS AND METHODS Effects on collagen-induced platelet aggregation were investigated using a platelet aggregometer, while the plasma coagulation times (prothrombin time, activated partial thromboplastin time and thrombin time) were determined using a blood coagulation analyzer. The data was corroborated with ex vivo platelet aggregation and in vivo rat bleeding time. RESULTS Raw and steamed Panax notoginseng significantly inhibit platelet aggregation and plasma coagulation. Steamed Panax notoginseng has significantly more potent antiplatelet and anticoagulant effects than the raw extract, and the antiplatelet and anticoagulant effects increase with increasing steaming durations. Comparing the three common Panax species, Panax notoginseng has higher antiplatelet effect than Panax ginseng and Panax quinquefolium. The in vitro antiplatelet and anticoagulant effects are positively translated into a prolongation of in vivo rat bleeding time after oral administration of the raw and steamed extracts. CONCLUSION The results indicate that the three common Panax species affect platelet aggregation and plasma coagulation differently, with steamed Panax notoginseng showing the greatest antiplatelet and anticoagulant effects. Panax notoginseng may be a good source of lead compounds for novel antiplatelet and anticoagulant therapeutics.

Ultra-high performance liquid chromatography/time-of-flight mass spectrometry (UHPLC/TOFMS) for time-dependent profiling of raw and steamed Panax notoginseng

The metabolic profiles of Panax notoginseng and its associated therapeutic values are critically affected by the duration of steaming. The time-dependent steaming effect of P. notoginseng is not well-characterized and there is also no official guideline on its duration of steaming. In this paper, a UHPLC/TOFMS-based metabolomic platform was developed for the qualitative profiling of multiparametric metabolic changes of raw P. notoginseng during the steaming process. Our method was successful in discriminating the differentially processed herbs. Both the unsupervised principal component analysis (PCA) score plot (R(2)X=0.664, Q(2) (cum)=0.622, and PCs=2) and the supervised partial least square-data analysis (PLS-DA) model (R(2)X=0.708, R(2)Y=0.461, and Q(2)Y=0.271) demonstrated strong classification and clear trajectory patterns with regard to the duration of steaming. The PLS-DA model was validated for its robustness via a prediction set, confirming that the UHPLC/TOFMS metabolic profiles of the raw and differentially steamed P. notoginseng samples were highly reproducible. Based on our method, the minimum durations of steaming for the maximum production of bioactive ginsenosides such as Rg3 and Rh2 were also predicted. Our novel time-dependent metabolic profiling approach represents the paradigm shift in the quality control of P. notoginseng products.

Isolation and identification of thiohomosildenafil and thiosildenafil in health supplements

Two unknown compounds are detected and isolated from health supplements for the enhancement of sexual function. The structures of the unknown compounds are elucidated using high-resolution MS, ESI-MS/MS, NMR, UV and IR. One compound is identified as an analogue of sildenafil in which the oxygen atom is substituted with a sulfur atom in the pyrazolopyrimidine moiety, and an ethyl group instead of a methyl group is attached to the piperazinyl nitrogen. Hence, this compound is named thiohomosildenafil. Another compound is also a sildenafil analogue in which the oxygen atom is substituted with a sulfur atom in the pyrazolopyrimidine moiety. This compound is named thiosildenafil. Both the two compounds are first detected in health supplements. The UV, IR and completely assigned NMR data of thiohomosildenafil and thiosildenafil are first reported.

Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product

A tadalafil analogue and hydroxyhomosildenafil were isolated from a herbal product marketed for erectile dysfunction. The structure of the tadalafil analogue was elucidated using LC-UV, high resolution MS, ESI-MS/MS, IR, and NMR. The compound was determined to be (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6] pyrido[3,4-b]indole-1,4-dione. This compound should be included as a target compound when screening for adulterants in herbal products. This is the first published paper on a tadalafil analogue and hydroxyhomosildenafil found as adulterants of a herbal product.

HPLC and GC–MS screening of Chinese proprietary medicine for undeclared therapeutic substances

Traditional Chinese medicine includes raw medicinal materials and Chinese proprietary medicine (CPM). Despite being of natural origin, toxic effects, adulteration with synthetic therapeutic substances and even deaths had been associated with CPM. There is thus a need to develop analytical technique to rapidly screen for undeclared toxic and therapeutic substances in CPM. In this study, a high performance liquid chromatography-diode-array detection method was developed and used to screen for undeclared therapeutic substances in CPM. An ultraviolet (UV) library of 266 drugs had been compiled. Solute identification was performed by comparing the analytical data (UV spectra, retention time and relative retention time) with those of the 266 standards. Gas chromatography-mass spectrometry was used as a confirmation method. These chromatographic methods had been shown to be selective and reproducible in screening for undeclared drugs in CPM. Using the method developed, 41 CPM samples in seven categories were screened for undeclared therapeutic substances. One anti-asthmatic CPM was found to contain codeine.

Structural identification of a new acetildenafil analogue from pre-mixed bulk powder intended as a dietary supplement

An analogue of acetildenafil was detected in an extract of pre-mixed bulk powder. To our knowledge, the powder was destined to be encapsulated and sold as a dietary supplement. The structure was identified by NMR, HR-ESI–MS, ESI–MS n and FTIR analyses. Owing to the inclusion of a hydroxyl group in acetildenafil, the detected compound was called ‘hydroxyacetildenafil’. With increasing use of dietary supplements marketed for penile erectile dysfunction, the detection of analogues of sexual performance enhancers is important and timely.