You are ill and the doctor prescribes a drug that will make you better. A classic scenario that takes place every day all over the world but there is evidence of a gradual shift towards different types of medication. Multiple drugs are beginning to find a place in the treatment regimes, replacing the single drug. This strategy is being driven by reports that the combination drugs can augment the effects of each other to improve the overall efficacy.
This is not a unique state of affairs. It has long been argued that traditional Chinese medicines (TCMs) are effective due to the synergistic effects of the individual components, possibly by targeting different centres within the body. They may also interact in some way that increases the concentrations of each drug in plasma, to enhance their bioavailability.
A team of scientists in China that studies the effects of TCMs has begun to examine the synergistic effects of the components to try and understand how combination therapy might work. Xijun Wang and colleagues from the Heilongjiang University of Chinese Medicine and the Key Laboratory of Chinese Materia Medica, Ministry of Education, Harbin, based their work on Yin-Chen-Hao-Tang, a common herbal formula.
This TCM comprises Artemisia annua L., Gardenia jasminoides Ellis and Rheum palmatum L., better known as sweet wormwood, gardenia and Chinese rhubarb, respectively. Some of the major active components are 6,7-dimethylesculetin (DE), geniposide (GP) and rhein (RH) but there have been no reports of their synergy.
Wang and his team devised a novel HPLC method for measuring the three components in plasma, based on a triple-wavelength diode array detection regime, which they claimed is the first non-mass spectrometric method that is sufficiently selective and sensitive to compete with mass spectrometry in this type of study.
Seven groups of rats were dosed with DE, GP and RH alone, in all three paired combinations, or as a triple drug. Plasma was collected over intervals after dosing and subjected to a simple protein precipitation step for HPLC analysis.
The compounds were well separated on a C18 column with retention times of 3.61, 5.05 and 9.02 minutes for GP, DE and RH, respectively, and there were no interferences in the chromatograms. They were each detected at a different wavelength, 241, 343 and 259 nm, respectively, to allow them to be detected together in the one run.
The low detection limits of 0.01-0.02 µg/mL illustrated the excellent method sensitivity and recoveries were considered to be good at more than 80%. The analytical criteria indicated that the method satisfied the requirements for accuracy and precision, and the quantitation ranges easily covered those likely to be encountered in experiments with rats.
Drugs helping each other
The concentration-time profiles appeared to support the synergy theory. For instance, the area under the curve (AUC), which is a measure of drug exposure, was higher for all of the triple dosage experiments than in the double and single doses. So, more of each drug was available to the body via plasma in the triple combination therapy.
The elimination rates for drug removal from plasma were reduced compared with those for single and double dosing, showing that the drug was available for longer within the body.
The overall trends in the maximum concentrations, AUCs, elimination rates, mean residence times and total body clearances, which are standard pharmacokinetic parameters, all pointed towards synergistic and/or additive properties of the triple therapy. So, the combination therapy with the three drugs, as a model for a TCM, supports the view of improved efficacy via drug-drug interactions.
The short run time of 10 minutes, simplicity and good sensitivity of the HPLC procedure suggest that it could be applied to study the pharmacokinetic behaviour of the active components of TCMs in general. In fact, Wang proposed that it could also be used to design novel TCMs and combination medications based on them.
The fact that the method is based on HPLC without the involvement of mass spectrometry lends itself to wider use since mass spectrometers are more expensive to purchase and operate and require a higher level of expertise.
In the meantime, the researchers are continuing their studies on Yin-Chen-Hao-Tang to try and unravel the synergistic mechanisms involved and understand more fully the drug-drug interactions that are taking place.
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