(Evans, 55)

Content discussed:

• modernized should  achieve three types of efficiency (high efficiency, quick efficiency, and long-lasting efficiency) and three areas of “small” advantages (small dosage, low toxicity, and fewer adverse reactions). 

Drug delivery system vs synergism, synergism = potentiation, synergism vs polyvalent action. 

 

• Synergism is an effect larger than additive, whereas antagonism is smaller than additive.
•  combinations of these rather than with
  isolated compounds. TCM, in particular, uses complicated recipes
  and it has sometimes been thought that the inclusion of some herbs
  was unnecessary, but the rationale for such combinations is gaining
  increasing acceptance. A TCM herbal treatment for eczema was the
  subject of a clinical trial of 37 young patients (M. P. Sheehan and J. D.
  Atherton, Br. J. Dermatol., 1992, 126: 179–184), and investigations
  were carried out to identify the ‘active constituent(s)’ of the mixture.
  However, a programme of pharmacological tests failed to find a
  single active herb or compound: it was the herbal mixture that was so
  effective (J. D. Phillipson, reported in European Phytotelegram,
  1994, 6: 33–40)
• To do so requires the extract to be fractionated, tested, recombined and retested
  in various permutations to see how each is interacting with the others.To do so
  requires the extract to be fractionated, tested, recombined and retested
  in various permutations to see how each is interacting with the others.
• issue: polyvalent action
• no real evidence as to which compounds are interacting.
• In some cases, the active ingredients
  may not even be fully known, and if synergy is involved, then
  bioassay-led fractionation (the usual method for identifying actives)
  would not even be possible (see P. Houghton, Phytother. Res., 2000,
  14(6): 419–423). The identities of the main actives of many important
  herbs are still under discussion, and it would be unwise to
  exclude, by overpurification, any constituents that might contribute
  to efficacy
• Enhancement or reduction of absorption or bioavailability : Ayurvedic formulae often have herbs such as liquorice
  or pepper included specifically to reduce or increase bioavailability
  of other ingredients, and this can be considered a form of synergy.
• Multiple pharmacologocal effects demonstrated in single plant (E. 59)- Anupana concept.
• New technology for looking of looking synergy and other interactions:

 

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425653/

CAN SYNERGISM REDUCE TOXICITY?

synergistic effect in effecting a cure or reducing toxicity.

evidence is accumulating to show that synergism does occur in extracts and mixtures, and that there is benefit in using whole extracts. However, it is still vital to ensure that
extracts are standardized for the active principles known at the time and
that any known synergistic interactions are taken into account. If done
properly, this should lead to improved products with increased efficacy
at lower doses and correspondingly reduced toxicity (Evans.61 conclusion)

Advances in Synergistic Combinations of Chinese Herbal Medicine for the Treatment of Cancer

TCM has established State Administration of Traditional Chinese Medicine. http://www.satcm.gov.cn/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425653/

ROLE OF Network pharmacology for Traditional medicine to drug discovery.

www.mdpi.com/1420-3049/22/7/1135/pdf

general public people doubt the security, efficacy, quality, and administrative
supervision of TMs [9]. World Health Organization. WHO Traditional Medicine Strategy: 2014–2023; World Health Organization: Geneva, Switzerland, 2013.

• Modernization : Good Agricultural Practice (GAP), Good Laboratory Practice (GLP), Good Clinical Practice
  (GCP), Good Manufacturing Practice (GMP)).
• modernized TCM will achieve three types of efficiency (high efficiency, quick efficiency, and long-lasting efficiency) and three areas of “small” advantages (small dosage, low toxicity, and fewer adverse reactions). 
• TMs have been under
  supervision of the Adverse Drug Reaction monitoring system in China since 1989, which aims to
  control any risks associated with the use of TCM through effective monitoring [23]. Zhang, L.; Yan, J.; Liu, X.; Ye, Z.; Yang, X.; Meyboom, R.; Chan, K.; Shaw, D.; Duez, P. Pharmacovigilance
  practice and risk control of Traditional Chinese Medicine drugs in China: Current status and future
  perspective. J. Ethnopharmacol. 2012, 140, 519–525. [CrossRef] [PubMed]
• Multidrug methods have been used to treat such complex diseases as cancer, diabetes,
  and hypertension. One well-known case is the common use of a cocktail of drugs in synergistically
  treating HIV infection [26,27].Pool, J.L. Is it time to move to multidrug combinations? Am. J. Hypertens. 2003, 16, 36–40. [CrossRef]
  27. Hurwitz, J.L.; Zhan, X.; Brown, S.A.; Bonsignori, M.; Stambas, J.; Lockey, T.D.; Sealy, R.; Surman, S.; Freiden, P.;
  Jones, B.; et al. HIV-1 vaccine development: Tackling virus diversity with a multi-envelope cocktail. Front.
  Biosci. 2008, 13, 609–620. [CrossRef] [PubMed]
• Two Chinese herbs, rehmanniae radix and astragali radix, are extensively
  used to treat diabetes mellitus. In a rat model of foot ulcer, no one of the two herbs was able to reduce
  the diabetic wound area. However, when the two herbs were combined in a 2:1 ratio, they were clearly
  able to reduce the diabetic wound area compared with controls. That ratio may result in special effects
  on different targets, thereby producing a synergistic effect. However, it could be that the synergistic
  effect was produced as a result of new compounds created during the preparation of the herbs [16,30]. Yang, Y.; Zhang, Z.; Li, S.; Ye, X.; Li, X.; He, K. Synergy effects of herb extracts: Pharmacokinetics and
  pharmacodynamic basis. Fitoterapia 2014, 92, 133–147. [CrossRef] [PubMed]
  Zhang, A.; Sun, H.; Yuan, Y.; Sun,W.; Jiao, G.;Wang, X. An in vivo analysis of the therapeutic and synergistic
  properties of Chinese medicinal formula Yin-Chen-Hao-Tang based on its active constituents. Fitoterapia
  2011, 82, 1160–1168. [CrossRef] [PubMed]
  

Advances in Synergistic Combinations of Chinese Herbal Medicine for the Treatment of Cancer

 

 

• Cancer, which is a disease that is refractory to most current therapies, evolves progressively in an increasingly complex fashion, which is coordinated by multiple genes, proteins and their respective signal transduction pathways. Many factors work together to promote carcinogenesis and to enable initial tumor cells to acquire hallmark characteristics, including sustained proliferative signaling, replicative immortality, tumor-promoting inflammation microenvironmental modulation, invasive and metastastic capabilities, angiogenesis, abnormal cellular energetics and the ability to avoid anti-tumorigenic mechanisms including growth suppressors, immune destruction and cell death [2].Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. [PubMed]
• The traditional applications of individual single-target drugs are insufficient to treat complex diseases including cancer, cardiovascular diseases or Alzheimer’s disease.
• tolerable synergistic drug combinations (the simultaneous application of two or more drugs that interact to enhance therapeutic effects, reduce side effects, abrogate drug resistance and to modulate anti-tumor immunity) are emerging.
• Principles of drug combinations might include the following: (1) drugs working on the same target via different pathways; (2) drugs working on different targets via the same pathway; (3) drugs working on different targets via different pathways; (4) drugs working on biological networks, involving complicated interactions among multiple genes, proteins and pathways at the pharmacological and phar-
  macokinetic levels.
• Many CHMs are bioactive, whereas individual isolated substituents might not exhibit bioactivity, indicating that multiple components within an herb work synergistically [3, 4].
  Foungbe S., Kouassi G., Kablan J.B., Marcy R. Study of Costus lucanusianus: plant juice, fraction combinations and pharmacologic estimation of natural product total activity. J. Ethnopharmacol. 1991;33(3):221–226. [PubMed]
  4. Schuster B.G. A new integrated program for natural product development and the value of an ethnomedical approach. J. Altern. Complement. Med. 2001;7(Suppl. 1):S61–S72. [PubMed]
• uniform design, fixed ratio design, factorial design,uniform design,Uniform design, orthogonal design
• hallmarks imortant

• UNWANTED SIDE EFFECTS OF SYNERGISTIC COMBINATIONS’

CalcuSyn is the definitive analyzer of combined drug effects, able automatically to quantify phenomena such as synergism and inhibition.

https://download.freedownloadmanager.org/Windows-PC/CalcuSyn/FREE-2.0.html

CompuSyn General Features

New, Easy, Versatile, Automation, and Quantitation of Synergism and Antagonism; Mass-Action Law Based.

• Automated Construction of Dose-Effect Curve
• Automated Construction of Isobologram
• Automated Determination of Combination Index (CI) and Dose-Reduction Index (DRI)
• Automated Generation of Fa-CI Plot and DRI Plot
• Automated Determination of IC₅₀, IC₉₀, ED₅₀, ED₉₀, LD₅₀, etc.
• Data Storage and Retrieval
• Color Graphics, Flexible Scale
• Editing and Transport of Data for strage and Retrieveal for Report
• User’s Guide for background, theoretical basis, illustration and sample analysis
• Small Size Experimentation, Requires Few Data Points for Single Drug or Combinations
• Can be Used for Constant or Non-Constant Ratio Drug Combination Design
• Schedule Dependency of Drug Combination
• Drug Combination Graphics at constant ratio (preferred) or at non-constant ratio

http://www.combosyn.com/register.html

 

Synergistic Effects of Chinese Herbal Medicine: A Comprehensive Review of Methodology and Current Research

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940614/

PharmMapper Server: an updated integrated pharmacophore matching platform with statistial method for potential target identification.

Drug target identification, which includes many distinct algorithms for finding genes and proteins, is the first step in drug discovery. When 3D structures of the targets are available, the problem of target identification is usually converted to finding the best interaction mode between the potential target candidates and probe small molecules. Pharmacophore, which is the spatial arrangement of features that is essential for a molecule to interact with a specific target receptor, is an alternative method despite of molecular docking for achieving this goal.

PharmMapper Server is a freely accessed web-server designed to identify potential target candidates for the given probe small molecules (drugs, natural products, or other newly discovered compounds with binding targets unidentified) using pharmacophore mapping approach. Benefited from the highly efficient and robust mapping method, PharmMapper bears high throughput ability and can identify the potential target candidates from the database within a few hours.

http://lilab.ecust.edu.cn/pharmmapper/