20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases
Abstract
:1. Purpose
2. Ecdysteroids
3. A Traditional Medicinal Product
4. Pharmacologial Effects of 20E in Animals
5. Protein Synthesis Stimulatory Effect In Vitro
6. Anti-Obesity Effect
7. Mechanism of Action of 20E in Mammals
- Increases ATP synthesis in muscles [106]
- Stimulates production of erythrocytes [74]
- Decreases hyperglycemia in diabetic animals [63]
- Reduces plasma cholesterol levels [107]
- Decreases the activity of triglyceride lipase [108]
- Protects against experimental atherosclerosis in rabbits [109]
- Activates acetylcholinesterase in the brain [110]
- Activates glutamate decarboxylase (=GABA synthesis) in the brain [111]
- Possesses immunomodulatory activity [112].
8. Toxicity, Bioavailability, Pharmacokinetics and Metabolism in Animal Models
Toxicity
9. Pharmacokinetics and Metabolism in Mice—Early Studies
10. Pharmacokinetics after Oral Administration in Mice—More Recent Studies
11. Pharmacokinetics and Metabolism in Humans
11.1. Early Studies
11.2. Recent Studies
12. The Major Routes of 20E Metabolism in Rodents and Humans
13. Large-Scale Production of Pure 20E for Drug Development
General Considerations
- Total chemical synthesis
- Isolation from the current plant source, e.g., Cyanotis sp. following cultivation and collection in China (Yunnan province)
- Cultivation of another species already identified as a good accumulator with a simple ecdysteroid profile (Rhaponticum, Serratula or Pfaffia sp.)
- Use plant cell or hairy-root cultures of an ecdysteroid-producing plant
- Generate recombinant yeasts using insect and/or plant enzymes of ecdysteroid biosynthesis.
- The plant should accumulate a high amount of 20E
- The plant should have a simple ecdysteroid profile (ideally just 20E)
- The plant should be easy and rapid to grow in accessible areas of the world
- The plant matrix should be amenable to the ready purification of ecdysteroids
- The purification and isolation of 20E should not involve expensive chromatographic methods
- The plant should not be susceptible to pests and diseases
- The species should not be rare or protected
- Culture, harvesting and processing costs should be low; initial processing should take place close to the culture site
14. Plants Species Presently Used to Produce Purified 20E
- Achyranthes (A. aspera, A. bidentata, A. fauriei, A. japonica): Perennial or HHA; warm temperate and sub-tropical plants; native to South-east Asia and/or Africa; all plant parts contain ecdysteroids with seeds containing the highest level (0.25%) in A. aspera and roots (1.74%) being the best source in A. bidentata;
- Cyanotis (C. arachnoidea, C. vaga): Perennial; tropical and sub-tropical plants; growing in tropical Africa, the Indian subcontinent and southern China; roots accumulate very high levels of 20E (up to 5.5% of the dw; Wang et al. [145]); simple ecdysteroid profile—major source for commercial 20E cultivated on a large scale in China;
- Pfaffia (P. glomerata, P. iresinoides): Perennial; tropical plants; native to South America; P. glomerata contains ecdysteroids throughout the plant; roots have a very simple ecdysteroid profile, consisting solely of 20E (0.9% of the dw);
- Rhaponticum (R. carthamoides): Perennial; sub-alpine plant; native to the Altai and Sayan Mountains in Central Asia; roots, flowers and seeds accumulate high levels of 20E (1–2% of dw); complex ecdysteroid profile, but >80% as 20E—used to prepare ECDYSTEN pills containing 5 mg of 20E (OPIH, Uzbekistan) [147];
- Serratula (S. centauroides, S. coronata, S. tinctoria, S. wolfii): Perennial; temperate plants; native to western and central Europe; S. tinctoria accumulates up to 2% of dw as ecdysteroids; the major ecdysteroids are 20E 3-Acetate, 20E and PolB; S. coronata is used to prepare SERPISTEN, a 8:1 mixture of 20E and 25S-inokosterone [148].
15. Purification Process
16. Quality Control and Stability
17. Regulatory Preclinical Studies
Preclinal Regulatory Requirements
18. Regulatory Studies with 20E Metabolites
18.1. Some Drugability Calculations
18.2. SAR Studies
19. Clinical Studies
20. Neuro-Muscular Diseases
Sarcopenia
21. Cardio-Metabolic Diseases
21.1. Pre-Diabetes
21.2. Obesity
21.3. Menopause
21.4. Metabolic Syndrome
22. Respiratory Diseases
22.1. Respiratory Failure in COVID-19 Patients
22.2. COVID-19
23. Other Diseases
23.1. Hepatitis
23.2. Chronic Glomerulonephritis
23.3. Celiac Disease
23.4. Sexual Dysfunction
23.5. Parasitoses (Giardiasis, Hymenolepiasis, Lambliasis)
24. Conclusions and Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
E | ecdysone |
20E | 20-hydroxyecdysone |
14d20E | 14-deoxy-20-hydroxyecdysone |
Post | poststerone |
14dPost | 14-deoxypoststerone |
3-epi-Post | 3-epi-poststerone |
16αOHPost | 16α-hydroxypoststerone |
20R/SPost | 20-dihydropoststerone |
21OHPost | 21-hydroxypoststerone |
20,26E | 20,26-dihydroxyecdysone |
PolB | polypodine B |
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Scientific Name | Plant Part | Major Constituents | Claimed Therapeutical Value | World Area | References |
---|---|---|---|---|---|
Achyranthes bidentata | root | 20E, Inokosterone, polysaccharides | Anticancer, anti-inflammatory, diuretic, anti-osteoporotic | India, China Taiwan | [8,9] |
Achyranthes japonica | root, leaf | Inokosterone, 20E, saponin, oleanolic acid, calcium oxalate | Antirheumatic, for amenorrhea, carbuncles, fever, dystocia, urinary ailments | Korea, Japan, China | [10] |
Ajuga bracteosa A. decumbens | whole plant | 20E, ajugasterone C ajugalactone, cyasterone, kiransin, β-sitosterol, cerotic acid, palmitic acid, luteolin | Antitussive, antipyretic, anti-inflammatory, antiphlogistic, antibacterial; treats bladder ailments, diarrhea, bronchitis | Taiwan | [11] |
Ajuga iva | aerial parts | 20E, cyasterone, ajugasterone C, apigenin, apigenin dihexoside, carvacrol | Diabetes, rheumatism, allergy, cancer, renal, metabolic disorders, digestive, cardiovascular, and respiratory disorders | Africa | [12,13] |
Ajuga turkestanica | aerial parts | 20E, turkesterone, cyasterone, iridoids | Weight deficiency, ulcers, burns, wound healing, heart protective, hair growth | Uzbekistan, Tadzhikistan | [14] |
Boerhaavia diffusa | root, aerial parts | 20E, flavonoids, rotenoids, punarnavoside | Immunomodulatory, anticancer, antidiabetic, anti-inflammatory, diuretic, hepatoprotective, antimicrobial, antifungal, anticonvulsant, antioxidant | Brazil, India, Iran, Angola, Ghana, Congo | [15] |
Cyathula prostrata | leaf, root | 20E, cyasterone, terpenoids, flavonols, tannins | Laxative, antitoxic, analgesic, alleviates flu, cough, rheumatism, dysentery, syphilis | Tropical Africa, China, Australia | [8,16,17] |
Cyanotis arachnoidea | aerial parts, root | 20E, ajugasterone C, poststerone, rubrosterone, daucosterol | Skin diseases, psoriasis, gastritis, tuberctulosis | China | [18] |
Diploclisia glaucescens | stem, leaf | paristerone, 20E, capitasterone, oleanane glycosides | Rheumatism, snake venom, biliousness, venereal diseases | China | [19] |
Helleborus niger | rhizomes, leaves | 20E, polypodine B, bufadienolides, | Stomachic, tonic, analgesic, antirheumatic | Romania | [20] |
Microsorum membranifolium | fronds | 20E, ecdysone, 2-deoxy-20E, 2-deoxyecdysone, various conjugates | Asthma, purgative, antiemetic, healing of fractured bones | French Polynesia | [21] |
Paris polyphylla | aerial parts | 20E, calonysterone, steroidal saponins, luteolin, quercetin | Antibiotic, anti-inflammatory, liver cancer | Southwest China | [22] |
Pfaffia glomerata | root | 20E, pterosterone, polypodine B, ginsenosides | General stimulant, analgesic, anabolic, anti-inflammatory, immunostimulant, sedative, hypocholesterolemic | Brazil | [23] |
Podocarpus macrophyllus var. nakaii | stem bark, leaf, root, fruit | 20E, ponasterone A, makisterones, pinene, camphene, cadinene, podocarpene, kaurene | Antihelminthic, blood disorders; tonic for heart, kidneys, lungs, stomach | South Africa | [8,24] |
Polypodium vulgare | rhizome | 20E, polypodine B, polypodaurein, polypodosaponin, flavonoids | Expectorant, cough, pertussis, diuretic | Poland | [25] |
Rhaponticum carthamoides | leaf, root | 20E, makisterones, triterpenes, sesquiterpene lactones, phenolic acids, flavonoids, thiophenes, lignans | Tonic, roborant, adaptogenic, antidepressive, antiparasitic | Eastern Europe | [26,27] |
Serratula chinensis | roots | 20E glycosides, sphingolipids, cerebrosides | Pharyngitis, measles, anti-inflammatory, hypocholesterolemic, anti-cancer, | Southern China | [8,28] |
Sida rhombifolia | root, seed | 20E, ecdysone, ecdysteroid glycosides, cyclopropenoid fatty acids | Enteritis, hepatitis, flu, pneumonia, improves blood circulation, resolves phlegm, alleviates pain | India | [8,29] |
Tinospora cordifolia | aerial parts | 20E, polypodine B, alkaloids, diterpenoid lactones, sinapic acid | Anti-osteoporotic, anti-inflammatory, anti-stress, immuno-modulator, anti-spasmodic, chemo- and radio-protective, anti-anxiety, neuroprotective | India | [30,31] |
Vitex scabra | bark, leaf | 20E, turkesterone, khainaoside, syringaresinol | Astringent, antihelminthic, gastrointestinal disorders, wound healing, sexual enhancer | Thailand | [32] |
Effect | 20E and/or Other Ecdysteroid Preparations |
---|---|
Anabolic (muscle) | [46,47,48,49,50,51,52,53,54] |
Fat-reducing/Hypolipidaemic | [55,56,57,58,59,60,61,62] |
Anti-diabetic | [56,62,63,64,65,66] |
Anti-fibrotic | [67] |
Anti-inflammatory | [68,69] |
Anti-oxidant | [70] |
Anti-thrombotic | [71,72] |
Vasorelaxant | [73] |
Hematopoiesis stimulation | [74] |
Angiogenic | [75,76] |
Cardioprotective | [62,77,78,79] |
Neuromuscular protective | [80,81] |
Neuroprotective | [81,82,83,84] |
Liver protective | [85,86] |
Lung protective | [69,72,87,88] |
Kidney protective | [58,67,89] |
Gastric protective | [90,91] |
Bone, cartilage protective | [92,93,94,95,96,97,98,99] |
Skin protective/repairing | [100,101,102] |
5 min | 10 min | 30 min | 1 h | 3 h | 6 h | 12 h | 24 h | |
---|---|---|---|---|---|---|---|---|
Blood plasma | 0.061 | 0.057 | 0.052 | 0.047 | 0.032 | 0.023 | 0.015 | 0.011 |
Urine | 0.482 | 0.921 | 1.534 | 0.281 | 0.102 | 0.096 | 0.087 | 0.046 |
Feces | 0.015 | 0.019 | 0.035 | 0.068 | 0.099 | 0.931 | 0.312 | 0.041 |
Bile | 0.421 | 0.456 | 1.042 | 0.901 | 0.301 | 0.209 | 0.198 | 0.094 |
Liver | 0.312 | 0.251 | 0.213 | 0.112 | 0.078 | 0.061 | 0.056 | 0.046 |
Heart | 0.062 | 0.052 | 0.035 | 0.033 | 0.031 | 0.029 | 0.023 | 0.022 |
Spleen | 0.041 | 0.026 | 0.024 | 0.018 | 0.023 | 0.027 | 0.032 | 0.027 |
Lungs | 0.116 | 0.069 | 0.057 | 0.053 | 0.049 | 0.045 | 0.036 | 0.028 |
Kidney | 0.137 | 0.123 | 0.098 | 0.071 | 0.055 | 0.043 | 0.037 | 0.032 |
Adrenals | 0.184 | 0.139 | 0.098 | 0.081 | 0.073 | 0.065 | 0.052 | 0.043 |
Testis | 0.048 | 0.036 | 0.029 | 0.026 | 0.023 | 0.021 | 0.019 | 0.017 |
Skeletal muscle | 0.021 | 0.023 | 0.028 | 0.017 | 0.015 | 0.013 | 0.011 | 0.010 |
Spinal cord | 0.019 | 0.028 | 0.067 | 0.041 | 0.033 | 0.024 | 0.020 | 0.018 |
Brain | 0.013 | 0.014 | 0.015 | 0.013 | 0.012 | 0.01 | 0.008 | 0.007 |
Small intestine | 0.254 | 0.139 | 0.094 | 0.083 | 0.076 | 0.061 | 0.05 | 0.033 |
Stomach | 0.034 | 0.047 | 0.075 | 0.061 | 0.053 | 0.041 | 0.032 | 0.023 |
Large intestine | 0.011 | 0.023 | 0.029 | 0.031 | 0.035 | 0.048 | 0.038 | 0.023 |
Bladder | 0.013 | 0.024 | 0.038 | 0.026 | 0.023 | 0.018 | 0.015 | 0.013 |
B1O101 PK Parameter (Unit) | 100 mg | 350 mg | 700 mg | 1400 mg |
---|---|---|---|---|
Cmax (ng/mL) | 141 (16.6) | 317 (37.9) | 399 (24.7) | 710 (20.2) |
tmax (h) | 2.03 (1.00–3.02) | 3.00 (1. 05–4.00) | 3.00 (2.00–4.02) | 3.50 (2.00–4.02) |
AUC0-t (ng·h/mL) | 767 (31.1) | 1924 (40.1) | 2578 (22.9) | 4148 (15.9) |
Non-Clinical Activities | Studies | Clinical Trial | ||
---|---|---|---|---|
Non Medicinal Drug Trial | Phase 1 | Phase 2 | ||
Regulatory requirements | ||||
Absorption | Pharmacokinetics | NA | ✓ | ✓ |
Toxicokinetics | NA | ✓ | ✓ | |
Transporters (Caco-2 cells) | NA | ✓ | ✓ | |
Metabolism | Microsomal metabolism | NA | NA | ✓ |
ADME $ study | NA | NA | ✓ | |
CYP inhibition/induction | NA | ✓ | ✓ | |
Metabolite identification | NA | ✓ | ✓ | |
Toxicology | Phototoxicity | NA | ✓ | ✓ |
Genotoxicity tests (Ames; micronuclei) | NA | ✓ | ✓ | |
Repeated toxicology studies | NA | ✓ | ✓ | |
Micronuclei tests | NA | ✓ | ✓ | |
Distribution | Red blood cell partitioning | NA | ✓ | ✓ |
Plasma protein binding | NA | ✓ | ✓ | |
Pharmacology | In vitro studies | ✓ | ✓ | ✓ |
In vivo studies | ✓ | ✓ | ✓ | |
Safety pharmacology | Cardiovascular system | NA | ✓ | ✓ |
Central nervous system and respiratory function | NA | ✓ | ✓ | |
Documents required for submission dossier | ||||
Investigational Medicinal Product Dossier (IMPD) | NA | ✓ | ✓ | |
Investigation Brochure (IB) | NA | ✓ | ✓ | |
Technical Product Dossier | ✓ | NA | NA | |
Literature related to the product | ✓ | NA | NA | |
Clinical Trial Protocol | ✓ | ✓ | ✓ | |
Informed consent | ✓ | ✓ | ✓ | |
Investigative New Drug (IND) Package for the FDA | NA | ✓ | ✓ |
Compound | MW | LogP | PSA (Å2) | Rotatable Bonds | H-Acceptors | H-Donors | TL Score |
---|---|---|---|---|---|---|---|
20E | 480.30 | 1.36 | 138.45 | 5 | 7 | 6 | 3 |
20,26E | 496.64 | 0.35 | 158.67 | 6 | 8 | 7 | 4 |
14d20E | 464.64 | 2.30 | 118.21 | 5 | 6 | 5 | 1 |
6αOH20E | 482.66 | 1.54 | 141.60 | 5 | 7 | 7 | 4 |
6αOH14d20E | 466.66 | 2.49 | 121.37 | 5 | 6 | 6 | 3 |
Post | 362.46 | 1.03 | 94.83 | 1 | 5 | 3 | 0 |
14dPost | 346.47 | 1.97 | 74.60 | 1 | 4 | 2 | 0 |
6αOHPost | 364.48 | 1.22 | 97.98 | 1 | 5 | 4 | 0 |
6αOH14dPost | 348.48 | 2.16 | 77.75 | 1 | 4 | 3 | 0 |
Aim | Age | N | Dose | Duration | Output | Ref |
---|---|---|---|---|---|---|
Sexual disadaptation | 27–61 | 93 20F, 73M | 7.5–10 mg/day | 1 month | Improvement of libido and sexual activity in 75% of patients | [165] |
Chonic glomerulonephritis | 35 ± 7 | 35 | 15 mg/day | 10 days | Improvement of kidney function and of microcirculation | [166] |
Sexual function | N/A, M | 60 | 5 mg, 2×/day | 30 days | Improved sperm quality and copulative function in patients with disturbed spermatogenesis as a complication of urologic diseases Improvement of sexual function during recovery from myocardial infarction | [158] |
40–60 M | 48 | 5 mg 3×/day | ||||
Giardiasis | N/A | 35 | 5 mg 3× or 4×/day | 10 days | Parasite elimination in 68.7% of patients | [167] |
Hepatitis | N/A | N/A | 5 mg b.i.d. | 30 days | In case of hepatitis B, improvement of liver state | [159] |
Lambliasis | N/A | N/A | 5 mg 4×/day | 10 days | Therapy eliminated most parasites within 10 days | [168] |
Hymenolepiasis | N/A | 22 | 5 mg 3×/day | 2 weeks | Reduction in symptoms and parasitological efficacy of 36.4% | [169] |
Metabolic syndrome | Overweight | 39 | 2 × 50 mg/day | 3 months? | Reduction in body weight (−1.3%) waist circumference (−3.2%), body fat (−7.6%), C-reactive protein (−38%), total cholesterol (−17%), triglycerides (−37%), muscle increase (+2.9%) | [170] |
Menopause disorders | Overweight | N/A | 100 or 200 mg/day | 3 months | Prevention of metabolic syndrome and osteoporosis, reduction in body weight, reduction in plasma cholesterol and CRP; proposed for hormone replacement therapy | [171,172] |
Sarcopenia | ≥65 | 231 | 175/350 mg b.i.d. | 6–9 months | Expected: change from baseline of gait speed (400MW test), appendicular lean mass and handgrip strength | [173] |
Metabolic syndrome | >18 | 64 test 28 Control | 40 or 90 mg/day | 3–6–9 months | Reductions in body mass, proportion of body fat, waist cicumference and hsCRP, retention of muscle mass | [174] |
Prediabetes | 30–60 | 34 | 300 mg/day | 12 weeks | Expected: changes in micronuclei, reduction in fasted glycemia, glycated hemoglobin | [175] |
ARDS in COVID 19 | ≥55 | 310 | 350 mg b.i.d. | 28 days | Expected: Prevention of respiratory deterioration in severe COVID-19 patients | [176] |
Celiac disease | Children 3–14 | 25 | 2.5 mg/kg/day | 14 days | Reduction in symptoms Improvement of energy metabolism | [177] |
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Dinan, L.; Dioh, W.; Veillet, S.; Lafont, R. 20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases. Biomedicines 2021, 9, 492. https://doi.org/10.3390/biomedicines9050492
Dinan L, Dioh W, Veillet S, Lafont R. 20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases. Biomedicines. 2021; 9(5):492. https://doi.org/10.3390/biomedicines9050492
Chicago/Turabian StyleDinan, Laurence, Waly Dioh, Stanislas Veillet, and Rene Lafont. 2021. "20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases" Biomedicines 9, no. 5: 492. https://doi.org/10.3390/biomedicines9050492
APA StyleDinan, L., Dioh, W., Veillet, S., & Lafont, R. (2021). 20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases. Biomedicines, 9(5), 492. https://doi.org/10.3390/biomedicines9050492