Centella asiatica

Description

Centella asiatica (also known as gotu kola and Hydrocotyle asiatica) is a perennial,herbaceous creeper with kidney shaped leaves, found in India, Sri Lanka, Madagascar, South Africa, Australia, China, and Japan. Centella prefers togrow in shady, moist, or marshy areas.

Active Constituents

Centella contains several active constituents, of which the most important are the triterpenoid saponins, including asiaticoside, centelloside, madecassoside, and asiatic acid. In addition, Centella contains other components, including volatile oils, flavonoids, tannins, phytosterols, amino acids, and sugars.3

Mechanisms of Action

Centella has several pharmacological actions, based primarily on in vivo experiments. After oral and topical administration in rats, increased cellular hyperplasia and collagen production were noted at the site of injury, measured by increased granulation tissue levels of DNA, protein, total collagen, and hexosamine. More rapid maturation andcross-linking of collagen were seen in animals treated with the herbal extract, as evidenced by elevated stability of acidsolublecollagen and increases in aldehyde content and tensile strength. Compared to control wounds, rats treated withgotu kola had a higher degree of epithelialization and a significantly more rapid rate of wound contraction.4,5

In addition to improving wound healing, Centella may also have an effect on connective tissue of varicosities. After receiving 30 mg total triterpenoid fraction of Centella asiatica (TTFCA) twice daily for three months, individuals with varicose veins had significantly reduced serum enzymes involved in mucopolysaccharide metabolism (betaglucuronidase, beta-N-acetylglucosaminidase, and arylsulfatase) compared to baseline values (p<0.01).6 style="text-align: justify;">The capacity to regenerate axons is an important component of healing following nerve damage. Rats given Centella extract in their drinking water recovered more quickly after nerve damage than controls, with increased axonal regeneration and more rapid functional recovery.7 The fresh juice extract of gotu kola at 200 and 600 mg/kg twice per day has proven to be protective against aspirin- and ethanol-induced gastric ulcers,8,9 with similar effects as the medication sucralfate.8 Centella significantly induced gastric mucin secretion and mucosal cell glycoprotein production, markers of increased gastric mucosal defense factors.8

Pharmacokinetics

A pharmacokinetic study suggests the active ingredients in TTFCA are well absorbed in human volunteers.10 After single oral administration of 30 and 60 mg of the extract, maximum plasma levels of asiatic acid were reached at 4.5 and 4.2 hours, respectively. Plasma half-lives were 2.2 hours in the 30-mg dose and 3.4 hours in the 60-mg dose, with no detectable levels of the aponin present 24 hours after single dosing. Seven-day treatment with the herb at the same dosing schedule resulted in higher peak plasma concentrations, longer half-lives, and greater area-under-thecurve

values.10


Clinical Indications
Venous Insufficiency

In a double-blind study, 94 patients (86 men, 8 women; ages 20-80) with venous insufficiency of the lower extremities for an average of 14 years, were randomized to one of three treatment groups: a triterpenoid extract of Centella asiatica (TECA) at a daily dose of 60 or 120 mg or placebo for three months. Individuals whotook gotu kola at either dose demonstrated significant

clinical improvements in limb heaviness (p=0.033), edema (p=0.026), and global evaluation of efficacy (p=0.05). Venous distension, measured by plethysmography, was significantly better in the active group at 40 mmHg (p=0.08), 50 mmHg (p=0.055) and 60 mmHg (p=0.09), compared to deteriorating placebo values.11

Venous Hypertensive Angiopathy

Forty patients (21 males, 19 females; mean age 48 years) with severe venous hypertension, ankle swelling, and lipodermatosclerosis, were randomized to receive TTFCA 60 mg twice daily or placebo for eight weeks; patients in the study did not wear compression stockings. After trial conclusion, patients taking the herbal extract experienced a significant decrease in skinflux and rate of ankle swelling compared to baseline values (p<0.05).>
Airline Flight Microangiopathy

Physical consequences of long-distance flights range from simple swelling of the lower limbs to the formation of dangerous blood clots. Centella’s effectiveness was evaluated in 66 flight passengers (33 men, 33 women; mean age 38) traveling in economy class for 3- 12 hours. Subjects were randomized to receive 60 mg TTFCA three times per day or a placebo two days before, the day of, and two days after the flight. Results showed significant improvements in microcirculatory function (transcutaneous pO2 and pCO2, laser doppler flowmetry, venoarteriolar response, rate of ankle swelling, and edema) in those utilizing TTFCA (p<0.05),>Echolucency in Carotid and Femoral
Plaques

Carotid artery plaques that are echolucent on ultrasound have greater amounts of certain physiological components (e.g., lipids, blood elements) and limited amounts of collagen, making plaque inherently weaker and increasing the risk of embolization. This unstable plaque is associated with a higher clinical risk of stroke and asymptomatic cerebral lesions.15

Asymptomatic patients (49 men, 38 women; mean age 56) with high-risk, echolucent carotid artery plaques were randomized to receive 60 mg TTFCA or placebo three times daily for one year; patients also took platelet anti-aggregating medication throughout the trial. After 12 months, sonographic evaluation indicated a significant decrease in plaque echolucency inthe TTFCA group. Incidence of positive MRI images indicating cerebral ischemic lesions was seven percent in the TTFCA group and 17 percent in the control group (p<0.05).15>

In a second study testing a similar dose of gotu kola, patients with femoral plaques demonstrated a decrease in plaque echolucency after 12 months of therapy,compared to no change in the control group. Degreeof stenosis and walking distance did not change in thetwo groups.16

Diabetic Microangiopathy
Diabetes is characterized by increased skin blood flow and decreased venous return, resulting in

blood pooling. Forty-eight patients with diabetic microangiopathy were randomized to one of three treatment groups for six months: 60 mg TTFCA twice daily, placebo, or no treatment. Using laser doppler flowmetry measurements, the researchers concluded those taking TTFCA had significant reductions in skin blood flow at rest after three (p<0.05)>

compared to baseline values. In addition, VAR scores (decrease of skin blood flow on standing) increased significantly from 6.4 percent to 23.9 percent at three months and 25.9 percent at six months (p<0.05).>Keloid and Scar Management

Centella has long been recommended for the treatment of keloids and/or hypertrophic scars. In one open clinical trial, 227 patients were divided into two groups and treated with oral Centella alone or surgical scar revision plus Centella at doses of 60-150 mg daily for up to 18 months. In the Centella-only group, 116 of 139 patients (82%) experienced relief of symptoms and disappearance of inflammation. In the 88 subjects in the combined surgery and Centella group, 72 percent demonstrated improvement.18 In addition to its oral use, Centella has been used as a topical cream in a comprehensive scar management program. Observationally, it was found to improve scar maturity from an average of six months without treatment to three months with

treatment.19

Anxiety

Centella is used in Ayurvedic medicine for the treatment of anxiety. A 2000 study supports this ancient claim. After assessing baseline measurements of acoustic startle response (ASR), mood self-rating scale, heart rate, and blood pressure, 40 healthy subjects (21 males, 19 females; ages 18-45 years) were randomized to receive 12 g non-standardized Centella dissolved in 300 mL grape juice or placebo. Evaluations were recorded at 30, 60, 90, and 120 minutes after beginning

therapy. Centella significantly decreased ASR amplitude compared to placebo at 30 (p<0.02)>change.20

Other Indications
Centella may also have potential application for scleroderma,21 alcohol-induced liver cirrhosis,22 leg ulcers,23 and as adjunctive treatment in leprosy.24 Animal studies indicate it may have potential for prevention of aspirin- or ethanol-induced gastric ulcers.8,9

Side Effects and Toxicity

Alcoholic extracts of gotu kola have shown no toxicity at doses of 350 mg/kg when given i.p. to rats.1 Reported adverse effects include GI upset and nausea. Topical use of the extract has led to reports of rash.25 Three cases of jaundice with elevated liver enzymes were reported in Argentina following dosing of Centella. Patients had taken Centella (standardization and dose unknown) for 20-60 days, and recovered on discontinuation of the herb.26

Dosage

In adults, the recommended daily dose of TTFCA (or TECA) extracts standardized for asiaticoside, asiatic acid, and madecassic acid is 60-120 mg. The recommended daily dosages of crude herb and 1:5 tincture are 0.5-6 g and 10-20 mL, respectively.27

Warnings and Contraindications
Gotu kola should be avoided during pregnancy, due to its emmenagogue action.28

References

1. Bhavan BV. Selected Medicinal Plants of India. Bombay, India; Tata Press; 1992.
2. www.CentellaAsiatica.com. [Accessed February 23, 2007]
3. Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. 2nd ed. New York, NY: John Wiley & Son; 1998:284.
4. Suguna L, Sivakumar P, Chandrakasan G. Effects of Centella asiatica extract on dermal wound healing in rats. Indian J Exp Biol 1996;34:1208-1211.
5. Shetty BS, Udupa SL, Udupa AL, Somayaji SN. Effect of Centella asiatica L (Umbelliferae) on normal and dexamethasone-suppressed wound healing in Wistar Albino rats. Int J Low Extrem Wounds 2006;5:137-143.
6. Arpaia MR, Ferrone R, Amitrano M, et al. Effects of Centella asiatica extract on mucopolysaccharide metabolism in subjects with varicose veins. Int J Clin Pharmacol Res 1990;10:229-233.
7. Soumyanath A, Zhong YP, Gold SA, et al. Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in vitro. J Pharm Pharmacol 2005;57:1221-1229.
8. Sairam K, Rao CV, Goel RK. Effect of Centella asiatica Linn on physical and chemical factors induced gastric ulceration and secretion in rats. Indian J Exp Biol 2001;39:137-142.
9. Cheng CL, Koo MW. Effects of Centella asiatica on ethanol induced gastric mucosal lesions in rats. Life Sci 2000;67:2647-2653.
10. Grimaldi R, De Ponti F, D’Angelo L, et al. Pharmacokinetics of the total triterpenic fraction of Centella asiatica after single and multiple administrations to healthy volunteers. A new assay for asiatic acid. J Ethnopharmacol 1990;28:235-241.
11. Pointel JP, Boccalon H, Cloarec M, et al. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987;38:46-50.
12. Cesarone MR, Belcaro G, De Sanctis MT, et al. Effects of the total triterpenic fraction of Centella asiatica in venous hypertensive microangiopathy: a prospective, placebo-controlled, randomized trial. Angiology 2001;52:S15-S18.
13. Cesarone MR, Belcaro G, Rulo A, et al. Microcirculatory effects of total triterpenic fraction of Centella asiatica in chronic venous hypertension: measurement by laser Doppler, TcPO2-CO2, and leg volumetry. Angiology 2001;52:S45-S48.
14. Cesarone MR, Incandela L, De Sanctis MT, et al. Flight microangiopathy in medium- to long-distance flights: prevention of edema and microcirculation alterations with total triterpenic fraction of Centella asiatica. Angiology 2001;52:S33-S37.
15. Cesarone MR, Belcaro G, Nicolaides AN, et al. Increase in echogenicity of echolucent carotid plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, placebo-controlled, randomized trial. Angiology 2001;52:S19-S25.
16. Incandela L, Belcaro G, Nicolaides AN, et al. Modification of the echogenicity of femoral plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, randomized, placebocontrolled trial. Angiology 2001;52:S69-S73.
17. Cesarone MR, Incandela L, De Sanctis MT, et al. Evaluation of treatment of diabetic microangiopathy with total triterpenic fraction of Centella asiatica: a clinical prospective randomized trial with a microcirculatory model. Angiology 2001;52:S49-S54.
18. Bosse JP, Papillon J, Frenette G, et al. Clinical study of a new antikeloid agent. Ann Plast Surg 1979;3:13-21.
19. Widgerow AD, Chait LA, Stals R, Stals PJ. New innovations in scar management. Aesthetic Plast Surg 2000;24:227-234.
20. Bradwejn J, Zhou Y, Koszycki D, Shlik J. A doubleblind, placebo-controlled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects. J Clin Psychopharmacol 2000;20:680-684.
21. Sasaki S, Shinkai H, Akashi Y, Kishihara Y. Studies on the mechanism of action of asiaticoside (Madecassol) on experimental granulation tissue and cultured fibroblasts and its clinical application in systemic scleroderma. Acta Derm Venereol 1972;52:141-150.
22. Darnis F, Orcel L, de Saint-Maur PP, Mamou P. Use of a titrated extract of Centella asiatica in chronic hepatic disorders (author’s trans). Sem Hop 1979;55:1749-1750. [Article in French]
23. Huriez C. Action of the titrated extract of Centella asiatica in the cicatrization of leg ulcers (10 mg tablets). Apropos of 50 cases. Lille Med 1971;17: S574-S579. [Article in French]
24. Chaudhury S, Hazra S, Podder GC, et al. New multidrug regimen with indigenous drugs and dapsone in the treatment of lepromatous leprosy (preliminary report). Indian J Dermatol 1987;32:63-67.
25. Eun HC, Lee AY. Contact dermatitis due to madecassol. Contact Dermatitis 985;13:310-313.
26. Jorge OA, Jorge AD. Hepatotoxicity associated with the ingestion of Centella asiatica. Rev Esp Enferm Dig 2005;97:115-124.
27. Turton S. Centella asiatica. Aust J Herbalism 1993;5:60.
28. Brinker F. Herb Contraindications and Drug Interactions. 2nd ed. Sandy, OR: Eclectic Medical Publications; 1998:78.

Bali dogs: Allergies to Pets

Bali dogs: Allergies to Pets

Triterphenoid saponnins : Induction of redox imbalance and apoptosis in multiple myeloma cells

Abstract

The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-L-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals.

Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.