Home About us Editorial board Ahead of print Current issue Archives Instructions Submit article Search Subscribe Contacts Login 
  • Users Online: 151
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 66-71

Tranexamic acid: An emerging depigmenting agent


Department of Dermatology, Bangalore Baptist Hospital, Bengaluru, Karnataka, India

Date of Web Publication27-Dec-2016

Correspondence Address:
Dr. Anju George
“Anjanam,” Chitatumukku P. O., Trivandrum - 695 301, Kerala
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-5847.196295

Rights and Permissions
  Abstract 

Tranexamic acid (TXA), an antifibrinolytic drug, is now gaining popularity as a depigmenting agent. It is a synthetic lysine amino acid derivative which mainly blocks the conversion of plasminogen to plasmin by inhibiting plasminogen activator. This results in less free arachidonic acid production, and hence a reduction in the prostaglandin (PG) levels as well. Thus, by reducing PG production, TXA reduces the melanocyte tyrosinase activity and plays an important role in the treatment of melasma, ultraviolet-induced hyperpigmentation, and other postinflammatory hyperpigmentation. It has been tried topically, orally, and intradermally in the management of melasma with minimal adverse effects. However, more randomized trials are needed to fully elucidate the exact mechanism of action, ideal route, frequency, and duration of administration of the drug, along with its potential to treat other pigmentary disorders.

Keywords: Antifibrinolytic, depigmenting agent, intradermal, melasma, tranexamic acid


How to cite this article:
George A. Tranexamic acid: An emerging depigmenting agent. Pigment Int 2016;3:66-71

How to cite this URL:
George A. Tranexamic acid: An emerging depigmenting agent. Pigment Int [serial online] 2016 [cited 2017 Dec 12];3:66-71. Available from: http://www.pigmentinternational.com/text.asp?2016/3/2/66/196295


  Introduction Top


Tranexamic acid (TXA) is primarily an antifibrinolytic drug, whose effects have traversed multiple systems and finally embarked upon the skin. It is a synthetic lysine derivative and was first described in 1966. The drug came as a boon in the treatment of menorrhagia in 1968 and mainly acts by blocking the lysine site on plasminogen, thereby inhibiting fibrinolysis. Since then the indications have become innumerable, and it has proved to be highly useful in controlling bleeding in various coagulation defects such as hemophilia, surgeries like cardiopulmonary bypass and arthroplasty.[1]

Besides coagulation disorders, TXA can ameliorate the necessity for a surgical intervention in menorrhagia or dysfunctional uterine bleeding and in upper gastrointestinal hemorrhage. It reduces the postoperative need for blood transfusion and hence mortality rates, with a good cost benefit and tolerance factor.[2]

It is worth mentioning that this old drug not only holds the position of an antifibrinolytic but also an adjuvant in pigmentary disorders like melasma and ultraviolet (UV)-induced hyperpigmentation.[3]


  Tranexamic Acid in Melasma Top


Melasma is an acquired hypermelanosis affecting the sun-exposed areas of skin, most commonly the face and neck. The exact etiopathogenesis is unknown; however, various etiological factors have been proposed in the literature. These include sun exposure, pregnancy, hormonal therapy, genetic factors, and vascular factors.[4] Innumerable studies evaluating melasma treatments are available; however, only a statistically minor proportion of the subjects have shown a complete clearance of melasma. The relapsing tendency and the deep dermal component in melasma are other hurdles in the treatment besides the adverse effects of commonly used topical triple combination regimens. The skin-whitening effects of TXA were incidentally found when it was used in the treatment of aneurysmal subarachnoid hemorrhage. TXA was reported to be useful in the treatment of melasma in 1979 by Nijor in Japan.[5],[6] The drug tackles mostly the vascular component of melasma and is now widely used as an adjuvant with significant results.[7],[8]


  Pharmacology and Mechanism of Action as A Depigmenting Agent Top


TXA (trans-4-aminomethylcyclohexane carboxylic acid) is a synthetic lysine amino acid derivative which controls and diminishes the dissolution of hemostatic fibrin. TXA exerts its antifibrinolytic effects by reversibly blocking lysine binding sites on plasminogen. This prevents plasmin from interacting with lysine residues on the fibrin polymer, leading to subsequent fibrin degradation. The native human plasminogen has 4–5 lysine binding sites. However, their affinity for TXA is low. The high-affinity lysine site of plasminogen is involved in its binding to fibrin. Plasminogen gets displaced from the surface of fibrin once the high-affinity binding site gets saturated with TXA. Although plasmin may be formed due to conformational changes in plasminogen, binding to and dissolution of the fibrin matrix is inhibited. TXA extends and disseminates throughout the intracellular and extracellular compartments and is finally excreted unchanged in the urine.[8],[9]

Inhibition of ultraviolet-induced plasmin activity

UV exposure increases plasminogen activator production by epidermal keratinocytes in situ.[10] TXA is a natural plasmin inhibitor which blocks the conversion of plasminogen to plasmin. The drug accomplishes this through the inhibition of plasminogen activator by creating a reversible complex with plasminogen.[2],[11]

TXA also prevents the binding of plasminogen to the keratinocytes and thus inhibits UV-induced plasmin activity in keratinocytes.[12] Plasmin is a protease that enhances the intracellular release of arachidonic acid (AA) and alpha-melanocyte-stimulating hormone (a-MSH). AA and a-MSH have the property of stimulating melanogenesis by melanocytes. Tranexamic acid being a plasmin inhibitor depletes the keratinocyte pool of AA involved in UV-induced melanogenesis.[6],[8],[13],[14] The topical application of TXA has shown reduction in UV-induced hyperpigmentation. An empirical study demonstrates the effective usage of TXA on guinea pigs where the pigmentation is explicitly developed by the application of topical AA in a controlled manner.[11],[15],[16]

Reduction in prostaglandin production

Following UV exposure, prostaglandins (PGs) activate signaling pathways involved in growth, differentiation, and apoptosis of melanocytes. PG E2 is released abundantly by keratinocytes following UV radiation (UVR). This stimulates the formation of dendrites in melanocytes and melanocyte tyrosinase activity. TXA inhibits PG production and thus reduces the melanocyte tyrosinase activity. This particular characteristic of TXA is successfully applied in the treatment of melasma, UV-induced hyperpigmentation, and other postinflammatory hyperpigmentation.[11],[15],[17]

Reduction of vascularity in melasma

A common speculation is that UVR stimulates the production of angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and interleukin-8. VEGF interacts with VEGF receptors present in epidermal keratinocytes which release metabolites of AA and plasminogen from the proliferated vessels. This enhances melanogenesis. TXA targets the vascular components of the skin and hence adds support to the vascular theory of melasma.[18],[19],[20]

Plasmin plays an important role in the release of b-FGF, which is a potent melanocyte growth factor and promotes melanocyte proliferation.[21] TXA indirectly reduces b-FGF production. It also suppresses angiogenesis and neovascularization induced by b-FGF. Experimental studies have shown a reduction in lesional mast cells, which might suppress various pathogenetic factors that initiate the development of melasma.[22] These mechanisms point to the fact that TXA may be tried for other conditions like periorbital melanosis and even early keloids, where the vascularity component can be targeted.

Effects on melanogenesis

Tyrosinase-related protein (TRP-1) and TRP-2 are important enzymes in the Raper mason pathway of melanogenesis. TXA not only reduces tyrosinase levels but also decreases the levels of TRP-1 and TRP-2. Activation of the signaling pathway extracellular signal-regulated kinase (ERK) induces microphthalmia-associated transcription factor (MITF) degradation, resulting in reduced melanogenesis. MITF is the key transcription factor regulating these enzymes involved in melanogenesis. TXA stimulates the ERK signaling pathway and downregulates MITF protein level. This reduces inflammation-induced melanogenesis by decreasing tyrosinase protein expression. TXA is also capable of suppressing melanogenesis by regulating tyrosinase transcription in addition to an anti-inflammatory action.[11],[14],[23] These mechanisms may pave the way for TXA being a potential drug in treating postinflammatory hyperpigmentation. More experimental studies are however needed to prove the exact mechanism and efficacy of the drug in treating the same.

Li et al. studied TXA intradermally on guinea pigs and found that at the basal layer of exposed epidermis, the number of melanocytes remained the same, but the melanin content was significantly lowered. This highlights the fact that TXA has no effect on the number of melanocytes but affects melanin expression.[24],[25]

It has been over four decades since TXA has been in use both orally and intravenously as a fibrinolytic inhibitor.[26] For depigmentation, the drug may be administered orally, topically, intradermally, or intravenously. However, literature lacks comprehensive studies on the efficacy of different modes of administration of the drug under diverse conditions.


  Oral Tranexamic Acid Top


In the prospective, randomized controlled trial (RCT) study conducted by Karn et al. in Nepal, oral TXA was administered to melasma patients in a dose of 250 mg twice daily for 3 months. A statistically significant decrease in the mean melasma assessment severity index (MASI) from the baseline was observed. The authors concluded that it provides a rapid and sustained improvement in the treatment of melasma.[13] Another descriptive study conducted on 65 melasma patients in Pakistan, the drug was prescribed at the same dose for 6 months. Sixty-three percent had a good response and 23% had an excellent response after 6 months.[27] The dose of oral TXA used in melasma is far less than that prescribed for its hemostatic action.

In many situations, it is used as an adjuvant with other drugs or procedures. Cho et al.[28] studied 51 melasma patients, where TXA was administered at a dose of 500 mg/day for 8 months. This was combined with intense pulsed light and Q-switched neodymium: yttrium-aluminum-garnet (Qs Nd-YAG) (four sessions). The combination treatment showed a better response when compared to laser therapy alone. In the randomized trial by Shin et al.,[29] TXA at a dose of 750 mg/day (for 8 weeks) was combined with low-fluence Qs Nd-YAG laser therapy. The combination showed a superior reduction in mean MASI score compared with laser therapy alone.

However, in the study by Wu et al., a recurrence of melasma was observed in 9.5% after 6 months of treatment. Nonetheless, these were effectively treated with repeated administration of TXA. Another notable observation in this study was the differential response of TXA on melasma patients having coexisting freckles and senile lentigo. The treatment was unresponsive to freckles and senile lentigo, whereas the melasma responded well.[14]

Padhi and Pradhan concluded that oral TXA at a dose of 250 mg twice daily along with fluocinolone containing topical triple combination cream for 8 weeks, produced a significant and faster improvement in melasma, and also saved patients from the adverse effects of long-term use of steroids and hydroquinone.[30]


  Topical Tranexamic Acid Top


Epidermal melasma has a better prognosis and hence topical TXA may show some efficacy in this variant, rather than the dermal and mixed melasma variants, which carry a poor prognosis.[15],[31] Exogenous ochronosis, guttate hypomelanotic macules, colloid milia, erythema, and stinging and burning sensation are few of the common side effects of hydroquinone.[27] As a result, patients often tend to discontinue such topical medications, and further seek alternative treatment modalities. Topical TXA shows rapid and more sustained results with very minimal adverse effects as far as epidermal melasma is concerned, and the drug has been proven to have almost similar cumulative effects of hydroquinone and dexamethasone.[3] A better probe is however needed to find out the efficacy of TXA as a combination therapy with other medications and with other methods used in the treatment of melasma.

In the study by Wu et al.,[14] patients with freckles were unresponsive to oral administration of TXA. On the contrary, Kondou et al.[32] successfully employed topical TXA emulsion for the treatment of melasma and freckles for 5–18 weeks. Here, the topical TXA also prevented the appearance of new lesions. A combination of oral and topical TXA showed both significant declines in epidermal pigmentation and improvement of dermal melasma.[33] However, the rationale of combination therapy is not very clear as oral TXA should take care of both epidermal and dermal components in melasma.

Kanechorn Na Ayuthaya et al.[34] conducted a double-blind RCT among Asians and used 5% TXA in a liposome gel formulation for epidermal melasma for a duration of 12 weeks. This was compared with the vehicle in a split-face trial. Even though 78.2% of patients showed a decrease in the melanin index, the results were not significant as compared with the vehicle. Moreover, in the study, topical TXA induced erythema in many subjects. The newer topical preparation of TXA cetyl ester HCl is available in recent cosmetic formulations. This might prove helpful in reducing erythema and stinging sensation experienced by a few. TXA is temperature-stable, not UV sensitive, and does not get oxidized easily. Thus, it makes a good component in fairness creams in contrast to hydroquinone which gets oxidized fast.[35]


  Intradermal Tranexamic Acid Top


The dermal and mixed variants of melasma are highly treatment resistant. In this case, TXA may be administered intradermally. The microneedling method proves to be efficacious in the intradermal delivery of the drug. In this method, multiple microinjuries are made in the dermis, using a derma roller and this facilitates transport of substances through various transport channels, leaving the epidermis intact. The derma roller is a handheld instrument consisting of a handle with a cylinder studded in eight rows with fine stainless steel needles of 0.5–3 mm in length, which is rolled in multiple directions.

TXA is available as 5 mL ampoule containing 500 mg of the drug. In an open-label RCT in South India, 4 mg/mL of TXA was used with microneedling on melasma lesions. This was done three times at monthly intervals (0, 4, and 8 weeks) and followed up for further 3 months at monthly intervals. Exactly 41.38% patients experienced more than 50% improvement without any major adverse events.[36]

In another study conducted in Korea on melasma patients, TXA was directly administered intradermally (4 mg/mL) weekly for a period of 12 weeks. More than 75% patients experienced a statistically significant improvement.[15] The time period between consecutive microneedling sessions is left to the prerogative of the operating personnel and hence a proper quantification is lacking. Moreover, pertinent is the scheduling of the maintenance sessions which are necessary as melasma is prone for recurrence.

Another notable application is the intravenous administration of TXA for the purpose of skin lightening. Here, a dose of 500 mg/week is administered for a period of 1–2 months and 500 mg every month for maintenance[6] [Table 1].
Table 1: Summary of tranexamic acid studies: As a depigmenting agent

Click here to view



  Adverse Effects Top


TXA is a well-tolerated drug and it is mostly considered safe at the usual dosage. Nausea and diarrhea are the most common side effects.[9] Other systemic side effects observed with low-dose administration include oligomenorrhea, gastric upset, and palpitations.[27] Venous thromboembolism, myocardial infarction, cerebrovascular accidents, and pulmonary embolism have been reported when given in hemostatic doses (up to 1000 mg daily). The contraindications of the drug include acquired defective color vision, active intravascular clotting conditions, and drug hypersensitivity.[13] Though it is used in low doses for a short duration as a systemic depigmenting agent, it is always vital to rule out underlying coagulation defects to prevent untoward adverse events. Hence, a thorough history along with essential investigations pertaining to coagulation defects will ensure better safety with the drug usage. Mild discomfort, burning sensation, and erythema were observed when it was used intradermally, which subsided without the need for other interventions.[36]


  Conclusion Top


The literature review reveals that TXA is a safe and promising drug not only in the treatment of melasma but also in other pigmentary conditions. However, larger RCTs with long-term follow-up are needed to fully elucidate the exact mechanism of action, ideal route, frequency, and duration of administration. None of the existing depigmenting drugs can provide fast and sustained results. Although the gold standard in the management of melasma involves the use of triple combination regimens, these have umpteen adverse effects. The thirst for a fair and clear skin can never be fully quenched. Hence, the quest for newer and safer depigmenting agents continues with TXA evolving to be a safe and effective one in the armamentarium of a dermatologist.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Binz S, McCollester J, Thomas S, Miller J, Pohlman T, Waxman D, et al. CRASH‑2 study of tranexamic acid to treat bleeding in trauma patients: A controversy fueled by science and social media. J Blood Transfus 2015;2015:874920.  Back to cited text no. 1
    
2.
Dunn CJ, Goa KL. Tranexamic acid: A review of its use in surgery and other indications. Drugs 1999;57:1005‑32.  Back to cited text no. 2
    
3.
Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci 2014;19:753‑7.  Back to cited text no. 3
    
4.
Sarkar R, Arora P, Garg VK, Sonthalia S, Gokhale N. Melasma update. Indian Dermatol Online J 2014;5:426‑35.  Back to cited text no. 4
    
5.
Nijor T. Treatment of melasma with tranexamic acid. Clin Res 1979;13:3129‑31.  Back to cited text no. 5
    
6.
Malathi M, Thappa DM. Systemic skin whitening/lightening agents: What is the evidence? Indian J Dermatol Venereol Leprol 2013;79:842‑6.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7.
Rajaratnam R, Halpern J, Salim A, Emmett C. Interventions for melasma. Cochrane Database Syst Rev 2010;7:CD003583.  Back to cited text no. 7
    
8.
Tse TW, Hui E. Tranexamic acid: An important adjuvant in the treatment of melasma. J Cosmet Dermatol 2013;12:57‑66.  Back to cited text no. 8
    
9.
Calapai G, Gangemi S, Mannucci C, Miniullo PL, Casciaro M, Calapai F. Systematic review of tranexamic acid adverse reactions. J Pharmacovigil 2015;3:1‑7.  Back to cited text no. 9
    
10.
Takashima A, Yasuda S, Mizuno N. Determination of the action spectrum for UV‑induced plasminogen activator synthesis in mouse keratinocytes in vitro. J Dermatol Sci 1992;4:11‑7.  Back to cited text no. 10
    
11.
Kim MS, Bang SH, Kim JH, Shin HJ, Choi JH, Chang SE. Tranexamic acid diminishes laser‑induced melanogenesis. Ann Dermatol 2015;27:250‑6.  Back to cited text no. 11
    
12.
Ando H, Matsui MS, Ichihashi M. Quasi‑drugs developed in Japan for the prevention or treatment of hyperpigmentary disorders. Int J Mol Sci 2010;11:2566‑75.  Back to cited text no. 12
    
13.
Karn D, Kc S, Amatya A, Razouria EA, Timalsina M. Oral tranexamic acid for the treatment of melasma. Kathmandu Univ Med J (KUMJ) 2012;10:40‑3.  Back to cited text no. 13
    
14.
Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y, et al. Treatment of melisma with oral administration of tranexamic acid. Aesthetic Plast Surg 2012;36:964‑70.  Back to cited text no. 14
    
15.
Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY, et al. Localized intradermal microinjection of tranexamic acid for treatment of melasma in Asian patients: A preliminary clinical trial. Dermatol Surg 2006;32:626‑31.  Back to cited text no. 15
    
16.
Maeda K, Naganuma M. Topical trans‑4‑aminomethylcy clohexanecarboxylic acid prevents ultraviolet radiation‑induced pigmentation. J Photochem Photobiol B 1998;47:136‑41.  Back to cited text no. 16
    
17.
Starner RJ, McClelland L, Abdel‑Malek Z, Fricke A, Scott G. PGE(2) is a UVR‑inducible autocrine factor for human melanocytes that stimulates tyrosinase activation. Exp Dermatol 2010;19:682‑4.  Back to cited text no. 17
    
18.
Passeron T. Melasma pathogenesis and influencing factors - An overview of the latest research. J Eur Acad Dermatol Venereol 2013;27 Suppl 1:5‑6.  Back to cited text no. 18
    
19.
Kim EH, Kim YC, Lee ES, Kang HY. The vascular characteristics of melasma. J Dermatol Sci 2007;46:111‑6.  Back to cited text no. 19
    
20.
Sonthalia S. Etiopathogenesis of melasma. In: Sarkar R, editor. Melasma: A Monograph. New Delhi: Jaypee; 2015. p. 6‑14.  Back to cited text no. 20
    
21.
Falcone DJ, McCaffrey TA, Haimovitz‑Friedman A, Vergilio JA, Nicholson AC. Macrophage and foam cell release of matrix‑bound growth factors. Role of plasminogen activation. J Biol Chem 1993;268:11951‑8.  Back to cited text no. 21
    
22.
Kang HY, Bahadoran P, Suzuki I, Zugaj D, Khemis A, Passeron T, et al. In vivo reflectance confocal microscopy detects pigmentary changes in melasma at a cellular level resolution. Exp Dermatol 2010;19:e228‑33.  Back to cited text no. 22
    
23.
Kim DS, Park SH, Kwon SB, Park ES, Huh CH, Youn SW, et al. Sphingosylphosphorylcholine‑induced ERK activation inhibits melanin synthesis in human melanocytes. Pigment Cell Res 2006;19:146‑53.  Back to cited text no. 23
    
24.
Li D, Shi Y, Li M, Liu J, Feng X. Tranexamic acid can treat ultraviolet radiation‑induced pigmentation in guinea pigs. Eur J Dermatol 2010;20:289‑92.  Back to cited text no. 24
    
25.
Elfar NN, El‑Maghraby GM. Efficacy of intradermal injection of tranexamic acid, topical silymarin and glycolic acid peeling in treatment of melasma: A comparative study. J Clin Exp Dermatol Res 2015;6:1‑7.  Back to cited text no. 25
    
26.
Tengborn L, Blombäck M, Berntorp E. Tranexamic acid - An old drug still going strong and making a revival. Thromb Res 2015;135:231‑42.  Back to cited text no. 26
    
27.
Aamir S, Naseem R. Oral tranexamic acid in treatment of melisma in Pakistani population: A pilot study. J Pak Assoc Dermatol 2014;24:198‑203.  Back to cited text no. 27
    
28.
Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in melasma patients treated with IPL and low fluence QS Nd: YAG laser. J Dermatolog Treat 2013;24:292‑6.  Back to cited text no. 28
    
29.
Shin JU, Park J, Oh SH, Lee JH. Oral tranexamic acid enhances the efficacy of low‑fluence 1064‑nm quality‑switched neodymium‑doped yttrium aluminum garnet laser treatment for melasma in Koreans: A randomized, prospective trial. Dermatol Surg 2013;39(3 Pt 1):435‑42.  Back to cited text no. 29
    
30.
Padhi T, Pradhan S. Oral tranexamic acid with fluocinolone‑based triple combination cream versus fluocinolone‑based triple combination cream alone in melasma: An open labeled randomized comparative trial. Indian J Dermatol 2015;60:520.  Back to cited text no. 30
[PUBMED]  Medknow Journal  
31.
Ejaz A, Raza N, Iftikhar N, Muzzafar F. Comparison of 30% salicylic acid with Jessner's solution for superficial chemical peeling in epidermal melasma. J Coll Physicians Surg Pak 2008;18:205‑8.  Back to cited text no. 31
    
32.
Kondou S, Okada Y, Tomita Y. Clinical study of effect of tranexamic acid emulsion on melasma and freckles. Skin Res 2007;6:309‑15.   Back to cited text no. 32
    
33.
Na JI, Choi SY, Yang SH, Choi HR, Kang HY, Park KC. Effect of tranexamic acid on melasma: A clinical trial with histological evaluation. J Eur Acad Dermatol Venereol 2013;27:1035‑9.  Back to cited text no. 33
    
34.
Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, Nakakes A. Topical 5% tranexamic acid for the treatment of melasma in Asians: A double‑blind randomized controlled clinical trial. J Cosmet Laser Ther 2012;14:150‑4.  Back to cited text no. 34
    
35.
Sarkar R, Chugh S, Garg VK. Newer and upcoming therapies for melasma. Indian J Dermatol Venereol Leprol 2012;78:417‑28.  Back to cited text no. 35
  Medknow Journal  
36.
Budamakuntla L, Loganathan E, Suresh DH, Shanmugam S, Suryanarayan S, Dongare A, et al. A randomised, open‑label, comparative study of tranexamic acid microinjections and tranexamic acid with microneedling in patients with melasma. J Cutan Aesthet Surg 2013;6:139‑43.  Back to cited text no. 36
[PUBMED]  Medknow Journal  



 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Conclusion
Tranexamic Acid ...
Pharmacology and...
Oral Tranexamic Acid
Topical Tranexam...
Intradermal Tran...
Adverse Effects
References
Article Tables

 Article Access Statistics
    Viewed3893    
    Printed28    
    Emailed0    
    PDF Downloaded436    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]