ProjectSummary/ProposalTopic:Tranexamic Acid in Melasma TreatmentStudentName:  Salman AhmadMScDermatology in Clinical PracticeUniversityof South WalesDateof Submission: 2 March 2018 Backgroundand Introduction: Acommon pigmentary condition, melasma, is best defined as localized, chronic -acquired hyper melanosis of the skin characterized by light to dark brownmacules and patches symmetrically involving the sun-exposed areas of the face,neck and occasionally the forearms. It is commonly observed in reproductive agegroup women, rarely in postmenopausal females and males (10% of cases).Causative factors implicated in the melasma pathogenesis include geneticsusceptibility, ultraviolet (UV) light exposure, pregnancy, sex hormones, oral contraceptivepills, thyroid dysfunction, cosmetics, phototoxic drugs (e.g., antiseizuremedications).(Grimes PE,1995)(Park et al,2017)Thereare three clinical patterns of melasma, malar (mostcommon), centro facial and mandibular. On the basis of visible light,wood’s light and lesional histology, melasma has been classified as epidermal,which has increased melanin predominantly in basal and suprabasal layers of theepidermis with pigment accentuation on Wood’s lamp.

The dermal type hasperivascular melanin-laden macrophages in the superficial and deep dermis anddoes not accentuate with Wood’s lamp. The mixed variety has elements of bothand appears as deep brown colors with Wood’s lamp accentuation of only theepidermal component.(Sanchez NP et al,1981)Melasmais well known for treatment resistance and relapses on treatmentdiscontinuation.Melasma is found to be refractory to treatment, with a tendencyto recur after treatment. There is not a single satisfactory treatmentmodality to date.(Del Rosario E.

, et al, 2018) Inmelasma treatment, the introduction of tranexamic acid ( oral, topical orintralesional) is relatively a novel concept. The skin?whitening effects ofTranexamic acid were incidentally found when it was used in the treatment ofaneurysmal subarachnoid hemorrhage. Nijor from Japan,1979 first reportedTranexamic Acid to be effective in melasma treatment. Objective: Thisdissertation proposal seeks to offer therapeutic benefits of the use ofTranexamic acid (TXA) as an innovative agent, either as an oral, topical orintralesional method for melasma treatment. Importanceof this Proposal: Tranexamic acid being originally a hemostatic agent. Its usein treating and gaining clinical benefits in Melasma treatment is not highlydocumented and there is scope for establishing and validating Tranexamic acidwith accurate, medically focused perspectives. Hypothesis:HI:Alternative hypothesis: There have been medically documented and validatedevidence that smaller doses use of Tranexamic acid (250 mg BD) has a beneficialrole in Melasma Treatment(Poojary & Minni, 2015).

  HO:Null Hypothesis: There is no medical evidence to even remotely suggest thatsmaller doses use of Tranexamic acid (250 mg BD) has a beneficial role inMelasma Treatment. Methodology: ThisProposal uses the qualitative method of research, to achieve the quantum ofliterature, findings, and studies to ascertain research question, as the firststep.  The literature used is secondary sources such as trial proceedingsof peers and data from published papers on the effect of TXA treatment onMelasma. All of the referenced publications will be no older than 10 years andwill not have a low rating. In the next step, the author will infer from theresearch and use the new-found knowledge to address the use of TXA.  Methods:The first phase of the research will investigate literature on the chosen topicto establish the effects of administering Tranexamic acid on Melasmatreatment.  Atthe outset, it is important to understand Melasma as a disorder and explore thereasons for its occurrence. Melasma is a pigmentation disorder and is commonamong women of Hispanic and Asian groups.

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The etiology of melasma has yet to beestablished, and the course of treatment continues to be a challenge.Treatmentmodalities include use of hypo pigmenting agents such as hydroquinone,tretinoin, topical corticosteroids, superficial peeling (lactic acid, glycolicacid, trichloroacetic acid and kojic acid), LASERS (including Q-switched rubylaser, Q-switched Alexandrite laser, erbium: yttrium-aluminum-garnet (Er: YAG)laser, Fraxel laser, and intense pulsed light.(Gupta AK et al,2006)Despitethe availability of these therapies, melasma is often recalcitrant totreatment, melasma poses a great challenge as its treatment can be oftenunsatisfactory with high recurrence rates.(Prignano F et al,2007)Additionally,the success rates of all these procedures are considered paradoxical darkeningand low, apart from their recognizable side-effects. Journal paper by Budamakuntla L., et al., titled “A Randomized,Open-label, Comparative Study of Tranexamic Acid Microinjections’ andTranexamic Acid with Microneedling in Patients with Melasma”,Cho,Choi, Cho, and Lee titled “Role of oral tranexamic acid in melasmapatients treated with IPL and low fluence QS ND: Yag laser.

Karnet al, 2012 concluded addition of oral Tranexamic acid to routine treatmentmeasures provide a rapid and better lightning in patients with melasma. Lowdose oral Tranexamic acid is thus recommended for melasma treatment.AamirS.et al, 2014 concluded a rapid and sustained improvement can be providedwith the introduction of tranexamic acid in melasma treatment which none of theexisting treatment modalities for melasma has provided till date.NaJi, et al., titled” Effect of tranexamic acid on melasma- a clinical trialwith Histological evaluation”EbrahimNaeini study called “Topical tranexamic acid as a promising treatment formelasma”. AnjuGeorge (2015) review article in Journal Pigment International, established thatTranexamic acid is an effective depigmenting agent as it is a syntheticderivative of lysine amino acid and useful in arresting the conversion ofplasminogen into plasmin (inhibiting plasminogen activator).

The result is alower production of arachidonic acid and thereby lowering prostaglandin levels.Thus, Tranexamic acid becomes responsible for lowered melanocyte tyrosinaseactivity and therefore, useful in treating melasma or UV-induced hyperpigmentation.AWM Tan et al, 2016 concluded low-dose oral Tranexamic acidcan serve as a safe and useful adjunct in the treatment of refractory melasma.

How Tranexamic acid works in lightening melasma is unknown, but itis possibly by modulating keratinocyte-melanocyte interactions and byreducing vascularity in melasma lesions and through its effects on mast cells. Padhi T et al,2015 concluded oral tranexamic acid can beused as an adjunct with fluocinolone based triple combination cream for thefaster and sustained improvement in melasma treatment. DelRosario E, Florez- Pollack S, Zapata Jr.

L, Hernandez K, Tovar-Garza A,Rodrigues M, Hynan LS, Pandya AG’s (2017), “Randomized,placebo-controlled, double-blind study of oral tranexamic acid in the treatmentof moderate to severe melasma” treated 250mg of TA/placebo capsules (2times a day, for three months) to 44 patients. 39 completed the study and theprimary outcomes were the Modified Melasma Area and the Severity Index (mMASI)score showing 49% lower mMASI in TA group and 18% in the controlgroup. Severe melasma showed higher rates of improvement over moderate melasma.

Further, after treatment stopped for three months, there was 26% reductionin mMASI in the TA Group, over the baseline results. Additionally, theywitnessed 19% reduction in the placebo arm and reported no adverse events inboth the groups. Hence, this study established that oral TXA was effective andsuperior to placebo in patients who had moderate to severe melasma, and thusideal alternative to standard therapies. The limitations of this groupwere:  the study was conducted at a single center where patient demographywas predominantly Hispanic women.

 Otherstudies which tested the efficacy of oral Tranexamic acid vs Triple combinationfor melasma treatment ( Neerja Puri, 2015) and concluded that recurring melasmais satisfactorily treated with oral TXA in comparison to the combination ofother modalities. ExpectedOutcomesThetherapeutic benefits of the use of Tranexamic acid (TXA), as an innovativeagent, either as an oral, topical or intralesional method for the treatment ofmelasmaGnatChartJanuary-February: Proposal writing create a list of potential studies to review.February-March:Initial review of primary resources with best results on use of TXA for melasmaMarch–April: Establish outline by cross-references and secondary data from journalarticles, studiesJune– July: Propose the best way to arrive at proposal objective July– August: Submit Thesis Recommendation:Fromthe research studies listed above and literature review, it can be said thatTranexamic acid as a liposomal topical formulation, Intralesional/IntradermalInjection of Tranexamic acid and Low-dose oral Tranexamic acid can be a safeand effective alternative for treating refractory melasma. Conclusion:Acrossthe nearly 30 journal articles, books, review articles on the therapeuticeffects of Tranexamic acid in melasma, the conclusion that can be drawn is asfollows: Topical, Intralesional, and low dose oral TranexamicAcid is highly useful in treating refractory melasma. Limitationsof study: The research includes the study of two different demographics –Hispanic and Asians. Therefore, the results of the studies vary in terms ofmoderate or high rates of success, is subjective to the population where thestudy was conducted.

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