Prescribing practices of tranexamic acid for melasma: Delphi consensus from the Pigmentary Disorders Society.

Introduction There is ambiguity regarding usage of tranexamic acid for melasma in India, be it in its pre-administration evaluation, administration route, dosing or monitoring. Hence, we conducted this study to understand various tranexamic-acid prescribing patterns and provide practical guidelines. Materials and methods A Google-form-based questionnaire (25-questions) was prepared based on the key areas identified by experts from the Pigmentary Disorders Society, India and circulated to practicing dermatologists across the country. In rounds 2 and 3, the questionnaire was re-presented to the same group of experts and their opinions were sought. The results of the practitioners' survey were denoted graphically alongside, to guide them. Consensus was deemed when at least 80% of respondents chose an option. Results The members agreed that history pertaining to risk factors for thromboembolism, cardiovascular and menstrual disorders should be sought in patients being started on oral tranexamic-acid. Baseline coagulation profile should be ordered in all patients prior to tranexamic-acid and more exhaustive investigations such as complete blood count, liver function test, protein C and S in patients with high risk of thromboembolism. The preferred oral dose was 250 mg orally twice daily, which can be used alone or in combination with topical hydroquinone, kojic acid and sunscreen. Repeated dosing of tranexamic-acid may be required for those relapsing with melasma following initial tranexamic-acid discontinuation. Coagulation profile should ideally be repeated at three monthly intervals during follow-up, especially in patients with clinically higher risk of thromboembolism. Treatment can be stopped abruptly post improvement and no tapering is required. Limitation This study is limited by the fact that open-ended questions were limited to the first general survey round. Conclusion Oral tranexamic-acid provides a valuable treatment option for melasma. Frequent courses of therapy may be required to sustain results and a vigilant watch is recommended for hypercoagulable states during the course of therapy.

Improvement and characterization of oral absorption behavior of clofazimine by SNEDDS: Quantitative evaluation of extensive lymphatic transport.

Clofazimine, an anti-leprosy drug, has been anticipated for a candidate to treat tuberculosis, cryptosporidiosis, and coronavirus infection, but its low oral bioavailability is considered a reason for its limited activity. In the current study, we have tried to improve the oral bioavailability of clofazimine by several SNEDDS formulations and characterized the absorption behavior from various aspects. Among four SNEDDS formulations prepared, SNEDDS A, prepared with castor oil as an oil component, provided the highest bioavailability (around 61%) and SNEDDS D, prepared with Capryol 90, gave the second highest bioavailability. SNEDDS A formed the finest nanoparticles, which were maintained under gastric and intestinal luminal conditions. The comparison in oral bioavailability between the SNEDDS formulation and its corresponding preformed nanoemulsion suggested that SNEDDS A would efficiently form nanoemulsion in the gastrointestinal tract after oral administration. AUC of mesenteric lymph node concentration was the highest for SNEDDS A, which would be one of the reasons for SNEDDS A to reveal the highest oral bioavailability. A cycloheximide-treated oral absorption study and single-pass perfusion study by utilizing a vascular-luminal perfused small intestine-liver preparation clearly indicated that over 90% of clofazimine absorbed to systemic circulation should be derived from lymphatic transport for both SNEDDS A and D. Furthermore, the fraction of dose absorbed was around 65% for SNEDDS D, but SNEDDS A achieved around 94%, indicating the excellent performance of SNEDDS A.

The optimal dose of oral tranexamic acid in melasma: A network meta-analysis.

BACKGROUND: Melasma is a chronic skin condition that adversely impacts quality of life. Although many therapeutic modalities are available there is no single best treatment for melasma. Oral tranexamic acid has been used for the treatment of this condition but its optimal dose is yet to be established. OBJECTIVES: We used network meta-analysis to determine the optimal dose of oral tranexamic acid for the treatment of melasma. METHODS: We conducted a comprehensive search of all studies of oral tranexamic acid for the treatment of melasma up to September 2020 using PubMed, EMBASE and the Cochrane Library database. The quality of the studies was evaluated using the Jadad score and the Cochrane's risk of bias assessment tool. Only high quality randomised controlled trials were selected. Some studies lacked standard deviation of changes from baseline and these were estimated using the correlation coefficient obtained from another similar study. RESULTS: A total of 92 studies were identified of which 6 randomized controlled trials comprising 599 patients were included to form 3 pair-wise network comparisons. The mean age of the patients in these studies ranged from 30.3 to 46.5 years and the treatment duration ranged from 8 to 12 weeks. The Jadad scores ranged from 5 to 8. The optimal dose and duration of oral tranexamic acid was estimated to be 750 mg per day for 12 consecutive weeks. LIMITATIONS: Some confounding factors might not have been described in the original studies. Although clear rules were followed, the Melasma Area and Severity Index and the modified Melasma Area and Severity Index were scored by independent physicians and hence inter-observer bias could not be excluded. CONCLUSION: Oral tranexamic acid is a promising drug for the treatment of melasma. This is the first network meta-analysis to determine the optimal dose of this drug and to report the effects of different dosages. The optimal dose is 250 mg three times per day for 12 weeks, but 250 mg twice daily may be an acceptable option in poorly adherent patients. Our findings will allow physicians to balance drug effects and medication adherence. Personalized treatment plans are warranted.

Treatment outcome of oral tofacitinib and ruxolitinib in patients with alopecia areata: A systematic review and meta-analysis.

BACKGROUND: Tofacitinib and ruxolitinib have been used off-label to treat alopecia areata. Although a number of case reports and small studies have been published, there are no comprehensive reviews examining the outcomes of using tofacitinib and ruxolitinib for the treatment of alopecia areata. AIMS: The aim of the study was to examine the outcome of patients with alopecia areata treated with oral tofacitinib or ruxolitinib in previously published studies. METHODS: A search of MEDLINE, Embase and Cochrane library was conducted. A systematic review and meta-analysis were performed focusing on the Severity of Alopecia Tool 50 achievement rate, the frequency of adverse events and recurrence after discontinuation of treatment. RESULTS: A total of 1244 studies were identified of which only 12 studies met the inclusion criteria. Of the 346 patients in these 12 studies, 288 had received oral tofacitinib and 58 had received oral ruxolitinib. The overall Severity of Alopecia Tool50 achievement rate was 66% (95% confidence interval, 54%-76%). Subgroup analysis revealed that drug choice, mean age, sex ratio and alopecia areata subtype ratio did not significantly affect the treatment response. Infections and laboratory abnormalities were the most common adverse events (98 and 65 cases of 319 patients, respectively). Patients treated for more than six months had a greater frequency of laboratory abnormalities as compared to those treated for shorter durations (24% vs. 7%; P = 0.04). Recurrence of alopecia areata was observed within three months after discontinuation of treatment in the majority (74%) of patients. LIMITATIONS: This analysis was limited by the small number of observational studies available for review, the heterogeneity of patient characteristics and the lack of long-term data. CONCLUSION: Both oral tofacitinib and ruxolitinib are effective and well tolerated in the treatment of alopecia areata. Clinicians should be aware of the expected efficacy, adverse events and high recurrence rate of oral JAK inhibitors for alopecia areata to effectively counsel these patients before starting therapy.

Oral Tolerance Induced by Heat Shock Protein 65-Producing Lactococcus lactis Mitigates Inflammation in Leishmania braziliensis Infection.

Cutaneous leishmaniasis caused by L. braziliensis induces a pronounced Th1 inflammatory response characterized by IFN-γ production. Even in the absence of parasites, lesions result from a severe inflammatory response in which inflammatory cytokines play an important role. Different approaches have been used to evaluate the therapeutic potential of orally administrated heat shock proteins (Hsp). These proteins are evolutionarily preserved from bacteria to humans, highly expressed under inflammatory conditions and described as immunodominant antigens. Tolerance induced by the oral administration of Hsp65 is capable of suppressing inflammation and inducing differentiation in regulatory cells, and has been successfully demonstrated in several experimental models of autoimmune and inflammatory diseases. We initially administered recombinant Lactococcus lactis (L. lactis) prior to infection as a proof of concept, in order to verify its immunomodulatory potential in the inflammatory response arising from L. braziliensis. Using this experimental approach, we demonstrated that the oral administration of a recombinant L. lactis strain, which produces and secretes Hsp65 from Mycobacterium leprae directly into the gut, mitigated the effects of inflammation caused by L. braziliensis infection in association or not with PAM 3CSK4 (N-α-Palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-L-cysteine, a TLR2 agonist). This was evidenced by the production of anti-inflammatory cytokines and the expansion of regulatory T cells in the draining lymph nodes of BALB/c mice. Our in vitro experimental results suggest that IL-10, TLR-2 and LAP are important immunomodulators in L. braziliensis infection. In addition, recombinant L. lactis administered 4 weeks after infection was observed to decrease lesion size, as well as the number of parasites, and produced a higher IL-10 production and decrease IFN-γ secretion. Together, these results indicate that Hsp65-producing L. lactis can be considered as an alternative candidate for treatment in both autoimmune diseases, as well as in chronic infections that cause inflammatory disease.

Safety and efficacy of methotrexate (0.3 mg/kg/week) versus a combination of methotrexate (0.15 mg/kg/week) with cyclosporine (2.5 mg/kg/day) in chronic plaque psoriasis: A randomised non-blinded controlled trial.

BACKGROUND: Psoriasis is a chronic, inflammatory, relapsing and remitting disease with no cure till date. There is a paucity of trials using a combination of methotrexate (MTX) and cyclosporine (CsA) in chronic plaque psoriasis, due to fear of added toxicity, although they are time tested treatment options for monotherapy. AIMS: The study aimed to compare the efficacy and adverse effect profile of the standard recommended dose of MTX (i.e. 0.3mg/kg/week) versus a combination of reduced doses of MTX and CsA (i.e. MTX 0.15 mg/kg/week with CsA 2.5mg/kg/day) in patients with chronic plaque psoriasis. METHODS: Study design was a non-blinded randomised controlled trial. Patients of chronic plaque psoriasis with PASI more than 10 were randomised in 1: 1 allocation to receive either 0.3 mg/kg/week of intramuscular MTX injection or a combination of 0.15 mg/kg/week of intramuscular MTX injection and 2.5 mg/kg/day of CsA rounded off to the nearest 25 mg. Patients were followed up at every 2 weeks for 12 weeks. The doses were kept fixed throughout the study period. RESULTS: A total of 66 patients received MTX monotherapy, whereas 67 patients received the combination. At baseline, both groups were comparable in their BSA (P = 0.105, Student t-test) and PASI (P = 0.277, Student t-test), which reduced significantly at 12 weeks in both groups (P < 0.001, paired t-test). The achievement of PASI-75 (P = 0.005), PASI-90 (P < 0.001) and PASI-100 (P = 0.001) was more in the combination group (Chi square test). Intention to treat analysis using Chi square test also showed better outcomes for PASI-75 (P = 0.027), PASI-90 (P < 0.001) and PASI-100 (P = 0.001) in the combination group. Combination group also had earlier onset of action (P = 0.001, Chi square test). There was no significant difference between the groups in terms of laboratory and clinical adverse events. LIMITATIONS: Non-blinded, no comparison with CsA monotherapy arm, no follow up beyond 12 weeks. CONCLUSION: The combination of reduced doses of MTX and CsA is more efficacious with earlier onset of action and similar adverse effects as with MTX monotherapy.

The Effectiveness and Value of Oral Semaglutide for Type 2 Diabetes Mellitus.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Fazioli, Rind, and Pearson are employed by ICER. Gazauskas and Hansen have nothing to disclose.

Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Evaluation of the sub-acute toxicity of Acacia catechu Willd seed extract in a Wistar albino rat model.

Acacia catechu (A. catechu) or Khair (Hindi) is used in several herbal preparations in the Ayurvedic system of medicine in India. Traditionally, this drug is beneficial against several gastrointestinal and stomach related ailments, and leprosy. The present investigation was carried out to evaluate the sub-acute oral toxicity of the ethanolic extract of A. catechu seeds in Wistar albino rats. Results obtained from the quantitative chemical analysis of A. catechu seed extract were compared with commercially available standards. A. catechu seed extract was administered orally at the doses of 250, 500 and 1000 mg/kg b.w. daily for 28 days. General behavior, bodyweight and mortality were examined during the entire study period. At the end of 28 days, hematological and biochemical parameters along with the relative organ weights were determined. It was observed that the extract did not induce death or any significant changes in the body weight, relative weight of vital organs and in hematological parameters for up to a dose of 1000 mg/kg. The oral administration of the plant extract did not produce any significant changes in the levels of glucose. In addition, there were no significant changes in the activity of both hepatotoxic and nephrotoxic marker enzymes in the serum. Oral administration of A. catechu also did not produce any significant changes in the levels of oxidative markers. Furthermore, the findings from the biochemical studies were, well corroborated with the histological findings.

Population Pharmacokinetic Model to Assess the Impact of Disease State on Thalidomide Pharmacokinetics.

A population pharmacokinetic (PPK) model to describe the pharmacokinetics of thalidomide in different patient populations was developed using data pooled from healthy subjects and patients with Hansen's disease, human immunodeficiency virus (HIV), and multiple myeloma (MM). The analysis data set had a total of 164 evaluable subjects who received various doses (50 to 400 mg) of oral thalidomide in single- and/or multiple-dose regimens. The plasma thalidomide concentrations were adequately described by a linear 1-compartment PPK model with first-order absorption and first-order elimination. Inclusion of MM as a covariate on apparent clearance (CL/F) accounted for 4.4% of the interindividual variability (IIV) of CL/F. Body weight as a covariate on CL/F and apparent volume of distribution (V/F) also improved model fitting slightly, accounting for 7.2% and 20% of IIV, respectively. Although inclusion of body weight and MM as covariates of CL/F and body weight on V/F improved the goodness of fit of the model in a statistically significant manner, the impact of this difference in CL/F is not considered clinically relevant. Other factors such as age, sex, race, creatinine clearance, and alanine transaminase had no effect on thalidomide pharmacokinetics. MM, HIV, and Hansen's disease have no clinically relevant effect on thalidomide disposition relative to healthy volunteers.

Oral administration of Debaryomyces hansenii CBS8339-ß-glucan induces trained immunity in newborn goats.

Beta-glucans from yeast can induce trained immunity in in vitro and in vivo models. Intraperitoneal doses of ß-glucans in mammals have shown to induce trained immunity, but the training effects of orally administering ß-glucans are unknown. Newborn goats are susceptible to infections in the neonatal stage, so the induction of trained immunity could improve animal survival. This study aimed to describe the in vitro effects of immunological training by ß-glucan from Debaryomyces hansenii (ß-Dh) on caprine monocytes, as well as its in vivo effects using oral doses on newborn goats upon challenge with lipopolysaccharide (LPS). Hence in vitro, goat monocytes trained with ß-Dh up-regulated the gene expression of macrophage surface markers (CD11b and F4/80) whereas enhanced cell survival and high phagocytic ability was found upon LPS challenge. In the in vivo experiment, newborn goats stimulated with two doses (day -7 and - 4) of ß-Dh (50 mg/kg) and challenged (day 0) with LPS showed an increase in respiratory burst activity, IL-1ß, IL-6, and TNFα production in plasma, and transcription of the macrophage surface markers. This study has demonstrated for the first time that trained immunity was induced with oral doses of ß-glucan upon LPS challenge in mammals using newborn goats.

Pollen Allergy Suppression Effect by the Oral Administration of Acetic Acid Bacteria (Gluconacetobacter hansenii).

BACKGROUND/AIM: Gluconacetobacter hansenii (G. hansenii) is an acetic acid bacterium of vinegar production. Its anti-allergic effect on mice upon oral administration was examined. MATERIALS AND METHODS: The amount of LPS was measured by the Limulus reaction. Mice were sensitized by peritoneal and intranasal administration of cedar pollen and alum followed by oral administration of 30 or 150 mg/kg of heated G. hansenii cells. Pollen was administered intranasally to evaluate nasal symptoms, and at 8 weeks, IgE and IL-10 levels in blood were measured by ELISA. RESULTS: The amount of LPS in dried bacterial cells was 10.4±3.3 mg/g. In the cedar pollinosis model of mice, a significant reduction was observed in nose scratching of both groups administered with the bacterial cells (30, 150 mg/kg). CONCLUSION: G. hansenii contains LPS, and its oral administration showed an anti-allergic effect by a significant mitigation of the symptoms in a pollen allergy mouse model.

Oral isotretinoin for treating mucocutaneous human papillomavirus infections: A systematic review and meta-analysis.

INTRODUCTION: Some viral warts are refractory to treatment, some others tend to recur. Oral isotretinoin is useful against warts to varying degrees. OBJECTIVE: To determine the efficacy of oral isotretinoin for treating mucocutaneous human papillomavirus infections. METHODS: A systematic review and meta-analysis of studies published from the date of inception of the databases to December 30, 2017 were conducted. Randomized controlled trials or case series with ≥10 patients with mucocutaneous human papillomavirus infection who had received oral isotretinoin treatment were analyzed. The meta-analysis estimated the pooled odds ratio and pooled response rate. RESULTS: The review included eight studies. Trials of oral isotretinoin versus placebo treatment revealed that isotretinoin effectively treated mucocutaneous human papillomavirus infections (odds ratio: 43.8, 95% confidence interval: 9.7-198.8). The pooled estimate of the complete response rate of oral isotretinoin to mucocutaneous human papillomavirus was 67.7% (95% confidence interval: 49.5-81.7%). Another pooled estimation revealed that 83.9% (95% confidence interval: 59.7-94.9%) of patients exhibited at least 50% lesion clearance, whereas 12.3% with complete response experienced recurrence. LIMITATIONS: This meta-analysis had a small sample size and high inter-study heterogeneity. CONCLUSION: Oral isotretinoin is superior to placebo for treating mucocutaneous human papillomavirus infections, particularly plane warts. The recurrence rate and risk of severe side effects are low.

In vitro susceptibility of dermatophytes to oral antifungal drugs and amphotericin B in Uttar Pradesh, India.

BACKGROUND: Dermatophytosis is a major public health problem in our country. Although resistance to conventional oral and topical antifungal agents is being increasingly encountered, the sensitivity pattern of dermatophytes has not been systematically analysed. AIMS: We aimed to determine the sensitivity pattern of dermatophyte isolates to amphotericin B and six oral antifungal drugs. MATERIALS AND METHODS: Patients with dermatophytosis attending the outpatient department of dermatology were enrolled in the study. Samples were collected for mycological examination and in vitro antifungal sensitivity testing was done by broth microdilution as per the Clinical and Laboratory Standard Institute M38-A standards. RESULTS: A total of 804 patients were enrolled. Specimens from 185 patients (23%) were both KOH and culture positive, and 44 of these isolates (41 Trichophyton mentagrophytes and 3 Trichophyton rubrum) were subjected to sensitivity testing. Minimum inhibitory concentrations (MIC) of itraconazole, ketoconazole, voriconazole and amphotericin B were comparable. The median MIC to fluconazole was higher than the other tested drugs. Dermatophytes were most susceptible to ketoconazole and voriconazole, followed by itraconazole, amphotericin B, fluconazole and griseofulvin. A high incidence of resistance was found to terbinafine and the difference was statistically significant in comparison to fluconazole, itraconazole, voriconazole, ketoconazole (P = 0.001) and griseofulvin (P = 0.003). The strains were more sensitive to amphotericin B as compared to griseofulvin (P = 0.02) and terbinafine (P < 0.001). LIMITATIONS: This was a hospital-based study and may not reflect the true pattern in the community. Only a few of the isolates were selected for study. The clinical response of patients, whose isolates were studied for in vitro sensitivity of the antifungals, was not studied. CONCLUSIONS: The sensitivity pattern of dermatophytes to various antifungals including amphotericin B, ketoconazole, voriconazole and itraconazole were determined. The studied isolates were least susceptible to terbinafine.

A randomized, open-label, comparative study of oral tranexamic acid and tranexamic acid microinjections in patients with melasma.

BACKGROUND: Melasma poses a great challenge as its treatment modalities are unsatisfactory. Treatment using tranexamic acid is a novel concept. AIM: This study aimed to compare the therapeutic efficacy and safety of oral tranexamic acid and tranexamic acid microinjections in patients with melasma. METHODS: This is a prospective, randomized, open-label study with a sample size of 64, 32 in each treatment arm. Thirty-two patients were administered localized microinjections (4 mg/ml) of tranexamic acid monthly in 1 arm, while in the other arm, 32 were given oral tranexamic acid 250 mg twice a day. Patients were followed up for 3 consecutive months. Clinical photographs were taken at each visit, and a modified melasma area and severity index scoring was performed at the beginning and end of treatment. RESULTS: Improvement in melasma area and severity index score in the oral group was 57.5% as compared to 43.5% in the intralesional group. All 32 patients in the oral group (100%) showed >50% improvement, out of which 8 showed >75% improvement. In the intralesional group, 17 (53%) patients had >50% improvement, of which 3 had >75% improvement. The remaining 15 patients in this group had <50% improvement. Thus, the oral group showed a more significant response as compared to the intralesional group. No major adverse effects were observed in both the groups. At 6-month follow-up, two patients (6.2%) in the oral group had recurrence as compared to three patients (9.4%) in the intralesional group. LIMITATIONS: A small sample size was one of the limitations in this study. The dose of tranexamic acid in microinjections and the frequency of injections could have been increased. CONCLUSION: Tranexamic acid provides rapid and sustained improvement in the treatment of melasma. It is easily available and affordable. Oral route is undoubtedly efficacious, but the results of microinjections, while encouraging, can probably be enhanced by either increasing the frequency of injections or increasing the concentration of the preparation.

Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial.

BACKGROUND: Cryptosporidium infection and diarrhea (cryptosporidiosis) is a life-threatening infection in persons with HIV and also in children of 6-18 months of age in the developing world. To date, only nitazoxanide is licensed for treatment of cryptosporidiosis, and only in persons after the first year of life and with healthy immune systems. Clofazimine (CFZ: Lamprene®), an established drug that has been used for leprosy for more than 50 years, recently has been described as effective against Cryptosporidium in vitro and in mouse infections. The efficacy and pharmacokinetics of CFZ in vivo, in HIV-infected patients with cryptosporidial diarrhea are not known. METHODS: CRYPTOFAZ includes a randomized, double-blind, placebo-controlled study of the safety, tolerability and Cryptosporidium inhibitory activity of orally administered CFZ in subjects with HIV infection and chronic diarrhea with Cryptosporidium. An additional open label aspect of the study will compare the pharmacokinetics (PK) of orally administered CFZ in HIV-infected individuals with and without Cryptosporidium-associated diarrhea. The study will recruit a total of 66 subjects. Study participants will be given either CFZ or a placebo for 5 days while in hospital and will be followed up after discharge. Cryptosporidium will be diagnosed by quantitative PCR as the definitive test and by stool ELISA, which will also be used to quantify the shedding of Cryptosporidium in stool. PK will be studied on plasma and stool samples. Primary endpoints include reduction in the number of Cryptosporidium shed in stools over a 5-day period and compared to placebo recipients and the PK of CFZ in plasma assessed by area under the curve, peak plasma concentration, and half-life (T ½) determined after the last dose. DISCUSSION: This study provides an opportunity to explore a possible treatment option for HIV-infected patients with cryptosporidial diarrhea, who, as of now in Malawi and most of sub-Saharan Africa, do not have a definitive treatment apart from supportive care. The strength of this study lies in it being a randomized, double-blind, placebo-controlled trial. If shown to be effective and safe, the findings will also lay a foundation for a future study of the use of CFZ in children 6-18 months of age. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03341767 . Registered on 14 November 2017.