Application of Dimethyl Sulfoxide as a Therapeutic Agent and Drug Vehicle for Eye Diseases.

Dimethyl sulfoxide (DMSO) is an amphipathic molecule widely used as a solvent for water-insoluble substances, cryopreserving, and cell-biological therapies. It has known properties as an inducer of cellular differentiation, a free radical scavenger, and a radioprotectant. In addition, DMSO is used for its various therapeutic and pharmaceutical properties, such as anti-inflammatory, local and systemic analgesic, antibacterial, antifungal, antiviral, and membrane penetration enhancement agents. DMSO treatment can be given orally, intravenously, or topically for a wide range of indications. The administration of DMSO exhibits favorable outcomes in human eye diseases with low to none observed ocular or systemic ocular toxicity. Nevertheless, DMSO is an essential and nonpatentable potential therapeutic agent that remains underexplored and ignored by pharmaceutical developers and ophthalmologists. This current review takes data from experimental and clinical studies that have been published to substantiate the potential therapeutic efficacy of DMSO and stimulate the research of its application in clinical ophthalmology. Given that DMSO is inexpensive, safe, and easily formulated into therapeutic medicinal products and conventional ophthalmological drugs, this compound should be further explored and studied in the treatment of a variety of acute and chronic ocular disorders.

A Comprehensive Review of the Clinical Trials Conducted for Dry Eye Disease and the Impact of the Vehicle Comparators in These Trials.

Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by loss of homeostasis of the tear film and accompanied by symptoms such as ocular discomfort and visual disturbance. DED is one of the most common reasons for seeking medical care in the United States and across the world. Despite this, there are a limited number of pharmacologic therapies for the treatment of DED in the United States and Europe. This review examines the different pivotal trials for DED medications and the impact the vehicle in each trial.In recent clinical trials, the vehicle of the active formulation of the medication is often used as the active comparator. A literature review of published dry eye clinical trials was performed to identify the pivotal clinical trials of DED medications and to compare treatment effect and further understand the impact of the vehicle on clinical trial outcomes.The pivotal clinical trials for the currently approved treatments for dry eye have widely varying study designs. The variations include differences in inclusion criteria, outcome measures and efficacy endpoints, and whether or not the use of concomitant artificial tears is allowed. These differences make it difficult for accurate comparisons to be made between DED medications. Each trial demonstrated that the vehicle alone has some beneficial effect on signs and symptoms of dry eye disease.This review discusses the varying trial designs and vehicles used in the pivotal studies for the four approved dry eye medications in the United States and Europe, as well as novel vehicles under development and clinical trial recommendations.

Capsaicin and Piperine as Functional Excipients for Improved Drug Delivery across Nasal Epithelial Models.

The fruit from various pepper plants has been employed for the seasoning of food, as perfuming agents, and also as traditional medicines. Phytochemicals isolated from different pepper species have been found to modulate the pharmacokinetics of orally administered drugs. This study investigated the possibility to apply capsaicin and piperine (extracted alkaloids) as modulators for drug delivery across the nasal epithelium. Both a nasal epithelial cell line (RPMI 2650) and excised sheep nasal tissue were used as models to investigate the effects of the selected pepper compounds on drug permeation. FITC-dextran 4400 (MW 4400 Da) was used as a large molecular weight marker compound for paracellular transport, while rhodamine 123 was used as a marker compound that is a substrate for P-glycoprotein-mediated efflux. From the permeation results, it was clear that capsaicin inhibited P-glycoprotein efflux to a larger extent, while piperine showed drug permeation enhancement via other mechanisms. The cell cytotoxicity studies indicated that capsaicin was noncytotoxic up to a concentration of 200 µM and piperine up to a concentration of 500 µM as indicated by cell viability above 80%. The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers indicated that some damage occurred after treatment with 200 µM capsaicin, but no changes were observed for piperine up to a concentration of 50 µM.

In vivo gum arabic-coated tetrahydrobiopterin protects against myocardial ischemia reperfusion injury by preserving eNOS coupling.

AIMS: Exogenous tetrahydrobiopterin (BH4), an indispensable cofactor of endothelial nitric oxide synthase (eNOS), supplementation has been proved to be of advantage to improve cardiovascular function. Nevertheless, due to its highly redox-sensitive and easy to be oxidized, there is an urgent need to develop an appropriate BH4 formulation for clinical therapy. Gum Arabic (GA) has been considered as an alternative biopolymer for the stabilization and coating of drugs. The effects of GA on protecting BH4 from being oxidized were investigated in a rat model of myocardial ischemia-reperfusion (I/R). MAIN METHODS: Rats were subjected to 60-min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic GA-coated BH4 supplementation (10 mg/kg, oral). Myocardial infarction, fibrotic area and left ventricle ejection fraction were correlated with cardiac BH4 content, eNOS protein, NOS enzyme activity, and ROS/NO generation. KEY FINDINGS: Pretreatment of rats with GA-coated 6R-BH4, 24 h before myocardial ischemia, resulted in smaller myocardial infarction, improved left ventricular function and inhibited fibrosis, correlated with maintained high levels of cardiac BH4 content, preserved eNOS activation and dimerization, and decreased ROS generation. However in uncoated group, 6R-BH4 treatment did not reduce acute and chronic myocardial I/R injury compared with control I/R rats, which was closely related with the marked loss of myocardial BH4 levels during I/R. SIGNIFICANCE: These findings provide evidence that in vivo pre-ischemic oral GA-coated BH4 administration preserves eNOS function secondary to maintaining cardiac BH4 content, and confers cardioprotection after I/R.

Effect of Using Different Vehicles on the Physicochemical, Antimicrobial, and Biological Properties of White Mineral Trioxide Aggregate.

INTRODUCTION: This study evaluated the physicochemical, antimicrobial, and biological properties of white mineral trioxide aggregate (MTA) mixed with aqueous and propylene glycol extracts of Arctium lappa L. and Casearia sylvestris Sw. METHODS: The setting-time test was performed according to American Society for Testing and Materials 266/2008 and flowability by American National Standards Institute/American Dental Association 57/2012 standard specifications. The following parameters were assessed: volumetric change by micro-computed tomography; pH level and calcium ion release measured after 3 hours and 1, 3, 7, and 15 days; antimicrobial effect by the dentin decontamination method with intratubular Enterococcus faecalis viability, verified by using confocal laser scanning microscopy; and biocompatibility by histologic-morphometric analyses of inflammatory infiltrate at subcutaneous implant sites after 15, 30, and 60 days. In addition, rat alveolar tissues with implants were processed to measure tumor necrosis factor-alpha and interleukin-10 cytokines by enzyme-linked immunosorbent assay. RESULTS: The plant extracts associated with MTA significantly increased the final setting time; however, they did not influence volumetric change (P > .05) and maintained medium alkalinity and calcium ion release. Propylene glycol extracts showed higher flowability. Casearia sylvestris increased the cementing effect against E. faecalis after 24-hour and 168-hour periods. Histologic evaluation of inflammatory infiltrate showed no significant differences between plant extracts groups and the distilled water group for all periods. Tumor necrosis factor-alpha and interleukin-10 expression was similar among groups (P > .05). CONCLUSIONS: Casearia sylvestris extracts increased the antimicrobial effect of MTA and did not influence biocompatibility but changed some physicochemical properties.

Efficacy of an emollient cream in the treatment of xerosis in diabetic foot: a double-blind, randomized, vehicle-controlled clinical trial.

BACKGROUND: Peripheral neuronal impairment compromises foot health in patients with diabetes. Clinically, xerosis is the most common mild complication, but it should not be underestimated. An effective treatment must be able to restore the cutaneous barrier and prevent water loss, to maintain adequate hydration and protection. OBJECTIVE: This study aimed to assess the efficacy of an emollient cream on foot xerosis in patients with diabetes. METHODS: This is a prospective, multicenter, randomized, double-blind contralateral vehicle-controlled study in 57 patients with diabetes. Patients were treated twice daily for 27 ± 2 days with the study emollient containing glycerol 15%, liquid and soft paraffin 10%, glycerol monostearate, stearic acid, polydimethylcyclosiloxane, silicone oil, macrogol 600, trolamine, propyl parahydroxybenzoate and purified water (Dexeryl® ; Pierre Fabre Medicament, Boulogne, France) or its vehicle (glycerol monostearate, stearic acid, polydimethylcyclosiloxane, silicone oil, macrogol 600, trolamine, propyl parahydroxybenzoate and purified water). Efficacy was assessed after a 28-day treatment period using a validated score [Xerosis Assessment Scale (XAS) score], instrumental measurements and subjective assessment. RESULTS: The XAS score decreased to 3.2 ± 2.6 points with the emollient and 4.1 ± 2.3 with the vehicle (P = 0.001). Improvement was observed from day 14 (P = 0.012). Compared with the vehicle, the emollient also significantly improved the overall skin score, hydration index, D-Squame® (CuDerm Corporation, Dallas, TX, USA) test, skin roughness and patients' opinions. CONCLUSION: Treatment with an emollient is effective for improving foot xerosis in patients with diabetes.

A randomized, double-blind, placebo-controlled study to test the efficacy of topical 2-hydroxypropyl-Beta-cyclodextrin in the prophylaxis of recurrent herpes labialis.

Herpes labialis affects one third of the population. We evaluated the topical application of an antiviral compound, hydroxypropyl-ß-cyclodextrin (2-HPßCD), in reducing herpes labialis relapses. In this double-blind, randomized, placebo-controlled trial, 40 patients were randomized to a polyethylene glycol (PEG) formulation containing 20% 2-HPßCD or to a vehicle control arm. The gel was applied to the lips twice daily for 6 months. The primary objective was reducing herpes relapses. Surprisingly, the drug group had significantly more relapses than the vehicle group (p = 0.003). While the median numbers of relapses in the preceding year were 12 in the vehicle group and 10 in the drug group, both groups experienced very few relapses during the 6-month treatment period, with a median of 0 in the vehicle group and a median of 2 in the drug group. The impressive reduction of relapses in both groups may be due to a placebo effect or due to the topical treatment with PEG.

The topical vehicle as a key factor in the management of the psoriatic patients' therapy.

This review deals with the importance of the topical vehicle as a key factor in the management of the psoriatic patients' therapy.

Pharmacokinetics and safety of Marqibo (vincristine sulfate liposomes injection) in cancer patients with impaired liver function.

Marqibo (vincristine sulfate liposome injection, VSLI) is a novel liposomal formulation of vincristine sulfate (VCR) being developed for the systemic treatment of cancer. This study evaluated the pharmacokinetics (PK) of Marqibo in subjects with melanoma and impaired hepatic function. Calculated PK parameters were similar in subjects with impaired liver function compared with those in subjects with adequate liver function. Subjects with impaired liver function universally had a monoexponential total plasma VCR concentration versus time decline, whereas two thirds of subjects with adequate liver function had a biexponential decline profile. Because one third of subjects with normal hepatic function demonstrated monoexponential disposition, lack of biexponential disposition in the hepatically impaired subjects cannot be clearly attributed to liver impairment. VSLI was generally well tolerated in all subjects.

[Microfoam truncal scleroobliteration in varicose disease].

Analysed herein are present-day views on using the technique of scleroobliteration of major veins (particularly, microfoam scleroobliteration) in treatment for varicose disease. Based on the analysis of literature data, attempts are made to systematize the indications for such interventions, underlying advantages and disadvantages of the technique, and analysing possible complications. A conclusion is drawn that the remote results of microfoam scleroobliteration are inferior to those of the currently popular thermal obliterating techniques. However, this method oftreatment may under certain conditions be used to remove the truncal reflux.

Slow release antibiotics for treatment of septic arthritis in large animals.

The search for an effective treatment for septic arthritis is ongoing. Current therapies are expensive since they require repeated joint lavage and long term antibiotic treatment. Local application of antimicrobial drugs is advantageous because high concentrations can be attained at the infection site, although repeated injections increase the risk of superinfection of the joint. Thus, slow release formulations, which have the advantage of local treatment yet single application of the drug, are appealing. Antibiotics used in slow release formulations are selected for tissue compatibility, an appropriate antibacterial spectrum, and stability both during the mixing procedure and within the carrier during the release period. Ideally the carriers should be bioresorbable. Promising reports on the clinical use of poly(methyl methacrylate) (PMMA) mixed with several different antibiotics, and of collagen sponges impregnated with gentamicin, should encourage the search for formulations optimally adapted to veterinary medical requirements.

Inflammatory response after phacoemulsification treated with 0.5% prednisolone acetate or vehicle.

PURPOSE: To compare the inflammatory response after phacoemulsification and intraocular lens implantation, using postoperative treatment with 0.5% prednisolone acetate eye drops or vehicle. DESIGN: A multi-center randomized double-masked vehicle-controlled, parallel group phase IV study. METHODS: Sixty-two eyes of 62 patients undergoing phacoemulsification were examined at five German university eye hospitals (Mainz, Heidelberg, Bonn, Erlangen, Frankfurt/Main). Patients received either 0.5% prednisolone acetate eye drops (group 1) or vehicle eye drop solution (group 2) four times a day until day 2, then open-label treatment with 0.5% prednisolone acetate eye drops four times a day continued until day 14 for all patients. Postoperative inflammation was evaluated by using laser flare photometry. Secondary efficacy variables included visual acuity, intraocular pressure, corneal edema, bulbar conjunctival hyperemia and ocular discomfort. RESULTS: In group 1, median flare rose from 7.4 photon counts/ms preoperatively to 31.0 photon counts/ms at day 1. In group 2, the flare increased from 8.6 photon counts/ms preoperatively to 30.5 photon counts/ms at day 1. The differences between the groups were not statistically significant. At day 3, flare measures were reduced in group 1 but remained fairly unchanged in group 2 (20.8 photon counts/ms vs 32.6 photon counts/ms), which was statistically significant (p = 0.0055). At day 14, photon counts were comparable in both groups (13.0 photon counts/ms vs 11.4 photon counts/ms), respectively. Both groups were comparable regarding secondary efficacy variables. CONCLUSIONS: 0.5% prednisolone acetate appeared to be significantly more effective as vehicle in controlling intraocular inflammation after phacoemulsification; both groups had a similar safety profile.

Clinical cure of bacterial conjunctivitis with azithromycin 1%: vehicle-controlled, double-masked clinical trial.

PURPOSE: To analyze the effect of azithromycin 1% ophthalmic solution in DuraSite (InSite Vision, Inc, Alameda, California, USA) on bacterial conjunctivitis. DESIGN: Prospective, randomized, vehicle-controlled, parallel-group, double-masked multicenter clinical study. METHODS: Eligible male or female participants with a clinical diagnosis of acute bacterial conjunctivitis were randomized to either 1% azithromycin in DuraSite or vehicle for five days. Infected eyes were dosed twice daily on days 1 and 2 and once daily on days 3 through 5. Conjunctival cultures were obtained at baseline, visit 2 (day 3 or 4), and visit 3 (day 6 or 7). The primary end point was clinical resolution of signs and symptoms (rating of zero on ocular discharge, bulbar and palpebral injection) at visit 3. Efficacy measures were clinical resolution and bacterial eradication as evaluated in the per-protocol population. Safety was assessed by adverse events, slit-lamp findings, and ophthalmoscopy. RESULTS: Two hundred and seventy-nine participants (n = 130, 1% azithromycin in DuraSite; n = 149, vehicle), age one to 96 years, were evaluated for efficacy. Clinical resolution with azithromycin ophthalmic solution was statistically significant compared with that of vehicle (P = .030) at visit 3. Bacterial eradication rates with azithromycin ophthalmic solution reached 88.5% at visit 3 (P < .001) and included some pathogens resistant to azithromycin in vitro. Overall, adverse event rates were similar in both treatment groups. CONCLUSIONS: Azithromycin 1% ophthalmic solution in DuraSite showed statistically significant differences in clinical resolution and bacterial eradication rates when compared with vehicle. Because it was well tolerated in this population, it may be a viable treatment option for children and adults with bacterial conjunctivitis.

A comparison of pentane-1,5-diol to other diols for use in dermatology.

BACKGROUND: The use of pentane-1,5-diol in topical pharmaceutical products is relatively new compared with, e.g., propane-1,2-diol (propylene glycol), also an aliphatic diol, which has been used for many years. Yet, what are the differences between diols in clinical efficacy, safety and other characteristics? OBJECTIVE: The objective of this overview was to compare the efficacy, safety, chemical and pharmaceutical characteristics of pentane-1,5-diol with other aliphatic diols used in pharmaceutical formulations in dermatology. METHODS: A survey of the literature was carried out based on searches limited to aliphatic diols. RESULTS/CONCLUSION: Pentane-1,5-diol was found to be safe and more effective than several other diols with respect to drug delivery-enhancing potency, pharmaceutical and cosmetic properties, antimicrobial spectrum and toxicity. Results from formal clinical trials with pentane-1,5-diol verify its efficacy and safety. These characteristics together with its low cost make pentane-1,5-diol an attractive substance for use in pharmaceutical formulations for topical administration.

A double-blind, randomized, vehicle-controlled clinical study to evaluate the efficacy and safety of MAS063DP (ATOPICLAIR) in the management of atopic dermatitis in paediatric patients.

A multicenter, randomized, double-blind, vehicle-controlled clinical study was conducted to evaluate the efficacy and safety of MAS063DP in 60 paediatric patients affected by atopic dermatitis (AD), aged between 2 and 17 years. Using the Investigator's Global Assessment (IGA) score for AD, patients with a score of 2 (mild) or 3 (moderate) were enrolled in the study. Patients were randomly selected to receive MAS063DP (20 patients), MAS060 (20 patients, a similar formulation with lower key ingredients' concentration and no preservatives) or vehicle (20 patients).The study consisted in a treatment period of 43 days, with clinical evaluations at baseline (day 1), days 8, 15, 22, 29 and 43, at which time the treatment was stopped. MAS063DP showed nearly 80% improvement in IGA score at day 22, compared with 16.6% and 26.3% with the MAS060 and vehicle respectively. A statistically significant difference was found by comparing MAS063DP with MAS060 (p < 0.0001); a similar result was evidenced comparing MAS063DP and vehicle (p = 0.001). By contrast, no significant difference was found between MAS060 and vehicle. A statistically significant difference was sustained until the end of the study. MAS063DP may therefore be considered as one of the available regimens effective in the treatment of mild-to-moderate AD in children and adolescents.

Comparison of initial treatment response to two enhanced-viscosity artificial tears.

PURPOSE: To compare the effectiveness of 1.0% carboxymethylcellulose (CMC) (Refresh Liquigel, Allergan, Inc., Irvine, CA) and propylene glycol/polyethylene glycol 400 (PG-HPG) (Systane, Alcon, Fort Worth, TX) in providing relief of dry eye symptoms and signs. METHODS: To evaluate patient comfort and drop preference, patients were given CMC in one eye and PG-HPG in the other. Five minutes after the initial drop application, patients were questioned on overall preference and comfort, as measured by stickiness, blurring, and soothing. Patients were then randomized to receive CMC or PG-HPG in both eyes for 1 week. Fluorescein staining was evaluated at baseline and week 1. RESULTS: Of patients with a preference, more patients preferred CMC than PG-HPG. Thirty-six percent preferred CMC, and 24% preferred PG-HPG. More (35%) patients found CMC to be more soothing than PG-HPG (22%). After 1 week of treatment, eyes treated with CMC consistently showed less ocular surface staining than did eyes treated with PG-HPG. Mean corneal staining score in the inferior region was significantly lower in the CMC group than in the PG-HPG group (P = 0.008) at week 1. CMC provided a statistically significant decrease in mean corneal inferior staining (P < 0.001), whereas the PG-HPG group (P = 0.185) had no significant change. In the temporal conjunctival region, CMC provided a significantly lower mean staining score than PG-HPG after 1 week of treatment (P = 0.005). CONCLUSIONS: Patients found CMC to be more comfortable than PG-HPG. After 1 week of use, CMC provided greater relief of dry eye signs and symptoms than PG-HPG.

Therapy with gentamicin-PMMA beads, gentamicin-collagen sponge, and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats.

INTRODUCTION: In spite of new surgical techniques and recently developed antibiotics, there is no satisfactory solution for the treatment of chronic posttraumatic osteomyelitis. The introduction of local antibiotic treatment with gentamicin-PMMA beads according to Klemm has provided new stimuli for the treatment of chronic osteomyelitis. With the development of collagen as an absorbable carrier substance, the disadvantages of the rigid carrier system became evident. Due to the varying surgical techniques and different forms of adjuvant therapy, it is difficult to assess therapeutic methods and compare different studies. Therefore, it seemed appropriate to study the effect of local treatment with different antibiotic carriers in the setting of an animal study. MATERIALS AND METHODS: The proven rat model for Staphylococcus aureus-induced osteomyelitis was used to compare the results of monotherapy with cefazolin, gentamicin-PMMA beads, or gentamicin-containing collagen sponge with the combination of local and systemic antibiotic treatment. RESULTS: Single-agent therapy with parenterally administered cefazolin reduced the CFU from 3.7 x 10(6) to 2.9 x 10(4) g(-1) of tibial bone. The effect on osteomyelitis was more pronounced with the local application of antibiotics. The best results were achieved with the gentamicin-containing collagen sponge which reduced the bacterial colony count to 1.4 x 10(2) CFU/g compared with 9.8 x 10(2) CFU/g achieved with gentamicin-PMMA beads. The effect was most marked using a 4-week combination therapy with local application of the gentamicin-containing collagen sponge and systemic administration of cefazolin. In 9 of 11 animals, no bacteria could be detected in the bone. CONCLUSION: Each of the treatment modalities resulted in a significant therapeutic effect. Due to its ability to quickly release large amounts of gentamicin, the flexible gentamicin-containing collagen sponge proved to be superior to the rigid PMMA system. Although the gentamicin-containing collagen sponge provided high antibiotic concentration at the site of implantation, an additive effect was attained when combined with systemic antibiotic treatment.

Histological effects of tazarotene 0.1% cream vs. vehicle on photodamaged skin: a 6-month, multicentre, double-blind, randomized, vehicle-controlled study in patients with photodamaged facial skin.

BACKGROUND: Topical tazarotene has been shown to offer efficacy in ameliorating multiple effects of photodamage. OBJECTIVES: To evaluate the histological effects of tazarotene cream on photodamaged skin. METHODS: In this multicentre, double-blind, randomized, vehicle-controlled study, 50 patients with photodamaged facial skin (at least mild fine wrinkling and mottled hyperpigmentation, with at least one of these being moderate) were randomized to apply tazarotene 0.1% cream or vehicle cream to their face, once daily for 24 weeks. RESULTS: Blinded assessments showed that tazarotene was less likely than vehicle to be associated with an increase in keratinocytic and melanocytic atypia, and more likely than vehicle to be associated with a reduction in atypia. Between-group comparisons in distribution of change from baseline categories of severity were in favour of tazarotene (P = 0.055 for keratinocytic atypia, P = 0.034 for melanocytic atypia, and P < 0.001 for the number of granular cell layers). Compared with vehicle, tazarotene was associated with an increase in epidermal polarity (P = 0.008) and epidermal thickness (P = 0.012), and a tendency for stratum corneum compaction. Tazarotene was also associated with widened intercellular spaces (reported as epidermal oedema) relative to vehicle (P < 0.001). CONCLUSIONS: Treatment of photodamaged skin with tazarotene is associated with an amelioration of keratinocytic and melanocytic atypia, an improvement in epidermal polarity, and an increase in epidermal thickness.

Utilization of a high-resolution digital imaging system for the objective and quantitative assessment of hyperpigmented spots on the face.

BACKGROUND/AIMS: The aim of this study was to quantify and confirm the efficacy of cosmetic formulations for hyperpigmented spots over a wide area of the face using a high quality digital imaging system that we developed. METHODS: A total of 120 Japanese female volunteers aged 25-60 years with solar lentigines were treated for 6 months with a skin lightening moisturizer (SLM, thereafter) containing 3% magnesium ascorbyl phosphate on one side of the face and vehicle on the other side. During the course of the study, facial images were collected by the image analysis to measure facial skin colour and the total area of hyperpigmented spots. The evaluation was also conducted by visual grading. Measurements were made before and 1, 3, and 6 months after starting the application, and again 6 months after discontinuing the treatment. Three similar clinical studies using the same protocol were repeated for up to one-month to confirm the reproducibility of the results and to examine seasonal variation. RESULTS: SLM significantly reduced the total area of hyperpigmented spots (P < 0.005) after one month of treatment compared to the vehicle, with no significant variation in facial skin colour tone in the areas outside the hyperpigmented spots. The results of the visual grading were consistent with those obtained by image analysis. The total area of hyperpigmented spots 6 months after discontinuing the treatment had returned to pre-treatment levels. The reproducibility of these clinical results was demonstrated in three follow-up studies. CONCLUSIONS: A high-resolution digital imaging method, combined with a split-face clinical protocol is sensitive enough to prove that SLM readily reduces hyperpigmented spots, while maintaining normal facial skin colour.