Donald Bissett

The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer

Summary Background Cutaneous hyperpigmentation occurs in multiple conditions. In addition, many Asian women desire a lighter skin colour. Thus, there is a need for the development of skin lightening agents. Niacinamide is a possible candidate.

Wavelength dependence of histological, physical, and visible changes in chronically UV-irradiated hairless mouse skin

Abstract— Albino hairless mice (Skh:HR–1) exposed chronically to sub‐erythemal doses of UV radiation display physical, visible and histological alterations. Using narrow bandwidth radiation covering the UV radiation spectrum from280–380 nm, the wavelength dependence of these alterations was determined. The wavelength dependence spectra indicate that for all but one parameter measured (skin sagging), UV‐B radiation is considerably more efficient than UV‐A radiation in producing changes in the skin. However, in natural sunlight there is considerably more UV‐A than UV‐B radiation, providing the potential for UV‐A to have a larger contribution to skin damage than UV‐B. This argues in favor of using broad spectrum photoprotective agents to shield the skin adequately from UV‐induced aging. The spectra were also used to develop potential associations among events by determining which events occur at similar wavelengths. There seems to be a correspondence between mouse visible skin wrinkling (UV‐B event) and two histological events: increase in glycosami‐noglycans and alteration in collagen. There was no obvious correspondence among UV‐A‐induced events.

Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung Cancer

PURPOSE Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. PATIENTS AND METHODS Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. RESULTS Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. CONCLUSION Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.

Chronic ultraviolet radiation-induced increase in skin iron and the photoprotective effect of topically applied iron chelators.

In the skin of albino hairless mice (Skh:HR‐l) there is a basal level of non‐heme iron. Chronic exposure of mice to sub‐erythemal doses of ultraviolet (UV) B radiation results in an increased skin level of non‐heme iron. The iron increase may be the result of a UVB radiation‐induced increase in vascular permeability, which we measured in vivo with the dye marker Evans Blue. We also observed greater non‐heme iron in sun‐exposed vs non‐exposed body sites of human skin, suggesting that similar events occur in man.

Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin

The palmitoyl pentapeptide palmitoyl‐lysine‐threonine‐threonine‐lysine‐serine (pal‐KTTKS) is a synthetic material that was designed as a topical agent to stimulate collagen production and thus provide a skin anti‐wrinkle benefit. To determine if pal‐KTTKS is effective, the clinical study reported here was conducted. Caucasian female subjects (n = 93, aged 35–55) participated in a 12‐week, double‐blind, placebo‐controlled, split‐face, left–right randomized clinical study assessing two topical products: moisturizer control product vs. the same moisturizer product containing 3 ppm pal‐KTTKS. Pal‐KTTKS was well tolerated by the skin and provided significant improvement vs. placebo control for reduction in wrinkles/fine lines by both quantitative technical and expert grader image analysis. In self‐assessments, subjects also reported significant fine line/wrinkle improvements and noted directional effects for other facial improvement parameters.

A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. Experimental Design: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. Results: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m2 (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m2. Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m2. Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m2 in phase Ia and one in a patient with gastric carcinoma at 175 mg/m2 in phase Ib. Conclusion: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.

Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT)

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mg m−2 (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m−2. Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mg m−2. The half-lives of both MAG-CPT and released CPT were prolonged (>6 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.

Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin1

Previous clinical testing of topical niacinamide (vitamin B3) has revealed a broad array of improvements in the appearance of aging facial skin. The study reported here was done to confirm some of those previous observations and to evaluate additional end points such as skin anti‐yellowing. Caucasian female subjects (n = 50, aged 40–60 years) participated in a 12‐week, double‐blind, placebo‐controlled, split‐face, left–right randomized clinical study assessing two topical products: moisturizer control product versus the same moisturizer product containing 5% niacinamide. Niacinamide was well tolerated by the skin and provided significant improvements versus control in end points evaluated previously: fine lines/wrinkles, hyperpigmentation spots, texture, and red blotchiness. In addition, skin yellowing (sallowness) versus control was significantly improved. The mechanism by which this array of benefits is achieved with niacinamide is discussed.

Chronic ultraviolet B radiation-induced biochemical changes in the skin of hairless mice.

Abstract— Skh:HR‐l hairless mice were irradiated chronically with sub‐erythemal doses of UVB radiation, and a number of biochemical parameters in the skin were determined after 6,12, 18, and 24 wk of exposure. The parameters measured were water, collagen, elastin, and glycosaminoglycan content; collagenase and elastase levels; and Bz‐Tyr‐OEt (7V‐benzoyl‐L‐tyrosine ethyl ester) and BAPNA (alpha‐N‐benzoyl‐DL‐arginine‐p‐nitroanilide) hydrolyzing activities. Data for UVB radiation‐exposed and chronological age‐matched control mice were compared with respect to unit area and to unit mass of skin. On a unit area of skin basis, UVB radiation exposure increased the level of most parameters. The particular exceptions were collagen and collagenase which remained constant. On a mass of skin basis, though, there is an apparent decrease in collagen content because of the increase in the other skin components. This suggests that there is insufficient collagen in UVB radiation‐exposed skin to support the increasing mass of the tissue.

Latest Insights into Skin Hyperpigmentation

Hyperpigmentary problems, including postinflammatory hyperpigmentation, solar lentigos, and melasma, occur widely in the human population and are thus of broad interest for control. On the basis of genomic and proteomic understanding of the melanocyte and melanogenesis, there are potentially hundreds of proteins and other effectors involved in pigmentation. This knowledge, although complex, should prove most useful in identifying specific abnormalities that lead to the hyperpigmentary problems. Also available are new laboratory screening methods and skin color measurement tools that are increasing the pace at which materials can be screened and evaluated clinically for their effectiveness. Combined with a clear consumer need for effective pigmentation control agents, advanced pigmentary system understanding and new research capabilities are setting the stage for future technological advancements.