The Melbourne Consensus Statement on the early detection of prostate cancer.

Various conflicting guidelines and recommendations about prostate cancer screening and early detection have left both clinicians and their patients quite confused. At the Prostate Cancer World Congress held in Melbourne in August 2013, a multidisciplinary group of the world’s leading experts in this area gathered together and generated this set of consensus statements to bring some clarity to this confusion. The five consensus statements provide clear guidance for clinicians counselling their patients about the early detection of prostate cancer.

BJU Int. 2014 Feb;113(2):186-8

Incidence and correlates of fatigue in metastatic castration-resistant prostate cancer: a systematic review.

Prostate cancer is the second most common malignancy of men in the western countries. Fatigue is the most stressful symptom of which patients with metastatic castration-resistant prostate cancer (mCRPC) complain. The aim of this article was to report available data about the incidence of fatigue in mCRPC and its correlates. The design involved a systematic review to define incidence of fatigue according to Common Toxicity Criteria in randomized controlled trials of medical treatments of mCRPC and according to International Classification of Diseases Revision 10 (ICD-10) criteria, and to define prevalence and correlates of fatigue in patients with mCRPC. The data source used was PubMed. In December 2014, 2 PubMed searches were performed and the clinical data on the occurrence of cancer-related fatigue along the course of metastatic disease, and findings about its pathogenesis were summarized. Cancer-related fatigue, as defined according to ICD-10 criteria, was reported in 12% to 21% of patients, and prospective clinical trials showed a prevalence of Grade 3/4 fatigue according to Common Toxicity Criteria of 0% to 18%. A list of possible correlates of fatigue in mCRPC, either patient-related, disease-related, or treatment-related, is proposed herein for future studies. Antineoplastic treatments, particularly chemotherapy and radiotherapy, have a major role in the pathogenesis of fatigue in metastatic prostate cancer, however, hormonal treatments remain the most prevalent therapies. A standardized tool for multidimensional assessment of fatigue in metastatic cancer is suggested.

Clin Genitourin Cancer. 2016 Feb;14(1):5-11

Clinical, pathological and molecular prognostic factors in prostate cancer decision-making process.

Prostate cancer is the most common urologic neoplasm and the second leading cause of cancer-related death among men in many developed countries. Given the highly heterogeneous behaviour of the disease, there is a great need for prognostic factors, in order to stratify the clinical risk and give the best treatment options to the patient. Clinical factors, such as prostate-specific antigen value and derivatives, and pathological factors, such as stage and Gleason grading, are well kown prognostic factors. Nomograms can provide useful prediction in each clinical sceario. The field of molecular biomarkers is briskly evolving towards personalized medicine. TMPRSS2-ERG fusion, deletion of PTEN ed and gene panels are some of the more extensively explored molecular features in prostate cancer outcome prediction. In the near future, circulating tumour cells, exosomes and microRNAs could give us further, not invasive important tools.

Urologia. 2016 Mar 5;82(1):14-20

Overdetection in screening for prostate cancer.

PURPOSE OF REVIEW: To describe mechanisms behind and extent of overdetection in prostate cancer screening as well as possible ways to avoid unnecessary overdiagnosis. RECENT FINDINGS: Overdetection and overtreatment is common in many areas of modern medicine. Current prostate-specific antigen (PSA) testing has resulted in a marked stage shift to early stages, which, together with improvements in treatment, has resulted in a substantial decrease in prostate cancer mortality. However, nonselective, widespread PSA-testing followed by liberal biopsy criteria has resulted in a high rate of overdiagnosis, which constitutes one major obstacle to introducing population-based screening. SUMMARY: Several steps are needed to decrease overdetection: do not screen elderly men unlikely to benefit, do not biopsy without a compelling reason, differentiate screening interval according to risk, work-up benign prostate disease by using reflex tests and/or complementary biomarkers, and focus on screening men at high risk for a life-threatening disease, for example evaluate men with above-median PSA levels in midlife. Recent results indicate that use of MRI to select men for biopsy and using only lesion-directed biopsies may be one way forward. However, more studies are needed before firm recommendations can be made. When the diagnosis is made, treat only those who need treatment. Tailor treatment to tumor biology and patient characteristics, and offer active surveillance to eligible men with low-risk tumors, especially small-volume disease, as the first management.

Curr Opin Urol. 2014 May;24(3):256-63

Prostate cancer: measuring PSA.

Population screening with prostate-specific antigen (PSA) for detection of prostate cancer is a topic associated with ongoing dissent and confusion within the oncology and wider medical community. The PSA blood test has been used in various stages of prostate cancer management, including screening and the assessment of future risk of prostate cancer development, detection of recurrent disease after local therapy and in the management of advanced disease. However, PSA-based decision-making in prostate cancer has significant shortcomings. This review will summarise the evidence and current recommendations for the use of PSA in detection and management of prostate cancer.

Intern Med J. 2014 May;44(5):433-40

The memorial sloan kettering cancer center recommendations for prostate cancer screening.

The Memorial Sloan Kettering Cancer Center (MSKCC) recommendations on prostate cancer screening were developed in response to three limitations of previous screening guidelines: insufficient evidence base, failure to link screening with treatment, and lack of risk stratification. The objective of the recommendations is to provide a schema for prostate cancer screening that maximizes the benefits, in terms of reduction in prostate cancer-specific mortality, and minimizes the harms, in terms of overdiagnosis and overtreatment. We recommend the following schema for men choosing to be screened following informed decision-making: starting at age 45, prostate-specific antigen (PSA) without digital rectal examination. If PSA ≥ 3 ng/mL: consider prostate biopsy; if PSA ≥ 1 but < 3 ng/mL: return for PSA testing every 2-4 years; if PSA < 1 ng/mL: return for PSA testing at 6-10 years. PSA testing should end at age 60 for men with PSA ≤ 1 ng/ mL; at 70, unless a man is very healthy and has a higher than average PSA; at 75 for all men. The decision to biopsy a man with a PSA > 3 ng/mL should be based on a variety of factors including repeat blood draw for confirmatory testing of the PSA level, digital rectal examination results, and workup for benign disease. Additional reflex tests in blood such as a free-to-total PSA ratio, the Prostate Health Index, or 4Kscore, or urinary testing of PCA3, can also be informative in some patients. The best evidence suggests that more restricted indication for prostate biopsy and a more focused approach to pursue screening in men at highest risk of lethal cancer would retain most of the mortality benefits of aggressive screening schema, while importantly reducing harms from overdetection and overtreatment.

Urology. 2016 Feb 2

Rationale for a “male lumpectomy,” a prostate cancer targeted approach using cryoablation: results in 21 patients with at least 2 years of follow-up.

BACKGROUND: Prostate cancer in men raises many of the same issues that breast cancer does in women. Complications of prostate cancer treatment, including impotence and incontinence, affect the self-image and psyche of a man no less than does the loss of a breast in a woman. We present a pilot study in which 21 patients were treated with a focal cryoablation procedure. METHODS: Focal cryoablation was performed using biplane transrectal ultrasound if the tumor was confined to only one prostate lobe. Preoperative PSA values were recorded. Cryoablation was planned to encompass the area of known tumor. PSA values were obtained every 3 months for 2 years and every 6 months thereafter. Potency and continence status was obtained at the same intervals. Routine biopsy was obtained at 1 year. RESULTS: Twenty-one patients had focal cryoablation. Follow-up ranged from 24 to 105 months with a mean of 50 months. Twenty of 21 (95%) patients have stable PSA values with no evidence for cancer, despite 10 patients being at medium to high risk for recurrence. All patients biopsied (n = 19) were negative for tumor. Potency was maintained in 17 of 21 patients (80%). No other complications, including incontinence or fistula formation, were noted. CONCLUSION: These preliminary results indicate a “male lumpectomy,” in which the prostate tumor region itself is destroyed, appears to preserve potency in a majority of patients and limits other complications, without compromising cancer control. If these results are confirmed by further studies and long-term follow-up, this treatment approach could have a profound effect on prostate cancer management.

Cardiovasc Intervent Radiol. 2008 Jan-Feb; 31(1):98-106

“Male lumpectomy”: focal therapy for prostate cancer using cryoablation.

The introduction of breast-sparing surgery (ie, “lumpectomy”) revolutionized the management of breast cancer. The use of lumpectomy showed that quality of life could be optimized without compromising treatment efficacy. Complications of prostate cancer treatment, including impotence and incontinence, adversely alter the male self-image similarly to the way the loss of a breast does for a woman. Traditional thinking holds that prostate cancer is multifocal and therefore is not amenable to focal treatment. However, histopathologic findings from published data have indicated that up to 25% of prostate cancers are solitary and unilateral. Furthermore, the significance of minute secondary cancers might be minimal. These observations raise the question of whether certain patients can be identified and treated with a limited “lumpectomy.” In this study, focal cryoablation has been used to ablate the area of known cancer as determined by staging biopsies. The serum prostate-specific antigen (PSA) concentration was obtained every 3 months for 2 years and every 6 months thereafter. American Society for Therapeutic Radiology Oncology (ASTRO) criteria for PSA recurrence were used. A total of 55 patients with > or = 1 year of follow-up had undergone focal cryoablation. Follow-up ranged from 1 to 10 years (mean, 3.6 years). At the original transrectal ultrasound biopsy, the mean and median numbers of cores taken were 9.9 and 10 (SD, +/- 3.5), respectively. Mean and median numbers of positive cores were 1.8 and 1 (SD, +/- 1.3), respectively. Of the 55 study patients, 52 (95%) had stable PSA levels with no evidence of cancer despite a medium to high risk for recurrence in 29 patients. All biopsy findings were negative among the 26 patients with a stable PSA level who had undergone routine biopsy at 1 year. No local recurrence was noted in treated areas. Potency was maintained in 44 (86%) of 51 patients. Of the 54 patients without previous prostate surgery or radiotherapy, all were continent. These preliminary results indicate that “male lumpectomy”—in which the prostate tumor region itself is destroyed—preserves potency in most patients and limits other complications (particularly incontinence) without compromising cancer control. Additional studies and long-term follow-up are needed to confirm that this treatment approach could have a profound effect on prostate cancer management.

Urology. 2007 Dec;70(6 Suppl):16-21

The “male lumpectomy”: focal therapy for prostate cancer using cryoablation results in 48 patients with at least 2-year follow-up.

BACKGROUND: The use of breast sparing surgery, i.e., “lumpectomy”, revolutionized management of breast cancer. Lumpectomy confirmed that quality of life issues can successfully be addressed without compromising treatment efficacy. Complications of prostate cancer treatment, including impotence and incontinence, affect the male self image no less than the loss of a breast does a woman. Traditional thinking held that prostate cancer was multifocal and therefore not amenable to a focal treatment approach. Recent pathology literature indicates, however, that up to 25% of prostate cancers are solitary and unilateral. This raises the question of whether these patients can be identified and treated with a limited “lumpectomy” or focal cancer treatment. METHODS: Focal cryoablation was planned to encompass the area of known tumor based on staging biopsies. PSAs were obtained every 3 months for 2 years and then every 6 months thereafter. RESULTS: Forty-eight patients with at least 2-year follow-up had focal cryoablation. Follow-up ranged from 2 years 10 years with a mean of 4.5 years; 45 of 48 patients (94%) have stable PSAs [American Society of Therapeutic Radiology and Oncology (ASTRO) criteria] with no evidence for cancer, despite 25 patients being medium to high risk for recurrence. Of the 24 patients with stable PSAs who were routinely biopsied (n = 24) all were negative. No local recurrences were noted in areas treated. Potency was maintained to the satisfaction of the patient in of 36 of 40 patients who were potent preoperatively. Of the 48, all were continent. CONCLUSION: These preliminary results indicate a “male lumpectomy” in which the prostate tumor region itself is destroyed, appears to preserve potency in a majority of patients and limits other complications (particularly incontinence), without compromising cancer control. If confirmed by further studies and long-term follow-up, this treatment approach could have a profound effect on prostate cancer management.

Urol Onco l. 2008 Sep-Oct;26(5):500-5

Three-dimensional prostate mapping biopsy has a potentially significant impact on prostate cancer management.

PURPOSE: To compare a new staging, three-dimensional prostate mapping biopsy (3D-PMB) method with traditional transrectal ultrasound (TRUS) biopsy and assess its possible impact on patient management. PATIENTS AND METHODS: One hundred eighty patients with unilateral cancer on TRUS biopsy, who were considering conservative management, underwent restaging with 3D-PMB. The 3D-PMB was carried out transperineally using a brachytherapy grid under TRUS guidance. Biopsies were taken every 5 mm throughout the volume of the prostate, and labeling of the specimen coordinates allowed accurate reconstruction of the location and extent of a patient’s cancer. RESULTS: 3D-PMB obtained a median of 50 cores (standard deviation, +/- 20.61). One hundred ten patients (61.1%) were positive bilaterally, and 41 patients (22.7%) had Gleason scores increased to 7 or higher. Thirty-six patients had negative results on 3D-PMB. Complications of 3D-PMB were self-limited and included 14 patients (7.7%) who required short-term indwelling catheter drainage and two patients with hematuria, one of whom required overnight bladder irrigation. CONCLUSION: 3D-PMB is a transperineal biopsy that can be safely used to accurately stage prostate cancer patients. At the present time, when patient management is increasingly based on the extent and characteristics of prostate cancer, 3D-PMB could have a profound effect on patient management.

J Clin Oncol. 2009 Sep 10;27(26):4321-6

Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities.

PURPOSE: Based on contemporary epidemiological and pathological characteristics of prostate cancer we explain the rationale for and concerns about focal therapy for low risk prostate cancer, review potential methods of delivery and propose study design parameters. MATERIALS AND METHODS: Articles regarding the epidemiology, diagnosis, imaging, treatment and pathology of localized prostate cancer were reviewed with a particular emphasis on technologies applicable for focal therapy, defined as targeted ablation of a limited area of the prostate expected to contain the dominant or only focus of cancer. A consensus summary was constructed by a multidisciplinary international task force of prostate cancer experts, forming the basis of the current review. RESULTS: In regions with a high prevalence of prostate specific antigen screening the over detection and subsequent overtreatment of prostate cancer is common. The incidence of unifocal cancers in radical prostatectomy specimens is 13% to 38%. In many others there is an index lesion with secondary foci containing pathological features similar to those found incidentally at autopsy. Because biopsy strategies and imaging techniques can provide more precise tumor localization and characterization, there is growing interest in focal therapy targeting unifocal or biologically unifocal tumors. The major arguments against focal therapy are multifocality, limited accuracy of staging, the unpredictable aggressiveness of secondary foci and the lack of established technology for focal ablation. Emerging technologies with the potential for focal therapy include high intensity focused ultrasound, cryotherapy, radio frequency ablation and photodynamic therapy. CONCLUSIONS: Early detection of prostate cancer has led to concerns that while many cancers now diagnosed pose too little a threat for radical therapy, many men are reluctant to accept watchful waiting or active surveillance. Several emerging technologies seem capable of focal destruction of prostate tissue with minimal morbidity. We encourage the investigation of focal therapy in select men with low risk prostate cancer in prospective clinical trials that carefully document safety, functional outcomes and cancer control.

J Urol. 2007 Dec;178(6):2260-7

Enhancement of learning and memory by elevating brain magnesium.

Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.

Neuron. 2010 Jan 28;65(2):165-77

Brain plasticity and functional losses in the aged: scientific bases for a novel intervention.

Aging is associated with progressive losses in function across multiple systems, including sensation, cognition, memory, motor control, and affect. The traditional view has been that functional decline in aging is unavoidable because it is a direct consequence of brain machinery wearing down over time. In recent years, an alternative perspective has emerged, which elaborates on this traditional view of age-related functional decline. This new viewpoint—based upon decades of research in neuroscience, experimental psychology, and other related fields—argues that as people age, brain plasticity processes with negative consequences begin to dominate brain functioning. Four core factors—reduced schedules of brain activity, noisy processing, weakened neuromodulatory control, and negative learning—interact to create a self-reinforcing downward spiral of degraded brain function in older adults. This downward spiral might begin from reduced brain activity due to behavioral change, from a loss in brain function driven by aging brain machinery, or more likely from both. In aggregate, these interrelated factors promote plastic changes in the brain that result in age-related functional decline. This new viewpoint on the root causes of functional decline immediately suggests a remedial approach. Studies of adult brain plasticity have shown that substantial improvement in function and/or recovery from losses in sensation, cognition, memory, motor control, and affect should be possible, using appropriately designed behavioral training paradigms. Driving brain plasticity with positive outcomes requires engaging older adults in demanding sensory, cognitive, and motor activities on an intensive basis, in a behavioral context designed to re-engage and strengthen the neuromodulatory systems that control learning in adults, with the goal of increasing the fidelity, reliability, and power of cortical representations. Such a training program would serve a substantial unmet need in aging adults. Current treatments directed at age-related functional losses are limited in important ways. Pharmacological therapies can target only a limited number of the many changes believed to underlie functional decline. Behavioral approaches focus on teaching specific strategies to aid higher order cognitive functions, and do not usually aspire to fundamentally change brain function. A brain-plasticity-based training program would potentially be applicable to all aging adults with the promise of improving their operational capabilities. We have constructed such a brain-plasticity-based training program and conducted an initial randomized controlled pilot study to evaluate the feasibility of its use by older adults. A main objective of this initial study was to estimate the effect size on standardized neuropsychological measures of memory. We found that older adults could learn the training program quickly, and could use it entirely unsupervised for the majority of the time required. Pre- and posttesting documented a significant improvement in memory within the training group (effect size 0.41, p<0.0005), with no significant within-group changes in a time-matched computer using active control group, or in a no-contact control group. Thus, a brain-plasticity-based intervention targeting normal age-related cognitive decline may potentially offer benefit to a broad population of older adults.

Prog Brain Res. 2006;157:81-109

Enhancement of synaptic plasticity through chronically reduced Ca2+ flux during uncorrelated activity.

The plasticity of synapses within neural circuits is regulated by activity, but the underlying mechanisms remain elusive. Using the dye FM1-43 to directly image presynaptic function, we found that large numbers of presynaptic terminals in hippocampal cultures have a low release probability. While these terminals were not readily modifiable, a transient but not permanent long-term reduction of network activity or Ca2+ influx could increase their modifiability. This modulation of plasticity was mediated by Ca2+ flux through NMDA and voltage-gated calcium channels and was lost within 48 hr. A more permanent enhancement of synaptic plasticity was achieved by selectively reducing the Ca2+ flux associated with uncorrelated activity via adjustment of the voltage-dependent Mg2+ block of the NMDAR. Upregulation of NR2B-containing NMDARs induced by this treatment is an important but not sole contributor to the enhancement of plasticity. Thus, quantity and quality of activity have differential effects on the intrinsic plasticity of neurons.

Neuron. 2004 Dec 2;44(5):835-49

By suppressing the expression of anterior pharynx-defective-1a and -1b and inhibiting the aggregation of b-amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice.

Alzheimer’s disease (AD) is associated with a magnesium ion (Mg(2+)) deficit in the serum or brain. However, the mechanisms regulating the roles of Mg(2+) in the pathologic condition of AD remain unknown. We studied whether brain Mg(2+) can decrease b-amyloid (Ab) deposition and ameliorate the cognitive decline in a model of AD, the APPswe/PS1DE9 transgenic (Tg) mouse. We used a recently developed compound, magnesium-L-threonate (MgT), for a treatment that resulted in enhanced clearance of Ab in an anterior pharynx-defective (APH)-1a/-1b-dependent manner. To further explore how MgT treatment inhibits cognitive decline in APP/PS1 Tg mice, the critical molecules for amyloid precursor protein (APP) cleavage and signaling pathways were investigated. In neurons, ERK1/2 and PPARg signaling pathways were activated by MgT treatment, which in turn suppressed (by >80%) the expression of APH-1a/-1b, which is responsible for the deposition of Ab and potentially contributes to the memory deficit that occurs in AD. More important, Ab oligomers in the cerebrospinal fluid (CSF) further promoted the expression of APH-1a/-1b (by >2.5-fold), which enhances the g-cleavage of APP and Ab deposition during AD progression. These findings provide new insights into the mechanisms of AD progression and are instrumental for developing better strategies to combat the disease.

FASEB J. 2015 Dec;29(12):5044-58

Magnesium in prevention and therapy.

Magnesium is the fourth most abundant mineral in the body. It has been recognized as a cofactor for more than 300 enzymatic reactions, where it is crucial for adenosine triphosphate (ATP) metabolism. Magnesium is required for DNA and RNA synthesis, reproduction, and protein synthesis. Moreover, magnesium is essential for the regulation of muscular contraction, blood pressure, insulin metabolism, cardiac excitability, vasomotor tone, nerve transmission and neuromuscular conduction. Imbalances in magnesium status-primarily hypomagnesemia as it is seen more common than hypermagnesemia-might result in unwanted neuromuscular, cardiac or nervous disorders. Based on magnesium’s many functions within the human body, it plays an important role in prevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic diseases, such as Alzheimer’s disease, insulin resistance and type-2 diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and attention deficit hyperactivity disorder (ADHD).

Nutrients. 2015 Sep 23;7(9):8199-226

Efficacy of cosmetic formulations containing dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid and kinetin.

The present study aimed to evaluate the photoprotective effects of cosmetic formulations containing a dispersion of liposome with magnesium ascorbyl phosphate (MAP), alpha-lipoic acid (ALA) and kinetin, as well as their effects on the hydration and viscoelastic skin properties. The photoprotection was determined in vitro (antioxidant activity) and in vivo on UV-irradiated hairless mouse skin. The hydration effects were performed with the application of the formulations under study on the forearm of human volunteers and skin conditions were analyzed before and after a single application and daily applications during 4 weeks in terms of transepidermal water loss (TEWL), skin moisture and viscoelastic properties. The raw material under study possessed free-radical scavenging activity and the formulation with it protected hairless mouse skin barrier function against UV damage. After 4 weeks of application on human skin, the formulation under study enhanced stratum corneum skin moisture and also showed hydration effects in deeper layers of the skin. Thus, it can be concluded that the cosmetic formulation containing a dispersion of liposome with MAP, ALA and kinetin under study showed photoprotective effects in skin barrier function as well as pronounced hydration effects on human skin, which suggests that this dispersion has potential antiaging effects.

Photochem Photobiol. 2012 May-Jun;88(3):748-52

In vitro antioxidant activity and in vivo efficacy of topical formulations containing vitamin C and its derivatives studied by non-invasive methods.

BACKGROUND/PURPOSE: Vitamins C and its derivatives, mainly due to their antioxidant properties, are being used in cosmetic products to protect and to reduce the signs of ageing. However, there are no studies comparing the effects of vitamin C [ascorbic acid (AA)] and its derivatives, magnesium ascorbyl phosphate (MAP) and ascorbyl tetra-isopalmitate (ATIP), when vehiculated in topical formulations, mainly using objective measurements, which are an important tool in clinical efficacy studies. Thus, the objective of this study was to determine the in vitro antioxidant activity of AA and its derivatives, MAP and ATIP, as well as their in vivo efficacy on human skin, when vehiculated in topical formulations. METHODS: The study of antioxidant activity in vitro was performed with an aqueous and a lipid system. The in vivo methodology consisted of the application of these formulations on human volunteers’ forearm skin and the analysis of the skin conditions after 4-week period daily applications in terms of transepidermal water loss (TEWL), stratum corneum moisture content and viscoelasticity using a Tewameter, Corneometer and Cutometer, respectively. RESULTS: In vitro experiments demonstrated that in an aqueous system, AA had the best antioxidant potential, and MAP was more effective than ATIP, whereas in the lipid system ATIP was more effective than MAP. In in vivo studies, all formulations enhanced stratum corneum moisture content after a 4-week period daily applications when compared with baseline values; however, only the formulation containing AA caused alterations in TEWL values. The formulations containing MAP caused alterations in the viscoelastic-to-elastic ratio, which suggested its action in the deeper layers of the skin. CONCLUSION: AA and its derivates presented an in vitro antioxidant activity but AA had the best antioxidant effect. In in vivo efficacy studies, only the formulation containing AA caused alterations in TEWL values and the formulation containing MAP caused alterations in the viscoelastic-to-elastic ratio. This way, vitamin C derivatives did not present the same effects of AA on human skin; however, MAP showed other significant effect-improving skin hydration, which is very important for the normal cutaneous metabolism and also to prevent skin alterations and early ageing.

Skin Res Technol. 2008 Aug;14(3):376-80

Postadministration protective effect of magnesium-L-ascorbyl-phosphate on the development of UVB-induced cutaneous damage in mice.

The effects of stable vitamin C, magnesium-L-ascorbyl-2-phosphate (MAP), administered after acute and chronic exposure to UVB irradiation were investigated using hairless mice. Intraperitoneal administration of 100 mg/kg of MAP immediately after acute exposure to 15 kJ/m2 of UVB significantly prevented increases of UVB-induced lipid peroxidation in skin and sialic acid in serum, an inflammation marker. Administration of 50 mg/kg of MAP immediately after each exposure significantly delayed skin tumor formation and hyperplasia induced by chronic exposure to 2 kJ/m2 of UVB. Intraperitoneal administration of 200 mg/kg of MAP produced an increase in ascorbic acid (As) levels in the serum, liver and skin within 15 min. Serum As levels quickly returned to normal, but hepatic and cutaneous levels remained elevated before returning to normal after 24 h, suggesting that MAP was converted to As in the serum and in those tissues. Ultraviolet B-induced hydroxyl radical generation in murine skin homogenates was scavenged by As-Na addition, which was directly detected by electron spin resonance (ESR). These results suggest that postadministration of MAP delays progression of skin damage induced by UVB irradiation. It is presumed that MAP, once converted to As, exhibits such inhibitory effects by scavenging hydroxyl and lipid radicals generated as a direct or indirect result of UVB exposure.

Photochem Photobiol. 1998 Jun;67(6):669-75

Protective effects of sodium-L-ascorbyl-2 phosphate on the development of UVB-induced damage in cultured mouse skin.

The protective effect of sodium-L-ascorbyl-2 phosphate (As-2P), a stable form of ascorbic acid (AsA), against photodamage induced by a single dose of UVB exposure (290-320 nm, Max 312 nm) was investigated using cultured mouse skin. When the cultured skin was treated with various As-2P concentrations, the cutaneous AsA level increased in proportion to the As-2P concentration. After 3 h of incubation, the AsA level in the cultured skin treated with 2, 20 and 100 mM As-2P increased 1.03-, 2.17- and 6.27-fold, respectively, compared with that of the control skin. These results suggest that As-2P was transported into the cultured mouse skin where it was converted to AsA. After 3 h, the cutaneous AsA level in irradiated (20 kJ/m2) skin was depleted to a half of that in the control skin. However, the level in skin pretreated with 20 mM As-2P was maintained within normal limits, even after 24 h. Pretreatment with 20 mM As-2P significantly prevented such photodamage as sunburn cell formation, DNA fragmentation and lipid peroxidation, which were caused by a single dose of UVB irradiation. These results suggest that the protective effect of 20 mM As-2P on UVB-induced cutaneous damage is due to the maintenance of a normal As level by conversion of As-2P to As in skin tissue.

Biol Pharm Bull. 1999 Dec;22(12):1301-5

Sodium ascorbyl phosphate shows in vitro and in vivo efficacy in the prevention and treatment of acne vulgaris.

Acne vulgaris is the most common inflammatory skin disorder and jeopardizes seriously the facial impression of a person. Development of acne involves a complex relation among several causes. Treatment and prevention success can be archived by affecting the main contributors positively like Proprionibacterium acnes or lipid oxidation leading to inflammatory reactions and follicular keratinization. Vitamin C tends to break down in cosmetic formulations resulting in a brownish discoloration. Sodium ascorbyl phosphate (SAP) represents a stable precursor of vitamin C that ensures a constant delivery of vitamin C into the skin. We were able to show that 1% SAP has a strong antimicrobial effect with a log reduction of 5 after 8 h on P. acnes in a time-kill study. Further on in a human in vivo study with 20 subjects an SAP O/W formulation significantly prevents the UVA-induced sebum oxidation up to 40%. Finally, we performed an open in vivo study with 60 subjects with a 5% SAP lotion over 12 weeks. The efficacy ranked as excellent and good of SAP was 76.9%, which was superior compared with a widely prescribed acne treatment. In conclusion, these data show that SAP is efficient in the prevention and treatment of acne vulgaris. SAP can be used in a non-antibiotic and effective treatment or co-treatment of acne with no side effects, which makes it particularly attractive for cosmetic purposes.

Int J Cosmet Sci. 2005 Jun;27(3):171-6

Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration.

Skin pigmentary abnormalities are seen as aesthetically unfavorable and have led to the development of cosmetic and therapeutic treatment modalities of varying efficacy. Hence, several putative depigmenting agents aimed at modulating skin pigmentation are currently being researched or sold in commercially available products. In this review we will discuss the regulation of processes that control skin complexion coloration. This includes direct inhibition of tyrosinase and related melanogenic enzymes, regulation of melanocyte homeostasis, alteration of constitutive and facultative pigmentation and down-regulation of melanosome transfer to the keratinocytes. These various processes, in the complex mechanism of skin pigmentation, can be regulated individually or concomitantly to alter complexion coloration and thus ameliorate skin complexion diseases.

Int J Mol Sci. 2009 Sep 15;10(9):4066-87

Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin.

Ferulic acid is a potent ubiquitous plant antioxidant. Its incorporation into a topical solution of 15%l-ascorbic acid and 1%alpha-tocopherol improved chemical stability of the vitamins (C+E) and doubled photoprotection to solar-simulated irradiation of skin from 4-fold to approximately 8-fold as measured by both erythema and sunburn cell formation. Inhibition of apoptosis was associated with reduced induction of caspase-3 and caspase-7. This antioxidant formulation efficiently reduced thymine dimer formation. This combination of pure natural low molecular weight antioxidants provides meaningful synergistic protection against oxidative stress in skin and should be useful for protection against photoaging and skin cancer.

J Invest Dermatol. 2005 Oct;125(4):826-32

Topical vitamin C: a useful agent for treating photoaging and other dermatologic conditions.

BACKGROUND: Cosmeceuticals containing antioxidants are among the most popular antiaging remedies. Topically applied antioxidants exert their benefits by offering protection from damaging free radicals produced when skin is exposed to ultraviolet light or allowed to age naturally. Vitamin C is a naturally occurring potent water-soluble antioxidant. Accordingly, it has been incorporated into a variety of cosmeceuticals designed to protect and rejuvenate photoaged skin. OBJECTIVE: This article reviews the scientific data and clinical studies supporting the use of topically applied vitamin C for treating
photoaged skin. Other innovative uses for vitamin C cosmeceuticals are also discussed. CONCLUSION: A significant body of scientific research supports the use of cosmeceuticals containing vitamin C. Cutaneous benefits include promoting collagen synthesis, photoprotection from ultraviolet A and B, lightening hyperpigmentation, and improvement of a variety of inflammatory dermatoses. Because of the diverse biologic effects of this compound, topical vitamin C has become a useful part of the dermatologist’s armamentarium.

Dermatol Surg. 2005 Jul;31(7 Pt 2):814-7

Vitamin C in dermatology.

Vitamin C is a potent antioxidant drug that can be used topically in dermatology to treat and prevent changes associated with photoageing. It can also be used for the treatment of hyperpigmentation. Because it is unstable and difficult to deliver into the dermis in the optimum dosage, research is being directed to find stable compounds of Vitamin C and newer methods of delivery of Vitamin C into the dermis.

Indian Dermatol Online J . 2013 Apr;4(2):143-6.

Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin.

Ferulic acid is a potent ubiquitous plant antioxidant. Its incorporation into a topical solution of 15% l-ascorbic acid and 1% alpha-tocopherol improved chemical stability of the vitamins (C+E) and doubled photoprotection to solar-simulated irradiation of skin from 4-fold to approximately 8-fold as measured by both erythema and sunburn cell formation. Inhibition of apoptosis was associated with reduced induction of caspase-3 and caspase-7. This antioxidant formulation efficiently reduced thymine dimer formation. This combination of pure natural low molecular weight antioxidants provides meaningful synergistic protection against oxidative stress in skin and should be useful for protection against photoaging and skin cancer.

J Invest Dermatol. 2005 Oct;125(4):826-32

Sodium L-ascorbyl-2-phosphate 5% lotion for the treatment of acne vulgaris: a randomized, double-blind, controlled trial.

BACKGROUND: Antioxidants are becoming increasingly important in the treatment of skin disease. In addition to their known anti-inflammatory effects, antioxidants may act to prevent the oxidation of sebum which has been proposed to be comedogenic in acne patients. Sodium L-ascorbyl-2-phosphate (APS) is a stable vitamin C derivative and highly effective antioxidant that has demonstrated efficacy in acne in open label studies. OBJECTIVE: To evaluate the efficacy and safety of APS 5% lotion for the treatment of acne in a blinded controlled study. METHODS: A total of 50 subjects were randomized in a double-blind controlled trial to receive APS 5% lotion or vehicle for 12 weeks. Evaluation included an Investigator’s Global Assessment Score, a Subjects’ Global Assessment Score, lesion counts, cutaneous tolerability, and adverse events. RESULTS: APS 5% lotion demonstrated statistically significant improvement when compared to vehicle in all of the parameters measured. The adverse event frequency and cutaneous tolerability profile for APS 5% lotion were similar to vehicle. LIMITATIONS: Adjunctive topical or oral agents and their impact on acne were not studied in this trial. CONCLUSIONS: This study demonstrates that 5% sodium L-ascorbyl-2-phosphate is efficacious as monotherapy for the treatment of acne. APS 5% lotion offers a novel addition to our current acne armamentarium.

J Cosmet Dermatol. 2010 Mar;9(1):22-7

The prevalence of acne in adults 20 years and older.

BACKGROUND: Acne, one of the most common skin diseases, is often mistakenly thought to affect exclusively the teenaged group. However, a significant number of patients either continue to experience acne or develop new-onset acne after the teenaged years. OBJECTIVE: A survey was designed to assess the prevalence of acne in the teenaged years, and aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older. METHODS: Adults aged 20 years and older were asked to complete surveys distributed at various sites on our university campus and medical complex. RESULTS: Of 1013 participants aged 20 years and older, 73.3% (n = 744) reported ever having acne. After the teenaged years, women were more likely to report having acne than men, with the difference being statistically significant in all age groups. The prevalence of acne reported in women versus men was as follows: 20 to 29 years, 50.9% (n = 276) versus 42.5% (n = 201) (P = .0073); 30 to 39 years, 35.2% (n = 152) versus 20.1% (n = 73) (P < .0001); 40 to 49 years, 26.3% (n = 93) versus 12.0% (n = 36) (P < .0001); and 50 years and older, 15.3% (n = 41) versus 7.3% (n = 18) (P = .0046). LIMITATIONS: Our results are based on the participant’s own perception of the presence or absence of acne rather than a clinical evaluation. CONCLUSIONS: Acne continues to be a common skin problem past the teenaged years, with women being affected at higher rates than men in all age groups 20 years or older.

J Am Acad Dermatol. 2008 Jan;58(1):56-9

Ultrasound enhanced skin-lightening effect of vitamin C and niacinamide.

BACKGROUND/PURPOSE: Cutaneous hyperpigmentation occurs in multiple conditions. There is a strong need for the improvement of hyperpigmentation especially among Asian women. However, the effect of existing skin-lightening agents is not sufficient. One reason attributes to the limited capability of active agents to be delivered transepidermally. Ultrasound is one promising approach to enhance transepidermal transport. In this work, we investigate the effect of the use of high-frequency ultrasound together with coupling gel containing skin-lightening agents (ascorbyl glucoside and niacinamide) on facial hyperpigmentation in vivo in Japanese women. METHODS: The effect of ultrasound on the absorption of skin-lightening agents into the stratum corneum was evaluated in a tape-stripping method on human forearms in vivo. The skin efficacy was assessed in a facial clinical trial involving 60 subjects with hyperpigmentation in a paired design. Subjects were assigned to two groups, each group using two treatments (one on each facial cheek): (1) skin-lightening gel with ultrasound vs. no treatment or (2) skin-lightening gel with ultrasound vs. skin-lightening gel treatment. Changes in facial hyperpigmentation were objectively quantified by computer analysis and visual grading of high-resolution digital images of the face in addition to the subjective assessment via questionnaire. RESULTS: Ultrasound radiation enhanced the absorption of skin-lightening agents in the stratum corneum in a radiation-time-dependent manner. In the facial clinical trial, use of ultrasound radiation together with the skin-lightening gel significantly reduced facial hyperpigmented spots compared with both no treatment and skin-lightening gel alone after 4 weeks. CONCLUSIONS: The data suggest that use of high-frequency ultrasound radiation together with skin-lightening gel is effective to reduce hyperpigmentation via enhancing transepidermal transport of skin-lightening agents.

Skin Res Technol. 2006 May;12(2):105-13

Successful short-term and long-term treatment of melasma and postinflammatory hyperpigmentation using vitamin C with a full-face iontophoresis mask and a mandelic/ malic acid skin care regimen.

BACKGROUND: Treatment of melasma and postinflammatory hyperpigmentation is often challenging. No ideal short-term and long-term treatment is available. Vitamin C alone and in combination with iontophoresis has been studied and found to be useful; however, no long-term studies have been published. METHODS: In this study, 35 patients (34 female, 1 male) were treated with a novel full-face iontophoresis mask (FFIM) and a proprietary vitamin C (ascorbyl glucoside) preparation. Patients received one in-office treatment and 12 to 24 at-home treatments over 1 to 2 months in conjunction with a strict maintenance regimen consisting of a mandelic/malic acid skin care regimen, broad-spectrum ultraviolet A/ultraviolet B sunblock, a wide-brimmed hat, and sun-avoidance behavior. Follow-up after the initial in-office treatment ranged from 1 to 54 months (mean, 26 months). Four independent observers graded improvement of melasma and PIH using a 4-point scale. Before the study, high-performance liquid chromatography was used to verify iontophoretic penetration of vitamin C into the skin to a level of 0.2 cm in healthy volunteers (2 male, 2 female). RESULTS: A mean 73% improvement in abnormal pigmentation was observed at the end of FFIM/vitamin C treatment. Greater than 25% improvement was observed in 32 of 35 patients, and greater than 50% improvement in 22 of 35 patients. Melasma Area and Severity Index scores demonstrated substantial improvement from baseline for all patients, with a mean improvement of 15.7. CONCLUSIONS: Full-face iontophoresis of vitamin C appears to be an effective short-term treatment for melasma and postinflammatory hyperpigmentation. A protocol of strict sun avoidance in combination with a mandelic/malic acid skin care regimen appears to be useful in maintaining the improvement.

J Drugs Dermatol. 2013 Jan;12(1):45-50