Association Between Licensure Examination Scoresand Practice in Primary Care Robyn Tamblyn; Michal Abrahamowicz; W. Dale Dauphinee; et al. Online article and related content current as of May 28, 2010. JAMA. 2002;288(23):3019-3026 (doi:10.1001/jama.288.23.3019) Topic collections Primary Care/ Family Medicine; Quality of Care; Quality of Care, Other
Skin Pharmacol Physiol 2014;27:113–119 Received: June 24, 2013 Accepted after revision: September 9, 2013 Published online: December 24, 2013 Oral Intake of Specific Bioactive Collagen
Peptides Reduces Skin Wrinkles and
Increases Dermal Matrix Synthesis
E. Proksch a M. Schunck b V. Zague d D. Segger c J. Degwert c S. Oesser b a Department of Dermatology, University of Kiel, and b Collagen Research Institute, Kiel , and c Skin Investigation and Technology, Hamburg , Germany; d Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo , Brazil Key Words
parison to the placebo group after 4 and 8 weeks (20%) of Bioactive collagen peptide · Collagen peptides · Skin · intake. Moreover a positive long-lasting effect was observed Wrinkles · Type I collagen · Elastin · Fibrillin 4 weeks after the last BCP administration (p < 0.05). Addition-ally, after 8 weeks of intake a statistically significantly higher content of procollagen type I (65%) and elastin (18%) in the Abstract
BCP-treated volunteers compared to the placebo-treated Dietary consumption of food supplements has been found patients was detected. For fibrillin, a 6% increase could be to modulate skin functions and can therefore be useful in the determined after BCP treatment compared to the placebo, treatment of skin aging. However, there is only a limited but this effect failed to reach the level of statistical signifi- number of clinical studies supporting these claims. In this cance. In conclusion, our findings demonstrate that the oral double-blind, placebo-controlled study, the effectiveness of intake of specific bioactive collagen peptides (Verisol®) re- the specific bioactive collagen peptide (BCP) VERISOL® on duced skin wrinkles and had positive effects on dermal ma- eye wrinkle formation and stimulation of procollagen I, elas- 2013 S. Karger AG, Basel tin and fibrillin biosynthesis in the skin was assessed. A hun-dred and fourteen women aged 45–65 years were random-ized to receive 2.5 g of BCP or placebo, once daily for 8 weeks, Introduction
with 57 subjects being allocated to each treatment group. Skin wrinkles were objectively measured in all subjects, be- Skin appearance and integrity get worse with age due fore starting the treatment, after 4 and 8 weeks as well as to the synergistic effects of chronological and photoaging, 4 weeks after the last intake (4-week regression phase). A hormonal deficiency and influences of environmental subgroup was established for suction blister biopsies analyz- factors  . As a consequence of a decline in several meta- ing procollagen I, elastin and fibrillin at the beginning of the bolic activities, like quantitative and qualitative changes treatment and after 8 weeks of intake. The ingestion of the in dermal collagen and elastin, the skin constitution specific BCP used in this study promoted a statistically sig- changes and typical symptoms of aging are visible. The nificant reduction of eye wrinkle volume (p < 0.05) in com- loss of connective tissue in cutaneous aging results in de- 2013 S. Karger AG, Basel Professor E. Proksch Christian Albrecht University of Kiel, Department of Dermatology Schittenhelmstrasse 7 E-Mail email@example.com DE–24105 Kiel (Germany) www.karger.com/spp E-Mail EProksch @ dermatology.uni-kiel.de 220.127.116.11 - 2/23/2016 4:18:55 PM creased elasticity, loss of skin tone and a progressive deep- come) and content of type I procollagen, elastin and fibrillin in ening of facial creases and wrinkling  .
skin fluid (secondary outcomes) after 8 weeks of daily intake.
The study was approved by the Freiburger Ethik-Kommis- Wrinkles on the face are the most prominent recog- sion International, Freiburg, Germany, and adhered to current nized signs of skin aging. Takema et al. [3, 4] reported an good clinical practice regulations. All test subjects received de-age-related decrease in skin elasticity and a coriaceous ap- tailed information listing every single parameter relevant to the pearance of affected skin areas. Especially facial skin sites study. All subjects gave signed, informed consent after receipt of like the corners of the eyes are mostly susceptible to wrin- the written information and having had a possibility for further questioning.
kle formation, also popularly known as crow's feet.
Skin functions and healthy appearance depend on a Subjects sufficient supply of essential nutrients. The relationship A total of 114 healthy female subjects, 57 subjects allocated to between nutrition and skin has become a hot topic all each treatment group, were enrolled in the study and randomized over the world. Intervention studies indicate that it is pos- to treatment with a daily dose of 2.5 g of BCP or placebo (malto-dextrin). Forty-eight of these (24 per treatment group) were in- sible to modulate or delay skin aging and to improve skin cluded in the suction blister biopsies for the subsequent analysis of integrity by dietary ingredient supplementation  .
different skin aging-related biomarkers.
In preclinical studies it was shown that collagen pep- The products were taken orally by the subjects at home accord- tides had stimulatory effects on type I collagen and other ing to the instructions given by the investigator. The powder was extracellular matrix molecules in human fibroblasts [6, to be dissolved in water or any other liquid.
Prior to the beginning of oral treatment and data acquisition 7] . Moreover, in animal studies it was demonstrated that there was a preconditioning period of at least 7 days. Within the density and diameter of fibroblasts as well as of col- this period and throughout the entire period of the study, the lagen fibrils increased by collagen peptide administration subjects had to refrain from using any leave-on products and whereas a UVB-induced reduction of type I collagen was oily or moisturizing skin-cleansing products on the arms and diminished after bioactive collagen peptide (BCP) treat- the area around the eyes. Moreover, use of make-up, skin-cleansing tissues, wipes for make-up removal and cleansing lo- ment [8, 9] .
tion on the test sites was prohibited. It was also prohibited to However, there is no clinical evidence that BCP sup- intensively expose the test sites to UV light (sun or solarium). plementation may reduce wrinkle formation and benefit The subjects were not allowed to visit saunas or swimming skin metabolism after oral intake in humans. In this study, pools, and to do intensive sport during the day prior to the study we objectively evaluated the efficacy of a specific BCP visits. Moreover, they were prohibited from changing their living or dietary habits, and from consuming any additional nu- with regard to the volume of eye wrinkles after 8 weeks of tritional supplement or vitamin preparations 4 weeks prior to daily intake. Moreover, the influence of the BCP treat- the start of the study and during the study. The treatment of the ment on the content of procollagen type I, elastin and fi- test areas with the following medication was not allowed prior brillin in blister suctions was assessed. To the best of our to the start and during the study: dermatological therapeutics knowledge, this is the first double-blind, placebo-con- (6 weeks previously), corticosteroids and antihistamines (4 weeks previously), anti-inflammatory drugs and antibiotics (2 weeks trolled study showing that a dietary supplement com- posed of a specific collagen peptide is effective in reducing wrinkles and aging-related skin biomarkers.
Inclusion Criteria The inclusion criteria were as follows: healthy females ranging in age from 45 to 65 years (homogeneous distribution between Material and Methods
treatment groups), phototypes I–III (Fitzpatrick scale), in general good health and mental condition, personal informed consents to Test Product participate in the study, personal presence on the predefined days The test product used in this study was a BCP composed of dif- at the institute, willing and able to follow the study rules and a fixed ferent specific collagen peptides with a high safety profile derived from a complex multistep procedure by degradation of porcine type I collagen. The product was provided by Gelita AG (Eberbach, Exclusion Criteria Germany), commercially available as Verisol . The product is clear- The exclusion criteria were as follows: any deviation from ly defined by a matrix-assisted laser desorption ionization mass the above-mentioned inclusion criteria, acute skin diseases (e.g. spectrometry mass peaks fingerprint with specific collagen pep- atopic eczema, atopic dermatitis, psoriasis) on the test sites, or tides of an average molecular weight of 2.0 kD.
other dermatological disorders (scars, sunburn, moles), food al-lergies against ingredients of the test products, gastrointestinal Study Design diseases or indigestion, tattoos on the test sites, topical medica- The study was carried out as a monocentric, double-blind, tion used in the test area within 6 weeks prior to the start of the randomized, placebo-controlled supplementation study on the study, systemic medication with anti-inflammatory agents or effects of a specific BCP on eye wrinkle volume (primary out- antibiotics within 2 weeks prior to the start, systemic medica- Skin Pharmacol Physiol 2014;27:113–119 18.104.22.168 - 2/23/2016 4:18:55 PM tion with corticoids and/or antihistamines within 4 weeks prior were taken per test site and measurement point in time. Then, the to the start, medication with an anticoagulant, proneness to hy- mean of the 3 single measurements was calculated for each test site perpigmentation or hypertrophic scar formation, other system- and point in time.
ic medication within 4 weeks prior to the start, systemic illness of the subject at the beginning of the study, pregnancy or a pe- Suction Blister Biopsies riod of breast feeding, immunological disorders, severe disor- To quantify the amount of procollagen I, elastin and fibrillin in ders within 6 months prior to the start, e.g. cancer, acute car- the skin of the volunteers before and after treatment with BCP, the diac and circulatory disorders, severe diabetes, alcohol and drug so-called suction blister model was applied, according to Kiistala abuse, participation in other studies with cosmetic products in  . Per point in time, 2 suction blisters of 7 mm in diameter were the test areas within 2 weeks prior to the start or during the generated in the test area. To induce the blisters, Plexiglas suction study, participation in a study with a pharmaceutical prepara- chambers with 2 circular openings each with a diameter of 7 mm tion within 4 weeks prior to the start, intake of nutritional sup- were placed on the test site. A vacuum pressure of about 450–850 plements within 4 weeks prior to the start and, except for the mbar was applied. The blisters were induced within 1.5–2.5 h. The test products administered during the study, change in lifestyle liquids of all suction blisters were collected using sterile hypoder- or eating habits during the study, treatment with leave-on prod- mic syringes. The liquids were pooled, collected in cryovials at ucts, oily or moisturizing skin-cleansing products on the arms, –20 ° C and stored frozen at –80 ° C immediately after preparation. or a change in the usual skin care routine, exposure to intensive The small wounds were covered with a wound occlusive and sunlight or artificial UV (solarium) light on the test sites within healed completely and scar free within 6–10 days. On completion 1 week prior to the start or during the study, swimming, sauna of the study, the blister fluids were used for the quantitative analy- or intensive sport within 1 day prior to measurements, lack of sis of procollagen type I, elastin and fibrillin.
compliance, intellectual or mental inability to follow study in-structions.
Enzyme-Linked Immunosorbent Assays for the Analysis of Procollagen Type I, Elastin and Fibrillin Assessments In vitro enzyme immunoassay kits were used for the quantita- tive analysis of human procollagen type I (Takara Bio Inc., Japan), The test sites were the wrinkle area around the left eye (lateral human elastin (Cusabio Biotech, China) and human fibrillin-1 canthus) for eye wrinkle measurements and the inner aspect of the (Cusabio Biotech) in the suction blister fluids.
right forearm for the suction blister biopsies used for the subse- The tests were performed according to the respective instruc- quent analysis of procollagen type I, elastin and fibrillin.
tion manual. Briefly, samples were diluted 1: 25 vol/vol with kit On every measurement day, the subjects had to expose their sample buffers to reach concentrations within the range of the uncovered test sites to the indoor climatic conditions (21.5 ° C; 50% standards. Every suction blister sample was measured in duplicate. relative humidity) for at least 30 min.
Moreover, the recovery of the enzyme immunoassay kits was ana-lyzed, revealing recovery rates of more than 80% on average.
Measurement Times There were 4 measurement times for eye wrinkle assessments: Statistical Analysis immediately before starting the product treatment (t 0 ), after 4 (t 1 ) All data were tested for normal distribution by the 1-sample and 8 weeks (t 2 ) of daily product intake, and 4 weeks after the last Kolmogorov-Smirnov test. Statistically significant differences be- intake (t 3 , 4-week regression phase).
tween both treatment groups were analyzed by the 2-sided inde- Suction blisters were generated before starting the treatment pendent samples t test. The hypothesis of a normal distribution (t 0 ) and after 8 weeks (t 2 ) of intake.
was accepted when there was a p value >0.05. As for the differ- In each case the subject's compliance (dosage and way of in- ences between the treatment situations, for a p value <0.05 the dif- take) and tolerance towards the products were checked after 1, 4 ference was accepted as statistically significant.
and again after 6 weeks of intake.
The following treatment situations for wrinkle volume changes were compared: treatment situations at points in time t 0 (baseline In vivo Measurement of the Eye Wrinkle Volume situation), t 1 and t 2 (after 4 weeks and 8 weeks of treatment) and t 3 The influence of BCP on the eye wrinkle volume was measured (4-week washout phase).
at the outer corner of the eye (lateral canthus) using the optical The results obtained from the blister suction fluids were ex- 3-dimensional in vivo measuring instrument Primos ® Compact pressed in relation to the initial situation and pairwise differences (GF-Messtechnik GmbH). Three measurements were conducted were tested for statistical significance between both treatments.
per test site. The size of the measurement area was 30 × 40 mm 2 . The postbaseline measurements were performed using the overlay function. For each subject, the original pictures of the reference files at the baseline and the corresponding measurement files of the postbaseline measurements were brought into congruence using the 3-dimensional matching function. Height images were com- Subjects and Dropouts puted according to the standard procedure using mathematical The results of 114 subjects were involved in data anal- filters. These height images were used to calculate the eye wrinkle ysis. The subjects were between 45.0 and 65.4 years old volumes (in cubic millimeters of one selected wrinkle). After man-ual marking of the selected eye wrinkles, the volume was comput- (55.6 ± 6.0), without statistically significant differences ed by the Primos software. This was performed for all 3 images that between the treatment group and the placebo group Bioactive Collagen Peptides, Skin Skin Pharmacol Physiol 2014;27:113–119 Wrinkles and Dermal Matrix Synthesis 22.214.171.124 - 2/23/2016 4:18:55 PM
( table 1 ; p = 0.998). A hundred and eight of the 114 sub- jects finished the study correctly and completely for the eye wrinkle measurements. There were 6 dropouts, none related to the product intake or the study procedure in As for analysis of the suction blister fluids, 40 of the Ey original data (mm Color version available online 48 subjects (20 per group) finished the study correctly and completely. The 40 subjects were between 45.8 and 65.0 years of age (55.9 ± 6). There were 8 dropouts, none related to the product intake or the study procedure in general.
No treatment side effects were observed in any of the Eye Wrinkle Volume At the beginning of the study the volume of eye wrin- kles between both treatment groups were not statistically significantly different (0.381 ± 0.36 vs. 0.375 ± 0.26 mm 3 , p = 0.93).
Fig. 1. a Orally administered BCP led to a statistically significant
After 4 weeks of treatment the BCP group showed a reduction of eye wrinkle volume after 4 and 8 weeks of treatment. statistically significantly reduced eye wrinkle volume of Over the same period of time, eye wrinkle volume in the placebo-more than 7.2% in comparison to the placebo group (p < treated group increased continuously (mean ± SEM; n = 57; * p < 0.05, * * p < 0.01). b Visible reduction of eye wrinkle volume after
0.05). This positive effect was more pronounced after 8 weeks of BCP intake. Exemplary pictures of 2 participants of the 8 weeks of intake. At this point in time wrinkle volume in active agent group before (left) and after (right) treatment. the BCP group was significantly (p < 0.01) reduced by 20.1% on average (0.326 ± 0.38 vs. 0.408 ± 0.25 mm 3 ) compared to the placebo group ( fig. 1 a, b). In particular a maximum reduction in eye wrinkle volume of 49.9% was achieved.
Four weeks after the last product intake (4-week re- gression phase), the BCP treatment group still showed a statistically significant decrease in eye wrinkle volume of 11.5% (p < 0.01), as shown in figure 2 . It is notable that in Ey original data (mm the active agent group at the end of the regression phase 4 weeks regression the same decreased mean eye wrinkle volume (0.326 mm 3 ) was determined as at the end of the treatment pe-riod after 8 weeks.
Fig. 2. Reduction of eye wrinkle volume persisted in BCP-treated
volunteers 4 weeks after last intake (mean ± SEM; n = 57; * * p <
Blister Suction Fluids Due to inhomogeneous data at the beginning of the investigation (prior to treatment) between the drug and Table 1. Demographic data on the study subjects
the placebo groups the results of procollagen, elastin and fibrillin measurements were expressed in relation to base- Group Baseline (t0) 4 weeks (t1) 8 weeks (t2) 4-week regression (t3) line data (t 0 ).
Procollagen Content Procollagen type I content was increased by 65% after 8 weeks of BCP treatment compared to the placebo group. Mean age ± SD, yearsA This pronounced impact on collagen synthesis was statis- tically significant (p < 0.01; fig. 3 ).
Skin Pharmacol Physiol 2014;27:113–119 126.96.36.199 - 2/23/2016 4:18:55 PM administered collagen peptides on skin health has been demonstrated in several investigations [14–17] .
The current study is the first investigating the efficacy of a specific, orally administered BCP (Verisol®) on eye wrinkles, demonstrating a statistically significant reduc- tion of eye wrinkle deepness (crow's feet) in comparison to a placebo treatment. At the end of the treatment after 8 weeks the eye wrinkle volume in the verum group had decreased by 17.7% compared to the baseline, whereas in the placebo group in the same time period the wrinkle Fig. 3. The amount of procollagen type I and elastin was statisti-
volume had increased by 14.5% (Δ 32.2%).
cally significantly increased 8 weeks after BCP administration, in The observed changes in the placebo group might have contrast to placebo treatment. The content of fibrillin in suction been caused by altered weather and climatic conditions blister fluid was increased after 8 weeks of BCP ingestion by trend during the study period. It is most unlikely that the deter- (mean ± SEM; n = 20; * p < 0.05). mined effect is caused by diet-related alterations, as the subjects were instructed not to modify their lifestyle dur- Elastin Content ing the study period. In addition, a direct impact of the In addition to procollagen, BCP intake also promoted placebo can be excluded as no influence of maltodextrin a statistically significant (p < 0.01) increase in elastin con- on skin physiology has been described in the literature. tent of 18% in comparison to the placebo treatment after Therefore it can be assumed that the variations in the pla-8 weeks ( fig. 3 ).
cebo group do not refer to systematic effects.
Apart from the observed efficacy of an oral Verisol® Fibrillin Content treatment, it is striking that the positive effect on skin Ingestion of BCP led to a clear increase in fibrillin con- health was persistent for at least 4 weeks after having tent of 6% in comparison to placebo after 8 weeks of treat- stopped the BCP intake. A possible explanation for this ment but this result failed to reach the level of statistical long-lasting improvement might be the pronounced in-significance ( fig. 3 ).
crease in the biosynthesis of essential dermal macromol-ecules such as collagen, elastin and fibrillin. It is known that collagen and elastin are the major components in the Discussion
dermis supporting preservation of skin structure, skin firmness and elasticity, and that they directly affect wrin- Throughout our life skin integrity changes and shows kle formation. In contrast to the healthy skin situation, an a decrease in elasticity and moisture, as well as a notice- alteration of elastic fibers and degradation of collagen able increase in wrinkles. Skin wrinkle formation is the bundles does occur in the dermis of wrinkled skin. It is most prominent sign of growing old [1, 2] and seems to known that collagen fiber deficiencies in aged and photo-be more common in the skin of Caucasian people  . In aged human skin are a major cause of skin wrinkling.
a prospective study it was found that wrinkle onset was Apart from the visible changes in skin wrinkles, in the delayed by about 10 years in Chinese women compared current study the synthesis of these dermal extracellular with French women  .
matrix proteins which are crucial for skin health and well- Independently of wrinkle incidence and skin ethnic being was investigated in suction blister fluids. It was aspects, concerns about changes in physical appearance demonstrated that at the end of the treatment period the brought on by aging are very common. As the demand for collagen content was increased 1.65-fold and that the interventions to ameliorate visible signs of aging is con- amount of elastin was increased 1.2-fold after Verisol tinuously growing  , interest in the development of treatment, compared to the placebo group.
dietary supplements and functional food products for In addition to these positive impacts the ingestion of skin health has increased as well.
BCPs led to an increase of 6% in the content of fibrillin in In preclinical and clinical studies food supplements comparison to placebo, by the end of the study period. have been considered as effective cosmeceutical sub- Fibrillins are the most important components of micro- stances with a potential for reducing wrinkles and im- fibrils and are necessary for the integrity of elastic fiber proving skin appearance. Especially the efficacy of orally bundles described by Lee et al.  , who observed a re- Bioactive Collagen Peptides, Skin Skin Pharmacol Physiol 2014;27:113–119 Wrinkles and Dermal Matrix Synthesis 188.8.131.52 - 2/23/2016 4:18:55 PM duced fibrillin-1 expression in wrinkled skin, which dem- Another factor that promotes wrinkle formation is de- onstrated the important role of fibrillin for skin function- creased skin elasticity, as shown by Fujimura et al.  . ality. Fibrillin connects elastic fibers with small leucine- Skin elasticity is influenced by several parameters, like rich proteoglycans (like decorin and biglycan) which are elastic fiber formation and skin moisture. In a previous essential for the water-binding capacity in connective tis- study we investigated the effects of daily Verisol® inges- tion in 35- to 55-year-old female volunteers on skin elas- Overall, BCP treatment seems to have a positive im- ticity and other skin wrinkle-related parameters. In a pact on important dermal macromolecules  which double-blind, randomized, placebo-controlled clinical have a direct influence on skin wrinkle formation. Our study, skin elasticity was significantly improved in wom-current findings confirm previous reports from experi- en who received 2.5 g/day of a specific BCP for 8 weeks. mental and animal trials demonstrating the stimulatory In addition, the results revealed that the observed positive effects of collagen peptides on anabolic processes sup- effects of BCP administration were more pronounced in porting the maintenance of the dermis extracellular ma- women who were over 50 years old, as indicated by in- trix [6–9, 20] . Our in vitro studies on primary human creased skin hydration and improved skin elasticity  .
dermal fibroblasts demonstrated a stimulatory effect of Verisol® on the expression of skin extracellular matrix macromolecules. After supplementation of the specific Conclusions
collagen peptides we were able to demonstrate a pro-nounced, statistically significant increase in type I colla- Based on the results of the study, it can be concluded gen expression as well as proteoglycan expression, such that the oral ingestion of specific collagen peptides led to as biglycan, decorin and versican (data not published).
a pronounced, statistically significant reduction of eye Apart from these positive influences of Verisol® for wrinkle volume. In contrast to most topically applied sub- dermal matrix synthesis it has been described that the dai- stances this positive effect on the skin seems to be caused ly intake of collagen peptides decreases expression levels by a direct impact on dermal extracellular matrix turn-of matrix metalloproteinase-2, a catabolic enzyme which over, as demonstrated by a significant increase in collagen is, for instance, responsible for collagen type IV break- and elastin synthesis. The direct effect on the dermal ma- trix might explain the long-lasting improvement of skin Type IV collagen forms a highly cross-linked network wrinkles for at least 4 weeks after the end of the supple- essential for mechanical stability of the basement mem- mentation of the collagen peptides. It has to be pointed brane and is therefore an important factor for skin wrin- out that the results presented are only valid for the spe- kles and furrow formation  . The observed stimula- cific collagen peptide composition (Verisol®) used in this tory impact on the dermal matrix of specific BCPs, as well study. Other collagen hydrolysates or collagen peptides as the reported anticatabolic effect, suggest a possible might exhibit dissenting effects. Here further research es-mechanism for explaining the significant wrinkle reduc- pecially into the mode of action of BCPs on dermal struc- tion demonstrated by the Verisol® treatment.
tures would be desirable. References
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KEEP OUT OF REACH OF CHILDREN READ SAFETY DIRECTIONS BEFORE OPENING OR USING TMENT ONLY TOR™ ACTIVE CONSTITUENT: 36.0 g/L ALBENDAZOLE OXIDE (equivalent to 34.0 g/L ALBENDAZOLE) 82.5 g/L LEVAMISOLE HYDROCHLORIDE (equivalent to 70.0 g/L LEVAMISOLE) 1 g/L SELENIUM as SODIUM SELENATE For the control of gastrointestinal roundworms, sensitive to benzimidazoles and levamisole including those resistant