SUMMARY
In the present double-blind investigation, the effects of a new formulation of natural cartilage polysaccharides on sun-damaged skin were studied in women aged 40-60 years. A group of 15 women were treated orally with 500 mg/day active substance (Vivida ) for 90 days and a second group of 15 women received 500 mg/day placebo for 90 days. Clinical examinations after 45 and 90 days' treatment showed significant improvements in skin condition in the actively treated group but not in the placebo group (P< 0.001). In the Vivida-treated patients, the epidermal thickness increased after 90 days from 0.11 mm to 0.29 mm, dermal thickness from 0.74 mm to 1.39 mm, skin elasticity index from 44% to 73% and the erythemal index decreased from 0.301 to 0.205. No changes were observed in the placebo group and no adverse effects were reported by either treatment group.

La présant étude, réalisée en double aveugle, a évalué chez des femmes âgées de 40 à 60 ans les effets d'une nouvelle combinaison de polysaccharides du cartilage sur la peau ayant subi des lésions dues au soleil. Un groupe de 15 femmes a été traité pendant 90 jours par 500 mg par jour per os de substance active (Vivida). Un second groupe de 15 femmes a recu 500 mg par jour de placebo pendant 90 jours. Les examens cliniques après 45 et 90 jours de traitement ont montré des améliorations significatives de l'état de la peau dans le groupe traité par le médicament actif, mais pas dans le groupe traité par placebo (P < 0.001). Chez les patients traités par Vivida, l'épaisseur de l'épidermie était passée de 0.11 mm à 0.29 mm après 90 jours, celle du derme de 0.74 mm à 1,39 mm; l'indice d'élasticité de la peau était passé de 44% à 73% et l'indice d'érythème s'était abaissé de 0.301 à 0.205. Aucun changement n'a été observé dans le groupe placebo, et aucun effet secondaire n'a été noté dans les deux groupes.

INTRODUCTION
Excessive exposure to sunlight results in premature ageing of the skin. To the clinician the signs of premature ageing represent actinically damaged skin or more accurately "photoageing". The clinical picture includes wrinkles, yellowing of the skin, laxity, mottling and a leathery dry appearance, with a variable assortment of premalignant and malignant neoplasms. The term "solar elastosis" is used to cover all these manifestations.

Both anatomically and histologically, photodamaged skin displays a wide spectrum of structural changes. A huge accumulation of tangled, thickened strikingly abnormal elastic fibres can be observed, and these changes are accompanied by an extensive loss of collagen and a large increase in ground substance glucosaminoglycans. At the endstage of actinic damage the dermal matrix becomes completely degenerated into an amorphous mass, with dissolution of the collagen and elastin network, resulting in laxity and loss of resilience. These changes are only noted in areas of skin exposed to the sun and not in areas of skin that have been protected.

In a study into the pathogenesis of elastosis, in which subjects in the age range 20-80 years were studied, the central finding was a perivenular infiltrate. This has been termed "heliodermatitis", signifying a lowgrade chronic inflammation that is generally invisible to the naked eye.

A previous study has shown that extracts from cartilage derived from marine fish had a strikingly good repairing effect on solar elastosis in females aged 40-60 years. In the present study, a new formulation containing purified natural polysaccharides from cartilage of marine fish (Vivida) was compared with placebo in a double-blind clinical trial in patients, aged 40-60 years, with moderate to severe solar elastosis.

PATIENTS
All 30 women enrolled in the study had exposed themselves to excessive sunlight in Scandinavia and/or the Mediterranean countries, or to solarium irradiation for 20 years, or more; all patients had skin type II or III and were in the age range 40-60 years (Table 1). The patients were all in good health and had given oral informed consent before they were enrolled in the trial.

TREATMENT At baseline, the study population of 30 women was randomly allocated to one of two treatment regimens: 15 subjects received 500 mg/day natural polysaccharides (Vivida) taken orally for 90 days; and the remaining 15 received 500 mg/day placebo tablets for 90 days (Table 1). Placebo and active treatment tablets appeared identical, and drugs were supplied to the patients in identical packages with instructions.

CLINICAL ASSESSMENTS
At baseline and after 45 and 90 days, all patients were examined clinically and asked about their subjective impression of the treatment. The following clinical measures were graded by the investigator on a three-point scale (0, absent; 1, moderate; 2, severe): thinning of the skin; laxity; wrinkles; mottles; dryness of skin; brittless of hair; and brittleness of nails. In addition, the thickness of the epidermis and dermis was measured 2 cm laterally from the left eye using Dermascan C equipment (Cortex Ltd, Denmark) and the elasticity index was determined for skin on the left cheek using Dermaflex equipment (Cortex Ltd, Denmark). An erythemal index of left-cheek skin was measured using an erythemal index meter (Diastron Ltd, UK). Each parameter was measured five times at each visit and the mean value was calculated for each patient.

STATISTICAL ANALYSIS
The Student's t-test and the Sign test were used for statistical analysis.

Table 1
Characteristics of patients with moderate to severe solar elastosis participating in the study of Vivida or placebo.

Treatment group
Parameter	Vivida	Placebo
No. of patients	15	15
Mean age (years)	47	49
Mean duration of skin damage (years)	10	11
Skin type
I	0	0
II	8	5
III	7	10

Table 2
Number of women with moderate to severe solar elastosis exhibiting signs of photodamage to facial skin before and after oral treatment with 500 mg/day Vivida (n = 15) or placebo for 90 days (n = 15)

	Vivida			Placebo
Symptom	Baseline	45 days	90 days	Baseline	45 days	90 days
Thinning
Severe	13	0	0	13	13	13
Moderate	2	15	1	2	2	2
Absent	0	0	14	0	0	0
Laxity
Severe	6	0	0	6	6	6
Moderate	9	13	1	9	9	9
Absent	0	2	14	0	0	0
Wrinkles
Severe	5	0	0	5	5	5
Moderate	10	15	5	10	10	10
Absent	0	0	10	0	0	0
Mottles
Severe	1	1	0	2	2	2
Moderate	11	11	9	9	9	9
Absent	3	3	6	4	4	4
Dryness
Severe	10	0	0	11	11	11
Moderate	5	6	0	4	4	4
Absent	0	9	15	0	0	0
Brittle hair
Severe	0	0	0	1	1	1
Moderate	12	12	0	7	7	7
Absent	3	3	15	7	7	7
Brittle nails
Severe	1	0	0	1	1	1
Moderate	8	9	0	9	9	9
Absent	6	6	15	5	5	5

Table 3
Mean (SD) epidermal and dermal thickness, skin elasticity and erythemal index in women with moderate to severe elastosis treated orally with 500 mg/day Vivida (n = 15) or placebo (n = 15) for 90 days in a double-blind study

Parameter	VIVIDA			PLACEBO
	Baseline	45 days	90 days	Baseline	45 days	90 days
Epidermal thickness (mm)	0.11±0.01	0.21±0.02	0.29±0.02	0.12±0.02	0.12±0.04	0.11±0.01
Dermal thickness (mm)	0.74±0.06	1.02±0.04	1.39±0.05	0.77±0.05	0.76±0.04	0.75±0.06
Skin elasticity (%)	44±0.02	62±0.03	73±0.03	42±0.03	41±0.03	42±0.03
Erythermal index	0.301±0.0581	0.238±0.038	0.205±0.029	0.325±0.041	0.328±0037	0.334±0.0072

RESULTS
At baseline, the signs of photodamage were similarly distributed in the two treatment groups (Table 2). After 45 days of treatment there was a definite improvement in most signs of skin damage in the Vivida - treated patients, whereas no changes compared with baseline could be observed in the placebo treatment group. The difference between the results in the two treatment groups was statistically significant (P < 0.01) with the exception of mottles. After 90 days of treatment, the difference between the two groups had increased and the numbers of mottles observed in the actively treated group had decreased, a change not seen after 45 days. After this period of treatment, skin dryness and brittle hair or nails had been completely cured in the actively treated group (Table 2), and the difference between the results on all signs of damage in the two groups had reached even greater statistical significance (P < 0.001).

At baseline, mean epidermal and dermal thicknesses, elasticities and erythemal indices were similar in the two treatment groups (Table 3). After 45 and 90 days of active treatment, epidermal and dermal thickness as well as the elasticity index had increased significantly and the erythemal index had decreased (Table 3). Compared with the corresponding baseline values and the values in the placebo treatment group, there was an already statistically significant difference after 45 days of treatment (P < 0.01) and the difference had increased after 90 days of treatment ( P < 0.001).

Some of the actively treated patients experienced mild pimples during the first 3 - 4 weeks of treatment; however, no other adverse effects were reported by the Vivida - or placebo-treated patients or observed by the investigators.

The mode of action of natural polysaccharides has yet to be clarified. Preliminary findings of a study in progress have indicated an increase in pro-collagen and collagen III, and a re-establishment of the histological pattern in patients treated with Vivida. During the treatment period, the perivenular infiltrate decreased and was sometimes completely absent after treatment. With people living increasingly longer, there will inevitably be an increase in the number of individuals with degenerated skin. In the future, therefore, there will be a growing need to develop new products for the prevention and repair of both biological and sun-induced skin damage. Further research and development work will be essential to develop effective and satisfactory treatment.

REFERENCES

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2. Schwartz W: Morphology and differentiation of connective tissue fibers. In: Connective Tissue (Turnbridge RE, ed). Springfield: Charles C Thomas, 1957; pp 144 - 156.
3. Gross J, Schmitt FO: The structure of human skin collagen as studied with the electron microscope. Exp Med 1948; 88:555 - 567.
4. Parry DAD, Barnes GRS, Craig AS: A comparison of the size distribution of collagen fibrils in connective tissue as a function of age and possible relation between fibril size distribution and mechanical properties: Proc R Soc Lond (Biol) 1978; 203: 305 - 321.
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Eskelinen and J Santalahti
Special Natural Cartilage Polysaccharides for the Treatment of Sun-damaged Skin in Females.
The Journal of International Medical Research 1992; 20:99 - 105
Received for publication 23 January 1992
Accepted 25 January 1992.