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Age-dependence of mechanical parameters was studied in vitro in human skin obtained at autopsy and in rat skin. Parameters indicating strength, e.g. ultimate load, tensile strength, modulus of elasticity, and ultimate extension, showed a steep increase during maturation, a maximum at adulthood and a slight but significant decrease during senescence. Parameters indicating viscosity or plasticity studied in hysteresis-, relaxation-, and creep-experiments showed a decrease during the whole life span. Simultaneous studies of biochemical parameters indicated a parallel behavior of strength with the content of insoluble cross-linked collagen and of plasticity with the content of glycosaminoglycans. The in vitro experiments in rats could be confirmed by in vivo studies. Further studies in rats indicated an excellent ability of skin in old rats for complete restoration (restitutio ad integrum) after repeated loading.

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The mechanical behavior of rat skin during repeated strain in vivo and the restoration process thereafter were studied following 10 days' treatment with desmotropic drugs (300 mg/kg p.o. D-penicillamine or 10 mg/kg s.c. prednisolone acetate). Repeated (30 times) elongations of up to 40% were performed under anesthesia both longitudinally and perpendicularly to the body axis. Evaluation of this first run of 30 cycles showed stress values as well as the moduli of elasticity to be decreased after D-penicillamine, whereas they were greatly increased after prednisolone acetate treatment. The decay of stress values during repeated strain revealed similar effects of treatment. In the second part of the experiment, the restoration process was evaluated by a second run of 30 cycles after 1, 6 and 16 h. In the late phases of recovery, an even better restitution ad integrum was found in treated animals. Overall, in contrast to other biomechanical parameters, the restoration process is barely influenced by treatment with desmotropic compounds.

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Male Sprague-Dawley rats were treated 10 times either with 2 or 10 mg/kg s.c. prednisolone acetate or with 300 or 1,000 mg/kg p.o. D-penicillamine or with 100 or 300 mg/kg p.o. aminoacetonitrile bisulfate. Samples of dorsal skin were tested either longitudinally or perpendicularly to the body axis. Relaxation and hysteresis experiments were performed at different degrees of elongation. Finally, ultimate values were measured. In all groups, ultimate strain was much higher perpendicularly than longitudinally to the body axis. A dose-dependent increase of all parameters indicating strength or elasticity was found after prednisolone acetate treatment, whereas the indicators of viscosity showed a decrease. D-Penicillamine treatment decreased all parameters of strength and elasticity and increased viscosity and plasticity. Aminoacetonitrile bisulfate induced biphasic changes: after high-dose treatments strength and elasticity were increased and viscosity decreased. The results are discussed in view of changes of biochemical composition and cross-linking of collagen.

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Traditional medicine using herbal drugs exists in every part of the world. The major areas are Chinese, Indian and European traditions. The philosophies of these traditional medicines have some resemblance to each other but differ widely from modern Western medicine. In view of the progress of Western medicine not only new synthetic drugs but also herbal drugs have to fulfill the international requirements on quality, safety and efficacy. Herbal drugs have the advantage of being available for patients in the geographical area of the special traditional medicine. The development procedure of herbal drugs for world-wide use has to be different from that of synthetic drugs.

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Age-dependence of mechanical and biochemical parameters has been studied in pigeons between 1 and 80 months and in rats between 1 and 30 months. In pigeons, body weight, bone weight and breaking strength of femur and tibia are only slightly increased during this time indicating that in this species maturation takes place as early as during the first 4 weeks after hatching. In contrast, in rats a sharp increase of these parameters during maturation and a significant decrease during senescence was observed. Similarly, ultimate load of aorta rings was only sightly influenced by aging in pigeons, but showed in rats a biphasic pattern due to maturation and aging. The prepatagial tendon in pigeons gives the unique opportunity to study an organ consisting mostly of elastic fibres. Only a slightly increase of strength during the whole life-span, but no decrease during senescence was found. Tail tendons in rats consisting almost entirely of collagen fibres show a pronounced increase during maturation and a decrease during aging. The mechanical values were followed closely by the collagen content, but not at all by the elastin content.

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The influence of maturation and aging on mechanical parameters was studied in rat skin by in vitro and in vivo methods. Parameters indicating strength increased during maturation to a high degree and decreased to a lower degree during aging. Parameters indicating viscosity decreased during the maturation and aging period. Complete restitution after repeated extension was even better in old animals than in young animals.

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Prednisolone-17-ethyl carbonate-21-propionate (PrEP, Hoe 777) was tested for antiinflammatory activity in various animal models by topical and systemic administration. In those models being indicative of topical efficacy, the potency of PrEP was the same as that of desoximetasone. However, systemic effects after topical administration of PrEP in shaved skin of the dorsum of rats were relatively weak compared with the reference compound. Moreover, there were less systemic corticoid effects after s.c. administration of PrEP than after desoximetasone. Thus, PrEP is obviously a compound with a considerable split of topical and systemic activity, suggesting its testing in man for systemic effects after topical administration.

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The following pharmaceutical preparations of prednicarbate (Hoe 777) were tested: fatty ointment 0.1% and 0.25%, ointment 0.1% and 0.25%, cream 0.1% and 0.25%, solution 0.25%. These pharmaceutical preparations were applied 10 times to the shorn back of male Sprague-Dawley rats. After sacrifice the following parameters were recorded: body weight, skin thickness as well as ultimate load, ultimate strain, tensile strength and modulus of elasticity of excised skin strips. Soluble fractions of collagen (soluble in 0.15 and 0.5 molar NaCl solution and in citrate buffer) and insoluble collagen as well as total collagen/g fresh weight were determined. The values of the treated animals were compared with the values of untreated animals and animals treated with the individual base only. As found in earlier studies prednicarbate induced a slight decrease of body weight and skin thickness. Ultimate extension and ultimate load were only barely changed. There was, however, a dose-dependent increase of modulus of elasticity and tensile strength, due to treatment with prednicarbate. Simultaneously, an increase on insoluble collagen and of total collagen per g fresh weight was noted. These results confirm previous findings, indicating a positive correlation between tensile strength and modulus of elasticity of connective tissue with the content of insoluble collagen. The effects of ointment, fatty ointment and cream are very similar, nevertheless, they depend on the type of formulation applied. In the case of prednicarbate solution the dependence of the effects upon the formulation used is very obvious. The increase of tensile strength and modulus of elasticity as well as of insoluble collagen show that very impressively.

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A new method was developed to study the in vivo recovery of mechanical properties of rat skin after repeated strain. Full recovery, i.e., restitutio ad integrum, can be observed only in in vivo experiments but not in in vitro conditions. For the in vivo studies, tabs were fastened on the back skin of rats to test stress-strain behaviour both perpendicular and longitudinal to the body axis. Under anesthesia, skin was extended repeatedly 30 times to an elongation of up to 50% of the distance between the tabs. The experiment was repeated in the same animals at either 0.5, 1, 6, or 16 h. Differences depending on the direction of stretching versus body axis were observed during the first run. A decrease in stress values depending on the logarithm of the number of cycles was found, in both directions, to be attributable to the relaxation phenomenon. The measured stress values after 0.5, 1, and 6 h were considerably lower compared to the first run, thus indicating an incomplete recovery. After 16 h, an almost complete recovery was observed, so that, in perpendicular samples, even higher values were observed, thus indicating an overshooting of the repair mechanisms. The difficulties associated with obtaining appropriate physical and mathematical models for the mechanical properties of skin are discussed.

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With the help of biomechanical and biochemical methods, the dependence of human and rat skin on maturation and aging could be demonstrated in excised samples. Ultimate load, tensile strength, and modulus of elasticity showed a sharp increase during maturation and a slow decrease during aging, in both rat and human skin. In both species, ultimate extension revealed a similar behaviour, but the increase during maturation was less pronounced. The age-depending changes of the mechanical parameters in rat skin were influenced by anisotropic properties, which at least partially could be explained by the existence of the skin muscle layer in rats. Tensile strength of skin was closely correlated with the contents of insoluble collagen, e.g. the degree of cross linking. There was, however, no correlation between tensile strength and the contents of soluble collagen, glycosaminoglycans, or elastin. Further experiments like hysteresis, relaxation, and creeping behaviour indicated that plasticity and viscosity of skin both decrease during maturation and aging. Taking into account the experimental conditions, the results gained "in vivo" correlate with those obtained "in vitro".

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The influence of several desmotropic drugs (D-penicillamine (D-Pc) at doses of 300 and 1000 mg/kg p.o., a lathyrogenic drug, e.g. aminoacetonitrile (AAN) at doses of 100 and 300 mg/kg p.o. and a glucocorticoid, e.g. prednisolone acetate at doses of 2 and 10 mg/kg s.c.) on viscoelastic properties of rat tail tendons has been studied after 10 days' administration. In this experimental series not only the ultimate values (ultimate load, tensile strength, ultimate load of elasticity, ultimate strain), but also the hysteresis loops after 2, 4, 6 and 8% strain were evaluated. The ultimate values showed similar results as found in earlier experimental series, e.g., an impressive decrease after D-Pc treatment, a less pronounced decrease after AAN and an increase after prednisolone acetate. At extension degrees below rupture the values of stress, modulus of elasticity and energy input showed the same pattern. In contrast, energy dissipation as indicated by the area between the hysteresis loop showed a different pattern. Consequently, the ratio between energy dissipation and energy input, which is the characteristic parameter of the hysteresis phenomenon, was highly increased by D-Pc and only barely influenced by AAN. In contrast, prednisolone acetate reduced this ratio. A similar pattern was found for residual extension. Since the hysteresis phenomenon can be regarded as a parameter of plasticity of tail tendons one can conclude that D-Pc increases plasticity, AAN has only a slight influence and prednisolone acetate decreases plasticity.

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Mechanical parameters of tail tendons have been studied depending on maturation and age using male Sprague Dawley rats at an age of 1, 2, 4, 12 and 24 months. Ultimate values, such as ultimate strain, ultimate load, tensile strength, and ultimate modulus of elasticity, were the highest at an age of 12 months. In old rats these values were slightly lower. Using tail tendons with the same diameter from the same rats hysteresis experiments have been performed at extension degrees of 2, 4, 6 and 8% respectively. Stress at the end of the loading phase was the highest at 4 months for 2 and 4% extension and at 12 months for 6 and 8% extension. Between 12 and 24 months no significant difference was found. Modulus of elasticity at the end of the loading phase showed a sharp increase due to maturation reaching the maximum at 4 months at 2 and 4% extension and at 12 month at 6 and 8% extension. Thereafter a decrease was noted as it was for ultimate modulus of elasticity. Energy input during the loading phase increased during maturation. This increase was less pronounced for energy dissipation indicated by the unloading phase. As a consequence, the ratio between energy dissipation and energy input decreases significantly during maturation, however, during aging merely a slight decrease is noted. Residual extension at the end of the unloading phase is considerably decreased during maturation. Between 12 and 24 months only minor changes of this parameter were noted. In conclusion the parameters describing the hysteresis phenomenon in rat tail tendons are considerably influenced by maturation but only to a minor degree by aging. In this phenomenon indicating plasticity no reversal in the direction of age dependent changes has been observed. The comparison of the results of the hysteresis experiments in rat tail tendons with similar experiments performed previously in rat skin shows similarities as well as significant differences between both tissues.

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Prednisolone-17-ethylcarbonate-21-propionate (PrEP, Hoe 777) was tested for antiinflammatory activity in various animal models by topical and systemic administration. In those models being indicative of topical efficacy, the potency of PrEP was the same as that of desoximetasone. However, systemic effects after topical administration of PrEP in shaved skin of the dorsum of rats were relatively weak compared with the reference compound. Moreover, there were less systemic glucocorticoid effects after s.c. administration of PrEP than after desoximetasone. Thus, PrEP is obviously a compound with a considerable split of topical and systemic activity, suggesting its testing in man for systemic effects after topical administration.

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Mechanical properties of rat back skin at low loads and at failure were studied in 2 directions, e.g., perpendicular and longitudinal to body axis beginning with early maturation (from 1 week onwards) until senescence (at 24 mo). Anisotropic behavior, known for human skin, has also been found in rats. Surprisingly, the changes due to maturation and aging were not the same for one area of skin regardless of the direction. Ultimate extension was more influenced by the aging process in samples perpendicular to the body axis than in those parallel to body axis. Elongation at zero load, that means load not measurable under the described conditions, was higher in the longitudinal samples than in the perpendicular ones in young and very old animals, whereas this difference was absent in mature animals. In contrast, ultimate load, tensile strength and modulus of elasticity were higher in perpendicular samples than in samples longitudinal to the body axis for young and very old, but not for mature animals. Elongation at low loads or low stresses shows a different pattern than at medium loads or medium stresses when both directions are compared. Apparently, elements contributing to the mechanical properties in the various directions are differently influenced by the maturation and aging processes. Moreover, the elements contributing to the changes at low loads react differently to the aging process from those responsible for the effects at medium and high loads.

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Female hairless mice (strain mutant hr/hr) have been irradiated with increasing doses of UV-B over a period of 4 weeks. They were compared with untreated controls Additional groups of 30 mice were treated with milk base or cream base or milk SPF6 or cream SPF6 or cream SPF8 daily before irradiation. No changes of body weight indicating systemic effects were found. Skin thickness was increased significantly after irradiation. These changes were partially antagonized by cream or milk bases and completely prevented by the corresponding formulations containing sunscreen agents. Under the chosen conditions ultimate load of excised skin samples was increased by irradiation. This effect was not reversed by the bases but by the sunscreen products. Ultimate strain of excised skin samples proved to be the most sensitive indicator. The decrease of ultimate strain after irradiation was partially antagonized by the bases. The sunscreen products had more powerful effect. Due to the effects on skin thickness and ultimate load tensile strength and modulus of elasticity did not show significant changes under the chosen conditions. Likewise, collagen and elastin content per gram wet weight did not show significant changes. Considering the increase of thickness of skin which is prevented by sunscreen products one may conclude also a prevention of formation of additional intercellular material. The results prove the value of sunscreen products. Furthermore, they demonstrate a new method for evaluation of chemicals and sun protection preparations.

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The influence of maturation and age on the physical and chemical properties of various organs of connective tissue has been studied in rats at ages of 4 weeks, 8 weeks, 4 monhs, 1 year and 2 years. The changes between young (4 weeks old) and adult (4 months to 1 year old) animals were considered as the effects of maturation, whereas the changes between adult and senescent (2 years old) rats were regarded as the effects of aging. Ultimate values, such as ultimate load, tensile strength and breaking strength, or ultimate modulus of elasticity, showed a sharp rise during maturation and a smaller but significant decrease during aging in all organs, such as skin strips, tail tendons, shaft bones, epiphyseal cartilage and aorta rings. Ultimate strain showed a similar pattern, but the maximum occurred earlier. These changes were parallel with the content of insoluble collagen. Other chemical parameters such as soluble collagen or glycosaminoglycans, showed a continuous decrease during the life span, whereas elastin rose continuously. More detailed analysis of mechanical properties in rat skin gave insight into the viscoelastic behaviour of skin. In creep experiments time until break under constant load rose continuously during the life span, whereas ultimate extension rate showed a sharp fall during maturation and a slow decrease during senescence. Stress at low extension degree and moduli of elasticity at low extension degree were decreased by maturation and increased by senescence, exactly the opposite of the changes at high extension degrees. The so-called step phenomenon was increased due to maturation and decreased due to aging. Relaxation and mechanical recovery were changed in the same direction by maturation and aging. Relative viscoelastic parameters, such as the hysteresis phenomenon and relative decrease of stress under cyclic strain, were barely influenced by the aging process. Changes of most of the mechanical parameters at high extension degrees during maturation may be explained by an increase of cross-linking of collagen. Other phenomena such as changes at low extension degrees or parameters of plasticity cannot be explained on this basis. Further studies are needed for a better understanding of the true aging process in connective tissue.

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Comprehensive analysis of the mechanical properties of rat skin revealed the "step phenomenon". This particular observation was made after constant strain rate (analysis of stress strain curves) as well as after constant load (creep experiments). Relative low extensions or low loads were necessary to provoke the steps. In most cases two, sometimes three steps were observed. The step phenomenon was found mainly in skin strips punched out perpendicularly to the body axis. Probably some bonds in the fibrous network are broken giving way to additional elongation whereafter stronger links take over the stress. Since earlier studies demonstrated a pronounced influence of age and of desmotropic drugs on mechanical properties at ultimate load, e.g., tensile strength, ultimate modulus of elasticity, and ultimate strain, also the step phenomenon was studied under these conditions. In stress-strain experiments most of the steps were found at the ages of 2 and 4 months. Total stress loss and total work loss due to the steps were the highest at the age of 4 months. If, however, these values were calculated as percentage of ultimate values, the highest figures were found in young animals. Elongation gain due to the steps also showed a maximum at time of maturation, e.g., 4 months. Similar findings were achieved in creep experiments at medium load (200 g). After treatment with prednisolone acetate more steps and after treatment with D-penicillamine fewer steps were observed. In stress-strain experiments total stress loss and total work loss due to steps were more than twice as high than controls after prednisolone treatment and only one half after D-penicillamine. If calculated as percentage of ultimate stress or percentage of work input, these changes disappeared because of similar changes at ultimate load. However, elongation gain due to steps, which was not significantly influenced by prednisolone acetate but significantly decreased by D-penicillamine, showed the same changes when calculated as percentage of ultimate strain. Under all conditions the step phenomenon mainly influenced the extension parameters. The data presented here confirm earlier observations that mechanical properties at low loads or low and medium extensions show at least to some extent a different pattern under the influence of maturation and age and after treatment with desmotropic drugs compared to the mechanical parameters at ultimate load.

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