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The use of antioxidants in healing
Martin A
Warner-Lambert Company, Morris Plains, New Jersey 07950, USA.
Dermatologic Surgery (USA), 1996, 22/2 (156-160)

BACKGROUND. Antioxidants enhance the healing of infected and noninfected wounds by reducing the damage caused by oxygen radicals.

OBJECTIVE. Studies were conducted to determine if the CRT components (vitamin E, sodium pyruvate, and specific fatty acids) could synergistically enhance healing.

METHODS. In vitro and in vivo studies were used to assess the effect of various combination of CRT components.

RESULTS. CRT reduced oxidative damage to keratinocytes and monocytes exposed to ultraviolet light and toxic chemicals and provided protection to human subjects exposed to ultraviolet irradiation. CRT dramatically facilitated healing of infected and noninfected wounds. In herpes-infected guinea pigs, CRT reduced vaginal viral lesion development, severity, and duration, thus facilitated healing of the lesions. CRT also reversed doxorubicin cytotoxicity in monocytes and reversed doxorubicin-impaired wound healing in rats.

CONCLUSION: The CRT colly to enhancing healing of injuries.

regulation of macrophage arginine metabolism: a proposed role in wound healing.
Shearer JD; Richards JR; Mills CD; Caldwell MD
Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
Am J Physiol (United States) Feb 1997, 272 (2 Pt 1) pE181-90

Nitric oxide (NO) and ornithine, products of NO synthase or arginase, respectively, have opposing biological activities. The effect of mediators of leukocyte activation and inhibition on arginine metabolism of resident mouse peritoneal exudate cells (MPEC) was determined. Factors that increased basal NO synthase activity, interferon (IFN)-gamma and lipopolysaccharide (LPS), decreased arginase activity in intact cells. Transforming growth factor (TGF)-beta1 decreased IFN-gamma-stimulated NO synthase activity and produced a reciprocal increase in urea and ornithine release. TGF-beta1 had no effect on the activity of these enzymes in LPS-stimulated MPEC. Corticosterone (Cort, 100 ng/ml) decreased the basal activity of both enzymes.However, Cort inhibited NO synthase activity and increased ornithine release in MPEC exposed to IFN-gamma or LPS. The difference between arginase activity in intact cells vs. that of cell lysates suggested intracellular inhibition of arginase activity. Products of NO synthase, NO and citrulline, were shown to inhibit MPEC arginase activity under maximal assay conditions. Intracellular pH was not altered by exposure of MPEC to LPS, IFN-gamma, TGF-beta, and Cort. This reciprocal change in arginine metabolism is proposed to be an important component of wound healing. Expression of NO synthase creates a cytotoxic environment that may be important to the early phase of wound healing. As wound healing progresses, increased arginase activity produces an environment favorable for fibroblast replication and collagen production.

The utilization of nutrient substances during wound healing
Mayer NA; Muller MJ; Herndon DN
Anesteziol Reanimatol (Russia) Sep-Oct 1996, (5) p29-39

The process of wound healing represents a series of complex physicochemical reactions requiring different nutritional microcomponents at each stage. In patients with extremely grave diseases and injuries the course of wound healing is impaired because of a hypermetabolic reaction to stress, leading to protein catabolism. The hypothalamus responds to cytokine stimulation by changes of thermoregulation (increase of heat production) and increased production of stress hormones (catecholamines, hydrocortisone, and glucagon). In turn, stress hormones trigsis and proteolysis processes. Hyperproduction of glucose at the expense of skeletal muscle tissue degradation leads to the formation of amino acid substrate for liver glyconeogenesis. Additional nutrients are obligatory for wound healing in such patients. Protein catabolism cannot be arrested by amino acids alone partly because amino acid transport is impaired; it can be normalized by anabolics, such as growth hormone and insulin-like growth factor 1. Treatment with growth hormone yields a dramatic positive effect in severely burned children. Proteins and vitamins, specifically arginine and vitamins A, B, and C provide the optimal nutritive support during wound treatment.

A multicenter clinical trial. Zinc acexamate versus famotidine in the treatment of acute duodenal ulcer. Study Group of Zinc acexamate (new UP doses)
Garcia-Plaza A; Arenas JI; Belda O; Diago A; Dominguez A; Fernandez C; Martin L; Pallares A; Rodrigo L; de la Santa Jw
Rev Esp Enferm Dig (Spain) Nov 1996, 88 (11) p757-62

A multicentric double-blind trial comparing 600 mg/d of Zinc Acexamate (ACZ) and 40 mg/d of Famotidine (FMT) in the short term treatment of acute duodenal ulcer included 199 patients, diagnosed by endoscopy. One-hundred and five patients received ACZ and 94 FMT, during four weeks. A clinical control took place at two weeks and a second clinical and endoscopic control at the end of the treatment (4 weeks). Complete cicatrization of the ulcer was observed in 56.5% of patients on ACZ and in 69.5% of patients of FMT (N.S.). A reduction of more than 50% of the ulcer diameter was recorded in 78.8% of the ACZ group and in 79.9% of the FMT group. Alcohol and smoking did not influence the results. Both treatments were equally effective in the disappearance of symptoms. The incidence of adverse reactions was very low in both groups (< 5%) and no patient dropped from the trial for this reason. In conclusion, a dosage of 600 mg/d of ACZ has ptors:

Endogenous zinc concentrations in cysteamine-induced duodenal ulcers in the rat.
Troskot B; Simicevic VN; Dodig M; Rotkvic I; Ivankovic D; Duvnjak M
Department of Gastroenterology, University Hospital Sestre Milosrdnice, Medical School, University of Zagreb, Croatia.
Biometals (England) Oct 1996, 9 (4) p371-5

Exogenously administered zinc compounds have been shown to possess anti-ulcer activity against a wide variety of ulcerogenic agents, both in laboratory animal models and in human peptic ulcer disease. However, a strong possibility exists that endogenous zinc may also play an important role during noxious events by various mechanisms. Therefore, the aim of this study was to focus on the changes of endogenous zinc serum and tissue concentrations in cysteamine-induced duodenal lesions. We used atomic absorption spectrophotometry to determine the tissue and serum concentrations of zinc in normal (control) rats and those with cysteamine-induced duodenal ulcers. The results obtained in this study indicated that the onset, development and spontaneous healing of ulcer lesions were associated with certain shifts in zinc serum and tissue concentrations. Prior to ulcer formation, a significant increase was noted in serum zinc values. With the onset of duodenal lesions, zinc serum concentrations significantly decreased, while there was a significant increase in duodenal tissue concentrations when compared to healthy control animals. Zinc tissue concentrations decreased and returned to starting values by the end of the first week of spontaneous healing. This decrease in zinc tissue concentration corresponded to the healing rate of the duodenal ulcers. Serum zinc concentrations also returned to starting values within the first week period. These observations indicate and confirm that zinc could play an important role in duodenal ulcer disease and represent a natural defense system in the body.

Vitamin supplementation? Experimental study on humans.
Vaxman F; Olender S; Lambert A; Nisand G; Grenier JF
INSERM U61 et Laboratoire Pautrier, Chirurgie B, Hopitaux Universitaires de Strasbourg, France.
Eur Surg Res (Switzerland) Jul-Aug 1996, 28 (4) p306-14

The improvement of the wound healing process in humans by vitamin supplements is still controversial because of the lack of a clearly demonstrated correlation with the mechanical properties of scars.

OBJECTIVE: The aim of this work was to study the effects of high doses of ascorbic acid (AA) and pantothenic acid (PA) on the wound healing process of human skin.

METHOD: Two groups of patients undergoing surgery for tattoo removal by the successive resection procedure received AA (1 or 3 g/day) and PA (0.2 or 0.9 g/day). More than 80 mechanical, biological and histological parameters were investigated in both preoperated skin and the scars.

RESULTS: The breaking energy of scars was higher in group 2, and energy and treatment were directly correlated (p = 0.006). Mg and Mn significantly rose in group 2 whereas Fe decreased in a dose-dependent manner. Intragroup comparison showed patient and treatment effects for Mg, a time.treatment effect for Cu and a treatment effect for Fe.

CONCLUSION: The degree and rapidity of variations rather than the variations of the absolute values themselves of fibroblasts, hydroxyproline, Fe, Cu and Mg are significantly related to the enhancement of the mechanical properties of scars. From this study, it may be assumed that in order to obtain 'better', more solid and resistant scars, the decrease of Fe must be quick and acute in order to avoid the harmful effects of toxic radicals; the increase of Cu, Mg and Mn must be early and high in order to have more stable and solid collagen.

Human dermal fibroblasts produce nitric oxide and express both constitutive and inducible nitric oxide synthase isoforms.
Wang R; Ghahary A; Shen YJ; Scott PG; Tredget EE
Department of Surgery, University of Alberta, Edmonton, Canada.
J Invest Dermatol (United States) Mar 1996, 106 (3) p419-27

Nitric oxide (NO) is produced by a variety of human and animal cells and is involved in a broad rray of physiological and pathophysiological processes. It can cause vasodilation, serve as a neurotransmitter, and have anti-neoplastic, anti-microbial, and anti-proliferative effects. In this study, we have demonstrated that fibroblasts derived from human skin spontaneously produce NO and that this production can be enhanced by stimulating the cells with interferon-gamma and lipopolysaccharide. The production of NO by human dermal fibroblasts can be blocked by NG-monomethyl-L-arginine (L-NMMA). The inhibitory effect of L-NMMA on NO production was restored by addition of L-arginine but not D-arginine. By measuring the rate of conversion of [14C]L-arginine to [14C]L-citrulline, we show that unstimulated cells expressed only Ca2+-dependent NO synthase (NOS) activity (1.36 +/- 0.57 pmol/mg/min; n = 4) whereas stimulated cells expressed both Ca2+-dependent (2.60 +/- 0.54 pmol/mg/min; n = 4) and -independent (1.59 +/- 0.14 pmol/mg/min; n = 4) NOS activities. With reverse transcription polymerase chain reaction (RT-PCR), the 422-bp RT-PCR product for human endothelial constitutive NOS and the 462-bp RT-PCR product for human hepatocyte inducible NOS were detected in proportion to the amount of mRNA-related RT-cDNA added to the reaction mixture. Further evidence by immunocytochemistry demonstrated that human dermal fibroblasts express both constitutive and inducible NOS proteins. These data collectively suggest that in addition to macrophages and other inflammatory cells, nitric oxide production by dermal fibroblasts could be important during the inflammatory stages of wound healing and possibly also in the later stages of proliferation and tissue remodeling after skin injury in humans.

Nutritional factors affecting wound healing
Thomas DR
Ostomy Wound Manage (United States) Jun 1996, 42 (5) p40-2, 44-6, 48-9

The consistent relationship between poor nutritional status and risk of complications forms the cornerstone of nutritional support. Yet there is controversy about the ability of nutritional support to reduce complications or improve wound healing. This controversy stems from a number of issues. Diagnosing poor nutrition is not always easy and straight forward. There is sometimes a question whether a patient is malnourished or simply in overall poor health. Studies examining the relationship between nutrition and patient outcome are typically based on animal rather than human models. Even in clinical settings, aspects of care such as enteral or parenteral nutrient delivery may decrease the benefit of nutritional support, making outcomes even harder to measure. The effect of specific nutrients have been examined, such as protein, amino acids, vitamins C and A, and zinc. However, there are still questions regarding how much individual supplementation of a nutrient will positively affect overall outcomes. Although the relationship between specific nutrients and wound healing is not clearly defined by current studies, each patient should be provided with a complete, balanced therapeutic diet. There is at least suggestive evidence that improvement in nutritional status can improve outcomes of wound healing.

Role of lactose, arginine and lysine combination in fracture healing (an experimental study)
Fini M; Giardino R; Nicoli Aldini N; Martini L; Rocca M; Bertoni F; Capelli S; Cantelli Forti G; Sapone A; Rossetti A; Morrone G; Giavaresi G
Cattedra di Fisiopatologia Chirurgica, Universita di Bologna.
Ann Ital Chir (Italy) Jan-Feb 1996, 67 (1) p77-82; discussion 82-3

L-arginine and L-lysine are essential amino acids which seem to possess some properties able to influence bone fractures healing. In fact, the increase of intestinal calcium adsorption but also in collagen synthesis, in insulin and growth hormone secretion and in osteoblastic activation. So, an experimental in vivo model was carried out by using 50 adult rabbits which, under general anaesthesia, were submitted to an osteotomy of the left fibula. Animals were divided into 5 groups and were daily treated with a mixture of lactose, L-arginine and L-lysine or with the only lactose (control group) at the same dosage as recommended for humans. They were sacrificed after 15, 30, 40, 50 and 60 days for radiological and histological studies. The results of the study showed that the pharmacological mixture containing L-arginine and L-lysine accelerates and ameliorates the healing processes and this positive effect was particularly evident from the 30th day after the osteotomy. We think that these results are linked not only to calcium metabolism but also to different biological properties which positively contribute to good healing of bone fractures.

Activation of a mouse macrophage cell line by acemannan: The major carbohydrate fraction from Aloe vera gel
Zhang L.; Tizard I.R.
Dept. of Veterinary Pathobiology, Texas A and M University, College Station, TX 77843 USA
Immunopharmacology (Netherlands), 1996, 35/2 (119-128)

Acemannan is the name given to the major carbohydrate fraction obtained from the gel of the Aloe vera leaf. It has been claimed to have several important therapeutic properties including acceleration of wound healing, immune stimulation, anti-cancer and anti-viral effects. However, the biological mechanisms of these activities are unclear. Because of this wide diversity of effects, it is believed that they may be exerted through pluripotent effector cells such as macrophages. The effects of acemannan on the mouse macrophage cell line, RAW 264.7 cells were therefore investigated. It was found that acemannan could stimulate macrophage cytokine production, nitric oxide release, surface molecule expression, and cell morphologic changes. The production of the cytokines IL-6 and TNF-alpha were dependent on the dose of acemannan provided. Nitric oxide production, cell morphologic changes and surface antigen expression were increased in response to stimulation by a mixture of acemannan and IFN-gamma. These results suggest that acemannan may function, at least in part, through macrophage activation.

Wound healing effects of aloe gel and other topical antibacterial agents on rat skin
Heggers J.P.; Kucukcelebi A.; Stabenau C.J.; Ko F.; Broemeling L.D.; Robson M.C.
Dept Surg Plastic/Microbiol/Immunol., Univ. Texas Medical Branch/Shriners, Burns Institute, Galveston, TX 77550 USA
Phytotherapy Research (United Kingdom), 1995, 9/6 (455-457YRE)

The effects of topical antibacterials were studied in an acute wound healing model. Sprague- Dawley rats after appropriate anaesthesia received four 1.5 cm2 dorsal defects through the skin and panniculus carnosus. Skin defects were treated for 14 days with 2% mupirocin ointment, 1% clindamycin cream, 1% silver sulfadiazine cream+Aloe vera gel, and silver sulfadiazine combined with Aloe gel. An untreated group served as controls. Each group was comprised of 10 animals each to achieve statistical significance. Wound closure rate was assessed by serial planimetry. Following healing, the breaking strength of each resultant scar was determined. Wound half-lives and overall healing rates were calculated by regressing the log of the areas of all wounds over time. Overall healing rates of all the treated groups were significantly different compared with control group (p<0.05) The Aloe group had the shortest half-life and healed faster than the control group. All the other treated groups had no longer half-lives when compared with the control group. While silver sulfadiazine+Aloe increased the breaking strength of the healed wound, Aloe alone did not, but demonstrated an increase over the control. Topical Aloe significantly enhances the rate of wound healing and when combined with silver sulfadiazine reverses the wound retardant effect observed with silver sulfadiazine. Clindamycin and mupirocin significantly delay wound closure. However mupirocin enhanced the breaking strength of the wound.

Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice
Roberts D.B.; Travis E.L.
Texas Univ. M. D. Anderson Can. Ctr., Box 66, 1515 Holcombe Blvd., Houston, TX 77030-4095 USA
International Journal of Radiation Oncology Biology Physics (USA), 1995, 32/4 (1047-1052)

Purpose: To determine (a) whether a wound dressing gel that contains acemannan extracted from aloe leaves affects the severity of radiation- induced acute skin reactions in C3H mice; (b) if so, whether other commercially available gels such as a personal lubricating jelly and a healing ointment have similar effects; and (c) when the wound dressing gel should be applied for maximum effect.

Methods and Materials: Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments, the gel was applied daily beginning immediately after irradiation. To determine timing of application for best effect, gel was applied beginning on day -7, 0, or +7 relative to the day of irradiation (day 0) and continuing for 1, 2, 3, 4, or 5 weeks. The right inner thigh of each mouse was scored on a scale of 0 to 3.5 for severity of radiation reaction from the seventh to the 35th day after irradiation. Dose- response curves were obtained by plotting the percentage of mice that reached or exceeded a given peak skin reaction as a function of dose. Curves were fitted by logit analysis and ED50 values, and 95% confidence limits were obtained.

Results: The average peak skin reactions of the wound dressing gel- treated mice were lower than those of the untreated mice at all radiation doses tested. The ED50 values for skin reactions of 2.0-2.75 were approximately 7 Gy higher in the wound dressing gel-treated mice. The average peak skin reactions and the ED50 values for mice treated with personal lubricating jelly or healing ointment were similar to irradiated control values. Reduction in the percentage of mice with skin reactions of 2.5 or more was greatest in the groups that received wound dressing gel for at least 2 weeks beginning immediately after irradiation. There was no effect if gel was applied only before irradiation or beginning 1 week after irradiation.

Conclusion: Wound dressing gel, but not personal lubricating jelly or healing ointment, reduces acute radiation-induced skin reactions in C3H mice if applied daily for at least 2 weeks beginning immediately after irradiation.

Anti-inflammatory and wound healing properties of Aloe vera
Udupa S.L.; Udupa A.L.; Kulkarni D.R.
Department of Biochemistry, Kasturba Medical College, 576119 Manipal, Karnataka India
Fitoterapia (Italy), 1994, 65/2 (141-145)

The fresh juice of the indigenous drug A. vera (0.2 ml/100 g, i.p.)was studied for its anti inflammatory and by observing percent reduction in carrageenin-induced paw oedema at 3 h. Wound healing effects were studied on incision (skin breaking strength), excision (percent wound contraction and epithelisation time) and dead space (granuloma breaking strength and biochemical parameters) wound models. A. vera showed significant anti-inflammatory activity in acute inflammatory model without any significant effect on chronic inflammation. Significant increase in breaking strength (skin and granuloma tissue), enhanced wound contraction and decreased epithelisation period were observed. An increase in lysyl oxidase activity and mucopolysaccharide content were also seen. This drug could therefore increase tensile strength by increasing cross-linking in collagen and interactions with the ground substance.

Beneficial effects of Aloe in wound healing
Heggers J.P.; Pelley R.P.; Robson M.C.
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77550 USA
Phytother. Res. (United Kingdom), 1993, 7/Spec. Iss. (S48-S52)

The therapeutic effects of Aloe vera have been examined in preventing progressive dermal ischaemia caused by burns, frostbite, electrical injury,distal dying flap and intra-arterial drug abuse. In vivo analysis of these injuries showed that the mediator of progressive tissue damage was thromboxane A2 (TxA2). Experimentally Aloe was compared to a variety of antithromboxane agents to include U38450, a lodoxamide, a lazaroid and Carrington wound gel. In the burn injury Aloe when compared with the control and the Carrington wound gel (p = 0.05). Tissue survival in the experimental frostbite injury was 28.2% when compared with the control (p = 0.05). Similar results were obtained for the electrical injury, and intra-arterial drug abuse. Clinically burn patients treated with Aloe healed without tissue loss as did those with frostbite (p = 0.001). In the intra-arterial drug abuse patients Aloe reversed the tissue necrosis. This therapeutic approach was used to prevent progressive tissue loss in each injury by actively inhibiting the localized production of TxA2. Aloe not only acts as a TxA2 inhibitor but maintains a homeostasis within the vascular endothelium as well as the surrounding tissue.

The stimulation of postdermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dressing
Fulton J.E. Jr.
The Acne Research Institute, 1587 Monrovia Street, Newport Beach, CA 92663 USA
J. Dermatol. Surg. Oncol. (USA), 1990, 16/5 (460-467)

Full-face dermabrasion provided an ideal opportunity to document the effects of dressings on wound healing management. Following the procedure, the abraded face was divided in half. One side was treated with the standard polyethylene oxide gel wound dressings. The other side was treated with a polyethylene oxide gel dressing saturated with stabilized aloe vera. The polyethylene oxide dressing provided an excellent matrix for the release of aloe vera gel during the initial 5 days of wound healing. By 24-48 hours there was dramatic vasoconstriction and accompanying reduction in edema on the aloe-treated side. By the third to fourth day there was less exudate and crusting at the aloe site, and by the fifth to sixth day the reepithelialization at the aloe site was complete. Overall, wound healing was approximately 72 hours faster at the aloe site. This acceleration in wound healing is important to reduce bacterial contamination, subsequent keloid formation, and/or pigmentary changes. The exact mechanism of acceleration of wound healing by aloe vera is unknown.

Aloe vera gel hindered wound healing of experimental second-degree burns: A quantitative controlled study
Kaufman T.; Kalderon N.; Ullmann Y.; Berger J.
Department of Plastic Surgery, Bruce G. MacMillan Burn Wound Healing Research Unit, Haifa Israel
J. Burn Care Rehabil. (USA), 1988, 9/2 (156-159)

In the present study, Aloe vera gel (AVG) was applied to experimental second-degree burns in guinea pigs, and its effects on epithelialization, wound contraction, newly formed granulation tissue, and regeneration of hair follicles was compared with that effected by 1% silver sulfadiazine cream (AgSD). Epithelialization (% mean plus or minus SEM) on postburn day 8, 16, and 24 of the AVG-treated wounds was 38.72% plus or minus 2.71%, 60.34% plus or minus 3.28%, and 92.46% plus or minus 2.26%, respectively, while that of AgSD-treated burns was 53.35% plus or minus 2.65%, 94.84% plus or minus2.65%wounds was significantly higher than that of the AgSD-tr eated burns during 24 days of the study (P < .001). The thickness of the newly formed granulation tissue was higher in the AVG-treated wounds (P < .001), while the hair follicles count was significantly lower (P < .001) compared with the AgSD-treated burns. It is concluded that this preparation of Aloe vera gel hindered the healing process of the present burn wound model when compared with 1% silver sulfadiazine cream.

Biological activity of Aloe vera
Davis R.H.; Leitner M.G.; Russo J.M.; Maro N.P.
Pennsylvania College of Podiatric Medicine, Department of Physiological Sciences, Philadelphia, PA 19107 USA
Med. Sci. Res. (UK), 1987, 15/5 (235)

In this study, the authors attempted to show the comparative biological activity of Aloe vera as measured by standard anti-inflammatory tests. Wound healing was improved 24% in mice by a 100 mg/kg Aloe vera dose whereas 10 mg/kg improved healing 31% in rats. A slightly greater response of 44% was obtained on inhibiting mustard induced edema by 10 mg/kg Aloe vera. A marked inhibition of 58% PMN infiltration into an inflamed area by 2 mg/kg aloe was noted. No reduction of granuloma tissue formation around a cotton pellet under the skin was shown at doses up to 400 mg/kg. These data suggest that Aloe vera inhibits inflammation and improves wound healing. Aloe vera probably does not act like a steroid since it was most effective on acute inflammation and had no effect on granuloma tissue formation.

Cutaneous tissue repair: Practical implications of current knowledge. II
Reed B.R.; Clark R.A.F.
Department of Dermatology, University of Colorado Health Sciences Center, Denver, CO 80262 USA
J. Am. Acad. Dermatol. (USA), 1985, 13/6 (919-941)

This article reviews the scientific basis for the certain factors that delay wound repair in the clinical setting. A brief history of wound healing is given, followed by a discussion of endogenous local factors (bacterial infection, hypoxia, foreign body, and desiccation) and endogenous systemic factors (nutritional deficiencies, aging, coagulation disorders, and the Ehlers-Danlos syndromes) associated with poor wound repair. Also reviewed are the mechanisms by which exogenously administered agents (glucocorticoids, antineoplastic agents, and anticoagulants) may delay healing. Commonly used topical antimicrobials, their spectrum of activity, and evidence of effects on wound healing are examined. Finally, properties of commercially available wound coverings and wound care in the future are discussed.

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