| Clinical Studies | Abstract |
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Use of sucralfate to treat baldness.
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Excerpts from patent:
The hair-growing effect in the patients responding to the treatment was typically apparent after 1 month of treatment and in comparison to treatment with topically applied minoxidil, the test preparation gave a markedly better effect.
A composition containing micronized sucralfate 5%, ethanol 25%, propylene glycol 25%, and distilled water 45%, was used in two daily applications on the scalp, the composition being dispensed in a bottle with sponge applicator. The average consumption of the test preparation in individual patients was about one bottle per month. One male aged about 55 years, and with male androgenic alopecia Hamilton grade 3, used the test preparation for two months, and there was a dense regrowth of small terminal hairs in the partly balded area of the scalp. The effects were lasting after stopping the treatment for about 4 months. Another six male patients aged from 30 to 48 years, and with male androgenic alopecia Hamilton grade 3 and 4, have used the test preparation for periods of 3 months to 6 months, and in all six cases there have been a definite regrowth of terminal hairs; the effect was typically seen after 6-8 weeks of treatment. In one patient aged 50 and with total alopecia for the last 20 years, a dense regrowth of fine short terminal hairs all over the scalp was observed after application of the test preparation for 6 weeks.
2 Patients suffered from subtotal or total alopecia, with underlying atopic dermatitis. The first was a 40 year male who had been bald for 20 years, and after treatment with the test drug for 10 months, complete regrowth of hair was observed. The second patient was a 17 year old male with 2-3 years of alopecia, and treatment for 8 months with the test drug, showed only little effect.
It can be concluded that topical application twice daily on the scalp of 5% micronized sucralfate suspension in a water/ethanol/propylene glycol vehicle is effective in the treatment of male androgenic alopecia, also including middle agedpatients.
1997 Patent PDF for Sucralfate
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Topical sucralfate treatment of anal fistulotomy wounds: a randomized placebo-controlled trial.
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BACKGROUND:
Sucralfate is a cytoprotective agent which adheres to mucoproteins and forms a protective barrier at wound sites. In oral form it is a common ulcer medication, and as a topical preparation it has been used to treat a wide variety of wounds.
OBJECTIVE:
The present study was designed to evaluate the effectiveness and safety of topical sucralfate in wound healing after anal fistulotomy.
DESIGN:
Double-blind, randomized controlled study comparing topical application of sucralfate or placebo.
SETTING:
Private outpatient clinic specializing in anorectal disease in Nagpur, India.
PATIENTS:
Patients with a wound length of at least 5 cm after low anal fistulotomy were eligible for the study.
INTERVENTION:
Patients were randomly assigned to receive ointment containing 7% sucralfate or a placebo ointment consisting of petroleum jelly. Patients were instructed to apply approximately 3 g of ointment to the wound twice daily after a sitz bath for 6 weeks or until the wound had healed.
MAIN OUTCOME MEASURES:
The wounds were examined by a blinded independent observer at 2, 4, and 6 weeks after the operation. The primary end point was the proportion of patients with wounds that had completely healed. Secondary end points included amount of mucosal covering (scored by the observer), adverse events, and postoperative pain (self-rated on a visual analog scale).
RESULTS:
Of 80 participants (29 women, 51 men; median age, 23 (range, 17-49) years), 76 participants completed the trial (sucralfate, 39; placebo, 37). At 6-week follow-up, complete wound healing was achieved in 37 patients (95%) in the sucralfate group and 27 patients (73%) in the placebo group (P = .009). Mucosal coverage of the wound was significantly greater with sucralfate than with placebo at each measurement point (P = .01). No adverse events were observed. Postoperative pain scores were significantly lower for sucralfate than for placebo at 2 and 4 weeks after the start of treatment.
LIMITATIONS:
Wound tissue specimens were not available for morphological and ultrastructural analysis.
CONCLUSIONS:
The results of this study add support to the evidence that topical sucralfate is a safe and effective method for promoting mucosal healing and for providing analgesia during wound treatment. Patients undergoing anal fistulotomy can benefit from the use of topical application of sucralfate.
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Role of caspase-3 and nitric oxide synthase-2 in gastric mucosal injury induced by indomethacin: effect of sucralfate.
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BACKGROUND:
Apoptosis is the process of programmed cell death characterized by a series of distinct biochemical and morphological changes which involve activation of caspase proteases cascade that remains under the regulatory control of nitric oxide. Here, we investigated the activity of a key apoptotic protease, caspase-3, and the expression of inducible nitric oxide synthase (NOS-2) and tumor necrosis factor-alpha (TNF-alpha) associated with gastric epithelial cells apoptosis during indomethacin-induced gastric mucosal injury, and evaluated the effect of antiulcer agent sucralfate on this process.
METHODS:
The experiments were conducted with groups of rats pretreated intragastrically with 200 mg/kg sucralfate or the vehicle, followed 30 min later by an intragastric dose of indomethacin at 60 mg/kg. The animals were killed 2 h later and their gastric mucosal tissue used for macroscopic assessment, assays of epithelial cells apoptosis and TNF-alpha, and the measurements of caspase-3 and NOS-2 activities.
RESULTS:
In the absence of sucralfate, indomethacin caused multiple hemorrhagic lesions occupying 29.3 mm2 of the corpus area, and accompanied by a 20-fold enhancement in gastric epithelial cells apoptosis and a 47% increase in mucosal expression of TNF-alpha, while NOS-2 showed an 11.9-fold induction and the activity of caspase-3 increased 3.9-fold. Pretreatment with sucralfate produced a 59.7% reduction in the extent of mucosal damage caused by indomethacin, a 41.2% decrease in the epithelial cells apoptosis and a 33.4% reduction in TNF-alpha, while the activity of caspase-3 decreased by 45% and that of NOS-2 showed a 44.7% decline.
CONCLUSIONS:
The results implicate caspase-3 in the process of indomethacin-induced gastric epithelial cells apoptosis, and point towards participation of NOS-2 in the amplification of the cell death signaling cascade. Our findings also show that sucralfate protection against gastric mucosal injury caused by indomethacin involves the suppression of NOS-2 and the apoptotic events propagated by caspase-3.
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Role of nitric oxide and prostaglandins in sucralfate-induced gastroprotection.
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We investigated the role of nitric oxide (NO) and prostaglandins (PG) in the prevention by sucralfate of ethanol-induced gastric damage and the decrease of gastric blood flow and compared them with those obtained with nocloprost, a potent locally acting gastroprotective agent. Sucralfate and nocloprost given intragastrically (i.g.) protected dose dependently the gastric mucosa against the damage by absolute ethanol and prevented the decrease in blood flow induced by ethanol. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase decreased dose dependently the protection and the maintenance of blood flow provided by sucralfate but not by nocloprost. This decrease of sucralfate protection was antagonized by L-arginine but not D-arginine. Pretreatment with indomethacin also reversed, in part, the protective and hyperemic effects of sucralfate but the combination of both indomethacin and L-NNA completely abolished these effects. We conclude that sucralfate activates both the NO and PG systems that cooperate in the gastroprotective action of this drug and that NO is not involved in the protection induced by a PGE2 analog.
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Nitric oxide in gastroprotective and ulcer healing effects of sucralfate.
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BACKGROUND:
Sucralfate is known to protect gastric mucosa against the damaging action of strong irritants and to accelerate healing of chronic ulcers, but the mechanisms underlying these effects have not been elucidated. Similar gastroprotective and healing effects can be obtained with exogenous donors of nitric oxide (NO) and prostaglandins (PG).
METHODS:
The area of gastric lesions was measured by planimetry. Gastric blood flow was determined using laser Doppler flowmetry. The role of NO in the prevention of ethanol-induced gastric damage and in the healing of gastric ulcerations by sucralfate and nocloprost, a stable PGE2 analog, was therefore assessed.
RESULTS:
Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, enhanced ethanol-induced mucosal damage and reduced dose-dependently the gastroprotective and hyperemic effects of sucralfate. The doses of L-NNA attenuating significantly the protective effects of sucralfate were 25-50 mg/kg. The effects of L-NNA were reversed by the addition of L-arginine but not D-arginine. For comparison, the gastroprotective (but not hyperemic) effects of nocloprost were not affected by the pretreatment with L-NNA and/or arginine. Daily treatment with L-NNA (50 mg/kg per day) prolonged the healing of chronic gastric ulcers and significantly reduced the acceleration of healing by sucralfate.
CONCLUSIONS:
We conclude that (i) the gastroprotective and hyperemic effects of sucralfate involve, at least in part, the NO-arginine pathway, (ii) the ulcer healing effects of sucralfate may also involve NO, probably through the hyperemia around the ulcer, and (iii) NO is not essential for the mucosal protection of PGE2 analog, but may account for the gastric vasodilatory effect of this PG.
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Epidermal growth factor as a biologic switch in hair growth cycle.
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The hair growth cycle consists of three stages known as the anagen (growing), catagen (involution), and telogen (resting) phases. This cyclical growth of hair is regulated by a diversity of growth factors. Although normal expression of both epidermal growth factor and its receptor (EGFR) in the outer root sheath is down-regulated with the completion of follicular growth, here we show that continuous expression of epidermal growth factor in hair follicles of transgenic mice arrested follicular development at the final stage of morphogenesis. Data from immunoprecipitation and immunoblotting showed that epidermal growth factor signals through EGFR/ErbB2 heterodimers in skin. Furthermore, topical application of tyrphostin AG1478 or AG825, specific inhibitors of EGFR and ErbB2, respectively, completely inhibited new hair growth in wild type mice but not in transgenic mice. When the transgenic mice were crossed with waved-2 mice, which possess a lower kinase activity of EGFR, the hair phenotype was rescued in the offspring. Taken together, these data suggest that EGFR signaling is indispensable for the initiation of hair growth. On the other hand, continuous expression of epidermal growth factor prevents entry into the catagen phase. We propose that epidermal growth factor functions as a biologic switch that is turned on and off in hair follicles at the beginning and end of the anagen phase of the hair cycle, guarding the entry to and exit from the anagen phase.
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Nitric oxide in gastroprotection by sucralfate, mild irritant, and nocloprost. Role of mucosal blood flow.
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Pretreatment with sucralfate is known to protect gastric mucosa against the damaging effect of strong irritants, and this protection is accompanied by an increase in mucosal blood flow but the mechanisms underlying these effects have not been elucidated. Similar gastroprotective and hyperemic effects can be obtained with exogenous prostaglandins (PG), mild irritants such as dilute ethanol, and by capsaicin. In this study we investigated the role of nitric oxide (NO) in the prevention of ethanol-induced gastric damage and gastric blood flow by sucralfate, mild irritant such as 20% ethanol, capsaicin, and nocloprost, a stable PGE2 analog. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, enhanced ethanol-induced mucosal damage and reduced dose-dependently the gastroprotective and hyperemic effects of sucralfate, dilute ethanol, and capsaicin. The doses of L-NNA attenuating significantly the protective effects of sucralfate or 20% ethanol were 25-50 mg/kg, while those reducing the protection by capsaicin were 6.2-12.5 mg/kg. The attenuating effect of L-NNA on gastroprotection was reversed by L-arginine but not D-arginine. For comparison, the gastroprotective (but not hyperemic) effect of nocloprost was not affected by the pretreatment with L-NNA and/or arginine. We conclude that sucralfate, mild irritant, and capsaicin activate the NO system that may contribute to their gastroprotective effect through enhancing mucosal circulation but that NO is not essential for the mucosal protection by PGE2 analog.
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Activation of arachidonoyl phospholipase A2 in prostaglandin-mediated action of sucralfate.
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1. The mechanism of sucralfate-induced gastric mucosal prostaglandin generation was investigated using mucosal cells labeled with [14C]choline and [3H]arachidonic acid. 2. In comparison to the controls, the cells maintained in the presence of sucralfate showed a concentration dependent increase in lysophosphatidylcholine (LPC) synthesis and PGE2 generation. The maximal effect was attained at 25 microM sucralfate giving a 45.7% increase in LPC and 70% increase in PGE2. 3. Pretreatment with indomethacin prior to sucralfate, while causing inhibition in PGE2 generation, had no effect on LPC production and led to accumulation of free arachidonic acid. In the case of pretreatment with NDGA, the sucralfate caused increased LPC synthesis accompanied by enhanced PGE2 generation without free arachidonic acid accumulation. 4. The stimulatory effect of sucralfate on LPC synthesis and PGE2 generation was inhibited by phospholipase A2 inhibitors, mepacrine and BPB. The inhibitory effect was concentration dependent and attained maximum at 40 microM for BPB and 80 microM for mepacrine. 5. The results for the first time demonstrate that the enhancement in gastric mucosal prostaglandin generation by sucralfate results from the stimulation of mucosal phospholipase A2 for arachidonic acid release.
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Antiulcer drugs and gastric prostaglandin E2: an in vitro study.
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Prostaglandin (PG) has been reported to be an important protective and acid-suppressive factor in the gastric mucosa. Although the mechanisms of some antiulcer drugs are attributed to their stimulatory effects on endogenous prostaglandins, an understanding of these actions has not been established. In the present study we investigated the effects of antiulcer drugs on PGE2 using cultured gastric mucosal cells. Rabbit gastric mucosal cells were cultured after isolation with collagenase and ethylenediaminetetraacetic acid. PGE2 was measured by enzyme-linked immunoassay. Histamine H2-blockers (cimetidine, ranitidine, famotidine), omeprazole, and sucralfate did not modulate the media content of PGE2, whereas sofalcone dose- and time-dependently increased it. Sofalcone-induced increase of PGE2 was dose-dependently prevented by indomethacin. Sofalcone did not affect intracellular Ca2+ as assessed by the calcium-sensitive probe indo-1. Deprivation of Ca2+ in the media did not modulate the action of sofalcone. Sofalcone significantly suppressed 15-OH-PG dehydrogenase. These results suggest that among the various antiulcer drugs only sofalcone increases PGE2, which may be a factor in its therapeutic effect against peptic ulcer diseases.
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Effect of sucralfate on components of mucosal barrier produced by cultured canine epithelial cells in vitro.
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The mucous gel maintains a neutral microclimate at the epithelial cell surface, which may play a role in both the prevention of gastroduodenal injury and the provision of an environment essential for epithelial restitution and regeneration after injury. Enhancement of the components of the mucous barrier by sucralfate may explain its therapeutic efficacy for upper gastrointestinal tract protection, repair, and healing. We studied the effect of sucralfate and its major soluble component, sucrose octasulfate (SOS), on the synthesis and release of gastric mucin and surface active phospholipid, utilizing an isolated canine gastric mucous cells in culture. We correlated these results with the effect of the agents on mucin synthesis and secretion utilizing explants of canine fundus in vitro. Sucralfate and SOS significantly stimulated phospholipid secretion by isolated canine mucous cells in culture (123% and 112% of control, respectively). Indomethacin pretreatment significantly inhibited the effect of sucralfate, but not SOS, on the stimulation of phospholipid release. Administration of either sucralfate or SOS to the isolated canine mucous cells had no effect upon mucin synthesis or secretion using a sensitive immunoassay. Sucralfate and SOS did not stimulate mucin release in the canine explants; sucralfate significantly stimulated the synthesis of mucin, but only to 108% of that observed in untreated explants. No increase in PGE2 release was observed after sucralfate or SOS exposure to the isolated canine mucous cells. Our results suggest sucralfate affects the mucous barrier largely in a qualitative manner. No increase in mucin secretion or major effect on synthesis was noted, although a significant increase in surface active phospholipid release was observed.
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Sucralfate induces proliferation of dermal fibroblasts and keratinocytes in culture and granulation tissue formation in full-thickness skin wounds.
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Sucralfate is used to induce healing of gastrointestinal tract ulcers. We evaluated its potential utility in the healing of skin wounds. Initial experiments examined the effects of the sucralfate on proliferation of cultured dermal fibroblasts and keratinocytes. Sucralfate induced proliferation in quiescent cultures of both cell types. Additionally, sucralfate enhanced prostaglandin E2 synthesis in basal keratinocytes and in interleukin-1-stimulated keratinocytes and dermal fibroblasts. Basal interleukin-1 and 6 release were not affected by sucralfate, but the agent enhanced interleukin-1-stimulated interleukin-6 release from fibroblasts. When applied daily to full-thickness wounds in rats, sucralfate increased the thickness of granulation tissue when assessed at day 12.
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Effect of sucralfate on human gastric bicarbonate secretion and local prostaglandin E2 metabolism.
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The protective and ulcer-healing properties of sucralfate on gastroduodenal mucosa are well established. In this study, the possible mode of action of sucralfate in humans has been explored by examining its effect on gastric bicarbonate secretion and luminal prostaglandin E2 (PGE2) output from the intact stomach. The gastric output of bicarbonate and PGE2 has been calculated using a perfusion technique before, during, and after perfusion with sucralfate (8 mg/ml) in eight healthy volunteers. A significant increase in bicarbonate output occurred during the period of sucralfate perfusion returning to basal values during the post-sucralfate period. Pretreatment with indomethacin (25 mg/hour) failed to influence this secretory response. Luminal PGE2 output was significantly increased in the post-sucralfate perfusion period only. These changes were caused mainly by an increase in gastric secretory volume with insignificant increases in concentrations of bicarbonate and PGE2. These results suggest that stimulation of gastric bicarbonate secretion and PGE2 output by sucralfate may play a role in its protective actions.
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Genesis and recovery of ethanol-induced gastric lesions in rats: possible involvement of prostaglandin D2.
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We investigated the different effects of administration of high and low concentrations of ethanol (from 3% to 50%) on gastric mucosa in rats in relation to the changes in prostaglandin (PG) levels. Gastric lesions were induced by 50% ethanol, and all kinds of PGs were significantly decreased 1 h after administration, concomitantly. Thirty percent ethanol did not induce gastric lesions and had no effects on PG levels. Five percent ethanol significantly increased 6-keto-PGF1 alpha, PGF2 alpha, and PGE2 levels. Ten percent ethanol increased significantly PGD2 level. Premedication with sucralfate protected significantly gastric mucosa against 50% ethanol, and maintained PG levels, concomitantly. We also investigated the recovery time course of gastric lesions by 50% ethanol. Gastric lesions did not recover significantly after 24 h, recovered considerably after 48 h, and fully after 96 h. Levels of 6-keto-PGF1 alpha, PGF2 alpha, and PGE2 were fully recovered 24 h after exposure to 50% ethanol; however, a significant decrease in PGD2 level still was observed. PGD2 was recovered significantly after 48 h. These results indicate that different concentrations of ethanol induce different effects on gastric mucosal PGs, and that not only PGE2, but also other PGs, especially PGD2, might be linked with the genesis and recovery of gastric lesions by 50% ethanol.
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