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PubMed1994

Cytoprotection of human dermal fibroblasts against silver sulfadiazine using recombinant growth factors.

Topical antimicrobial agents, silver sulfadiazine (SSD) and mafenide acetate (MA), have been associated with delayed wound healing. Previous in vitro studies with human dermal fibroblasts (HDF) have shown progressive cellular cytotoxicity with increasing concentrations of SSD and MA. However, preexposure of HDF to epidermal growth factor, basic fibroblast growth factor, or platelet-derived growth factor has resulted in cytoprotection of HDF against 0.01 and 0.03% concentrations of SSD as determined by phase-contrast microscopy (PCM), hemocytometer cell counts, and total cellular protein content. PCM, however, showed slower destruction of HDF at the 0.05% concentration of SSD. These data suggest that cells activated by growth factors either take up less SSD or are more resistant to the direct cytotoxic effects of this drug.

Epidermal Growth Factor↗
PubMed2000

Cytoprotective effect of taurine against hypochlorous acid toxicity to PC12 cells.

Taurine has been shown to be an effective scavenger of hypochlorous acid (HOCl). The role of HOCl is well established in tissue damage associated with reperfusion injury mediated by neutrophils. The role of HOCl in CNS injury and inflammatory reactions has not been well established. Myeloperoxidase activity is present in the CNS and it has been associated with ischemic injury. The aim of the present study was to determine the cytotoxicity of HOCl in a neuronal cell line (PC12) and the ability of taurine to prevent or reverse neurotoxicity. PC12 cells were grown in 96 well plates at a plating density of approximately 100,000 cells per well. HOCl was made up fresh from NaOCl for each experiment and the concentration verified spectrophotometrically. PC12 cells were exposed to HOCl for 1 hour in phosphate-buffered saline. Taurine was added at the time of HOCl treatment and in some experiments a post-treatment with taurine was performed by adding 1 or 10 mM taurine to the culture media (RPMI 1640). The cells were allowed 24 hours to recover and viability was determined using a tetrazolium-based (MTT) assay. The first series of experiments evaluated the toxicity of HOCl and the efficacy of taurine to protect PC12 cells. HOCl at 50 microM reduced PC12 cell viability by 50% and 150 microM reduced viability to <25% of control levels. Taurine (0.5-20 mM) was tested for cytoprotection against 150 microM HOCl and PC12 cells treated with 0.5 mM taurine exhibited only a 20% reduction in viability compared to untreated controls. Taurine concentrations of 1 mM or higher provided nearly 100% protection against HOCl. A second study was performed comparing taurine to beta-alanine, glutathione and isethionic acid. HOCl (100 microM) reduced viability to 25 +/- 1% of controls and taurine, beta-alanine and glutathione at 1 mM provided nearly complete protection. In contrast, isethionic acid, which lacks an amino group, failed to provide protection. Taurine (1 or 10 mM) added after 50 microM HOCl treatment did not provide any protection and PC12 cell viability was reduced to <39% of controls. In contrast, if taurine (50 microM) was present during the HOCl treatment and 1 mM taurine was added after the treatment, PC12 cell viability was 80 +/- 5% of controls. A combination of 250 microM taurine during the HOCl treatment and 1 mM taurine post-treatment produced 100% protection. These results clearly show that taurine is an efficient scavenger of HOCl and can prevent neuronal damage caused by HOCl. Since myeloperoxidase expression in the CNS is increased by ischemia, one function of taurine released during an ischemic event may be to scavenge HOCl and provide neuroprotection.

Animals↗
PubMed1994

Amifostine: potential for clinically useful cytoprotection.

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radioprotectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclosphosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on nonhematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.

Amifostine↗
PubMed1987

Effects of FCE20700, a new PGE2 derivative, on gastric acid secretion and cytoprotective processes in man.

The pharmacodynamic effects of FCE20700, a new PGE2 derivative, have been investigated in 6 healthy volunteers given single intragastric (i.g.) and intraduodenal (i.d.) doses of 1 and 2 mg and placebo, according to a double-blind, within-subjects design. For 30-270 min following i.g. administration the effect of FCE20700 on peptone-stimulated gastric acid secretion (AS) was assessed by i.g. titration, and serum gastrin (G) levels were also determined. For the same period after i.d. dosing the effect of the compound on pentagastrin-stimulated AS and on mucoproteins and bicarbonate content in the gastric juice was measured. Blood pressure (BP), heart rate and possible side-effects were monitored. Following i.g. administration there was a moderate, dose-related, significant inhibition of AS; significant inhibition of G levels was observed only after the highest dose. After i.d. administration there was a very modest though dose-related and significant inhibition of AS; a brief maximal increase in mucoproteins and in bicarbonate levels was apparent after the 1 mg dose. After i.d. but not after i.g. administration of 2 mg there was a modest but significant decrease in BP. No side-effects of clinical relevance were reported. The results appear to suggest a major activity of FCE20700 on cytoprotection rather than in inhibiting gastric acid secretion. The observed change in BP may indicate that after i.d. administration there will be some systemic effects of FCE20700.

Adult↗
PubMed1983

Prostanoids cytoprotection for maintaining remission in ulcerative colitis. Failure of 15(R), 15-methylprostaglandin E2.

To establish whether the cytoprotective properties of prostanoids can be used for maintaining remission in ulcerative colitis, 24 patients with ulcerative colitis in remission were randomly assigned to receive either 15(R), 15-methyl-PGE2 (200 micrograms/day) or to continue with sulfasalazine (2.0 g/day) for up to 28 weeks. All patients included were symptom free and sigmoidoscopy and rectal biopsy performed upon entering the trial did not reveal any signs of disease activity. Of the 12 patients who discontinued sulfasalazine and were allocated to receive 15(R), 15-methyl-PGE2, five flared up within the first four weeks and three others had to stop the trial because of severe diarrhea. Because of the high incidence of side effects and flare-up, the other four patients were instructed to stop the trial. In contrast, only two of the 12 sulfasalazine-treated patients flared-up and the other 10 concluded the 28 weeks of the trial symptom free. These results indicate that 15(R), 15-methyl-PGE2 cannot be used to control and support remission in ulcerative colitis patients.

Adult↗
PubMed1985

Inhibition of gastric motor activity by 16,16-dimethyl prostaglandin E2. A possible explanation of cytoprotection.

Effects of 16-dimethyl prostaglandin E2 (16-dmPGE2) and necrotizing agents on gastric motility and gastric mucosa were studied in conscious rats. Gastric motility was determined using a miniature balloon positioned in the glandular part of the stomach, which was connected to a pressure transducer and polygraph. Necrotizing agents, such as absolute ethanol, 0.6 N HCl, 0.2 N NaOH, or 4 M NaCl, were instilled into the stomach through a small fistula prepared in the forestomach. One milliliter of these agents produced streak lesions in the glandular part of the stomach within 1 hr, which were preceded by violent gastric contraction in every case. An intragastric administration of 16-dmPGE2 (0.3-3 micrograms/kg) by itself increased a tonus of the gastric wall but dose-dependently lessened the number and the amplitude of contractions. In those rats treated with 16-dmPGE2 (3 micrograms/kg), necrotizing agents failed to enhance the motility or to induce streak lesions. Pretreatment with 1 M NaCl as a mild irritant also inhibited gastric motility and lesion formation, but those actions were significantly antagonized by indomethacin (5 mg/kg). These results indicate that necrotizing agents induce a violent gastric contraction, followed by development of lesions in the stomach, and that the inhibition of gastric hypercontraction may be involved in a cytoprotective action of a prostaglandin against those induced gastric lesions in rats.

16,16-Dimethylprostaglandin E2↗
PubMed1983

Prostaglandin cytoprotection. Prostaglandin does not protect against aspirin- or alcohol-induced red blood cell hemolysis.

The hypothesis that prostaglandin cytoprotection involves cell membrane stabilization was tested in vitro using rat erythrocytes. Low concentrations of sodium acetylsalicylate, 0.02, 0.2, 2.0, and 20 mM, inhibited hypotonic hemolysis of red blood cell suspensions. While 35, 140, and 280 mM sodium acetylsalicylate had no hemolytic effect, 560 mM caused marked hemolysis. The prostaglandin E2 analog, 16,16-dimethyl prostaglandin E2, 0.4 X 10(-3), 10(-4), and 10(-5) M concentrations, did not alter this hemolysis. Fourteen percent ethanol caused red cell hemolysis, and this was unaffected by the prostaglandin. The findings do not support the hypothesis.

Animals↗
PubMed1988

Cytoprotective effect of acetaminophen against taurocholate-induced damage to rat gastric monolayer cultures.

Acetaminophen has recently been reported to protect against drug damage to gastric mucosa in vivo. The present study tested acetaminophen protection in cultured rat gastric mucous cells against sodium taurocholate-induced damage and assessed the role of endogenous prostaglandins. Cell damage was assessed by phase-contrast microscopy and quantitated by Chromium-51 release assay which positively correlated with the trypan blue dye exclusion test (r = 0.98). The effect of acetaminophen on the production of PGE2 and 6-keto-prostaglandin F1a (6KF) was also studied. Sodium taurocholate caused cell death in a dose-dependent manner as indicated by increased 51Cr release. Preincubation with 5 mM acetaminophen significantly reduced 51Cr release caused by 5 mM sodium taurocholate, producing a 40% increase in cell survival. This cytoprotection was not blocked by indomethacin. PGE2 and 6KF of the media did not change after preincubation with nondamaging concentrations of acetaminophen or taurocholate. These results indicate that: (1) acetaminophen exerts a direct protective effect on gastric mucous cells cultured in vitro independent of indirect factors such as blood flow and (2) this protection is not associated with increased prostaglandin production.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Gastric contents retained in rat stomach following mild irritant exposure contribute to adaptive cytoprotection.

Fluid retained in the gastric lumen immediately preceding the administration of a damaging product will dilute that product and decrease its injurious capacity. In an attempt to explain the phenomenon of adaptive cytoprotection, we studied the effect of mild irritant exposure on the volume of fluid retained in the gastric lumen. Rats treated with 0.2 N-0.4 N HCl had a larger volume of gastric fluid retained as compared to animals treated with 0.4 N NaCl. Additionally, a mixture of gastric juice derived from rats exposed to 0.4 N HCl with 2 ml ethanol was significantly less damaging to the gastric mucosa than a similar mixture containing an equal volume of gastric juice derived from 0.4 N NaCl-exposed rats. We conclude from our observations that in mild irritant-exposed stomachs, the gastric juice is a main contributor to the protection against ethanol injury.

Adaptation, Physiological↗
PubMed1990

Different effects of cytoprotective drugs on ethanol- and aspirin-induced gastric mucosal injury in pylorus-ligated rats.

In anesthetized rats oral administration (2 ml) of both ethanol (50% in 150 mM HCl) and aspirin (80 mM in 150 mM HCl) produced bandlike lesions in the stomach, while more generalized lesions occurred in the pylorus-ligated stomach when the irritant was given intragastrically through the fistula prepared in the rumen and the mucosal folds were removed by stomach distension. The bandlike lesions induced in the intact stomach by both irritants were significantly and dose-dependently prevented by 16,16-dimethyl PGE2 (dmPGE2: 3 and 10 micrograms/kg, subcutaneously), cysteamine (30 and 100 mg/kg, subcutaneously) or timoprazole (10 and 30 mg/kg, per os) at the doses which significantly inhibited gastric motility. In the pylorus-ligated stomach, however, neither of these agents showed any protection against the generalized lesions induced by ethanol, but such lesions caused by aspirin were significantly prevented only by dmPGE2. These agents also showed similar effects against the reduction of transmucosal PD in the pylorus-ligated stomach exposed to ethanol and aspirin. These results suggest that (1) the formation of bandlike lesions caused by ethanol and aspirin depends on the presence of mucosal folds and may be prevented by the agents that inhibit gastric motility, (2) the pathogenesis of the lesions induced by aspirin and ethanol may be different in the pylorus-ligated stomach, and (3) dmPGE2 has a unique protective ability that is not shared by usual cytoprotective agents.

16,16-Dimethylprostaglandin E2↗
PubMed1986

Release of cytoprotective PGE2 from cultured macrophages induced by antacids and sucralfate.

Aluminium-containing antacids and sucralfate possess cytoprotective effects supposedly due to the release of endogenous prostaglandins. In the present study possible mechanisms of prostaglandin production by aluminium-containing and related compounds were investigated in cultured macrophages. We found no indication that mechanical action, particle size or hyperosmolality (up to certain limits) play a major role in initiating enhanced prostaglandin production. Instead, it is likely that specific physicochemical properties as surface charge and the corresponding octahedral crystalline structure of Al(OH)3 are major factors mediating the necessary membrane interactions leading to prostaglandin release.

Aluminum↗
PubMed1984

Are prostaglandins cytoprotective in the human large intestine? The effect of indomethacin on rectal mucosal function and prostaglandin E2 release in vivo.

To test the hypothesis that prostaglandins are cytoprotective in the human large intestine, we investigated the effect of withdrawal of treatment with indomethacin suppositories on bowel habit and on rectal mucosal electrolyte transport and prostaglandin production in 8 patients taking such treatment for rheumatological disorders. Discontinuation of indomethacin doubled rectal mucosal prostaglandin E2 release (p less than 0.05) measured by in vivo rectal dialysis. Although there was no significant overall change in stool frequency, stool consistency, rectal bleeding or sodium absorption (also assessed by rectal dialysis), sigmoidoscopic appearance (p = 0.05), rectal mucosal potential difference (p less than 0.05) and potassium transport (p = 0.01) each reverted towards normal on indomethacin withdrawal. These results accord with the theory that, as in the upper gastrointestinal tract, prostaglandins may play a role in the maintenance of rectal mucosal structure and function.

Adult↗
PubMed1994

The gastric cytoprotective action of adenosine and prostaglandin E2 in rabbits.

The direct protective action of adenosine and prostaglandin E2 (PGE2) was examined in an isolated gastric gland preparation in rabbits. Ethanol (8%, v/v) incubation markedly increased the release of lactate dehydrogenase (LDH) and number of non-viable glands in the preparation. Both effects were prevented by PGE2 preincubation in a concentration (10(-6), 1.4 x 10(-5) or 2.8 x 10(-5) M)-dependent manner. The protective action was smaller in adenosine-treated groups, and yet the highest concentration (10(-4) M) of the compound also significantly inhibited the cytotoxic effects of ethanol. These findings indicate that both adenosine and PGE2 possess cytoprotective action on gastric glands in rabbits, but the former compound exerts its action beyond physiological concentrations. It is concluded that endogenous PGE2, but not adenosine may act as an ulcer modulator in the stomach.

Adenosine↗
PubMed1994

Effects of the H2-antagonists famotidine and nizatidine and the cytoprotectant misoprostol on human colonic and rat peritoneal mast cells.

The H2-antagonists famotidine and nizatidine produced a dose-dependent inhibition of histamine release from human colonic mucosal and muscle mast cells stimulated with anti-IgE. The IC30 values were in the range 0.5-10 microM and the maximum inhibition approached 50%. The compounds showed similar efficacy against rat peritoneal mast cells but were more potent. The cytoprotectant misoprostol had a striking effect on the human colonic mast cells, producing more than 50% inhibition at concentrations of 0.1-1 nM, but was much less active against the rat cells.

Animals↗
PubMed1994

Cytoprotective effect of tocopherols in hepatocytes cultured with polyunsaturated fatty acids.

When highly unsaturated fatty acids are added to cell cultures, it can become important to include antioxidants in the culture medium to prevent cytotoxic peroxidation. To find an optimal antioxidant for this purpose, the effect of 50 microM alpha-tocopherol, gamma-tocopherol, alpha-tocopheryl acetate, alpha-tocopheryl acid succinate, or alpha-tocopheryl phosphate, or of 1 microM N,N'-diphenyl-1,4-phenylenediamine, was investigated with respect to the agent's ability to prevent lactate dehydrogenase leakage in long-term rat hepatocyte cultures supplemented with 0.5 mM highly unsaturated fatty acids. Formation of thiobarbituric acid reactive substances in the cultures was also measured. alpha-Tocopheryl acid succinate was found to be the most effective cytoprotective compound, followed by N,N'-diphenyl-1,4-phenylenediamine, alpha-tocopherol, gamma-tocopherol and alpha-tocopheryl acetate, and alpha-tocopheryl phosphate was without effect.

Animals↗
PubMed1998

Determination of the cytoprotective agent WR-2721 (Amifostine, Ethyol) and its metabolites in human blood using monobromobimane fluorescent labeling and high-performance liquid chromatography.

PURPOSE: WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] is a chemoprotective agent that is currently in pediatric clinical trials. It is a prodrug that is dephosphorylated by alkaline phosphatase to the active free thiol form, WR-1065 [S-2-(3-aminopropylamino)ethanethiol]. It is likely that adequate and sustained cellular levels of the drug are necessary for optimum cytoprotection. To date, a method to measure both plasma and cellular levels of WR-2721 and its metabolites in clinical samples has not been available. METHODS: In the study reported here the monobromobimane (mBBr) fluorescent labeling method was used to measure these levels when drug was added in vitro to blood samples from normal volunteers. In addition, we present pharmacokinetic data from a pediatric patient receiving WR-2721 (825 mg/m2 x 2). RESULTS: The results can be summarized as follows: (1) WR-2721 was detected in the patient's plasma with a half-life of about 10 min; (2) the WR-1065 concentration in the blood cellular fraction was similar to that of plasma; (3) both WR-1065 and WR-SS-low molecular weight (WR-SS-LMW) metabolites disappeared from plasma and the cellular fraction by 3.6 h after WR-2721 infusion; (4) a large proportion of WR-1065 was oxidized in plasma to WR-SS protein and WR-SS-LMW; (5) a large proportion of WR-1065 in the cellular fraction was oxidized to WR-SS-protein; (6) the WR-SS-LMW concentration in the cellular fraction was low; and (7) saturation of plasma and cellular protein binding sites was possible. CONCLUSIONS: The pharmacokinetic data that were generated with this technique could guide clinical trials using WR-2721.

Amifostine↗
PubMed2002

Acetic acid-derived prostaglandin-dependent colonic adaptive cytoprotection is preserved in chronic colitis: role of cyclo-oxygenase.

BACKGROUND AND AIMS: We recently reported the phenomenon of prostaglandin-dependent colonic adaptive cytoprotection (CAP) against acute colonic injury induced by acetic acid (AA) in the normal colon. This study investigated whether the CAP is preserved in the chronic inflamed colon. MATERIALS AND METHODS: Normal rats and a chronic colitis model, induced by trinitrobenzene sulfonic acid, received an intracolonal administration (0.5 ml) of saline or AA at low concentration (1%) followed by high concentration (8%) 30 min later. The distal colon was removed 48 h after 8% AA administration, and colitis was assessed by macroscopic scoring and measurement of the myeloperoxidase (MPO) activity. Indomethacin (5 mg/kg), a nonselective cyclo-oxygenase (COX) inhibitor, or N-[2-cyclohexyloxy-4-nitrophenyl] methane-sulfonamide (NS398, 1 mg/kg), a COX type 2 selective inhibitor, was injected intraperitoneally 1 h before pretreatment with 1% AA. RESULTS: Intracolonal administration of 8% AA induced colonic mucosal damage (macroscopic score 10.0+/-0.9) and elevated MPO activity (2.8+/-0.2 U/g), which were significantly reduced to 3.3+/-0.8 and 1.8+/-0.2 U/g by 1% AA pretreatment, respectively. Indomethacin abolished the gross mucosal protective effect by 1% AA pretreatment in 8% AA-derived colitis in normal rats while the NS398 had no effect. Both indomethacin and NS398 reversed the MPO activity reduction induced by 1% AA pretreatment. In chronic inflamed colon 8% AA treatment resulted in an increase in the macroscopic score to 11.5+/-0.4 from 4.7+/-0.4, but not the MPO activity, which was significantly reduced to 5.7+/-0.9 by 1% AA pretreatment. This gross mucosal protective effect by 1% AA pretreatment in chronic inflamed colon was reversed by indomethacin while the NS398 had no effect. CONCLUSION: These data show that COX-1 and COX-2 derived prostaglandins induced by low concentration AA pretreatment reduce the colonic mucosal injury and the increase in the MPO activity in colitis, respectively. The protective effect of COX-1 is preserved in chronic inflamed colon. These findings support the existence of a low concentration of AA-derived prostaglandin-dependent CAP and suggest that colonic AA, which is derived from bacterial breakdown of carbohydrate and protein in the colon, plays a crucial role in the endogenous defense mechanisms.

Acetic Acid↗
PubMed1997

A pilot study to evaluate the feasibility of using willingness to pay as a measure of value in cancer supportive care: an assessment of amifostine cytoprotection.

The most commonly used method for pharmacoeconomic studies has been the cost-effectiveness analysis (CEA), where the outcome is expressed as an incremental cost per unit of effectiveness (e.g. quality-adjusted life years). Although CEA is a valuable tool for identifying therapies that are more effective and less expensive, deficiencies develop when a given treatment is both more expensive and more effective. An alternative that has not been investigated in the oncology setting is the willingness-to-pay (WTP) method. In this pilot study, a WTP strategy was utilized to estimate the value that the Canadian tax-paying public puts on amifostine, a new cytoprotective agent that reduces the risk of chemotherapy-induced toxicity. The method of WTP was used within the framework of a classical cost-benefit analysis to estimate the net cost or benefit of prophylactic amifostine in patients with ovarian cancer who were receiving chemotherapy. This included direct costs for amifostine administration and hospital savings secondary to the reduced incidence of antineoplastic toxicity. A random sample of 50 Canadian tax-payers were interviewed to ascertain their maximum WTP for the new drug. The WTP survey instrument was simple to administer and easily understood by participants. Respondents stated that they would be willing to pay an average of $Can3,476 (95% confidence interval = $Can2,275 to $Can4,676) as an income tax increase to be paid over their lifetime for the value offered by the product. The benefit was then subtracted from the overall cost of amifostine ($Can3,826). This produced a net cost of $Can350 per patient (95% confidence interval = -$Can850 to $Can1,551), suggesting a situation of cost neutrality. WTP as a measure of value for oncology products is feasible and should be considered for future economic evaluations. The strategy is currently being used at this institution to determine the net societal cost or benefit of other cancer supportive care therapies, such as epoetin-alfa.

Adolescent↗