A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis

Abstract Background Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model. Methods Male Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase – MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing. Results At the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance. Conclusion The presence of a H2S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H2S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.

A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis

BACKGROUND: Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model. METHODS: Male Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase - MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing. RESULTS: At the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance. CONCLUSION: The presence of a H2S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H2S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.

A COMPARISON OF TWO METHODS FOR THE DETECTION OF FECAL POLLUTION IN DRINKING WATER (HYDROGEN SULFIDE, INDICATOR, MODIFICATION)

A new technique for the detection of microbiological fecal pollution in drinking and in raw surface water has been modified and tested against the standard multiple-tube fermentation technique (most-probable-number, MPN). The performance of the new test in detecting fecal pollution in drinking water has been tested at different incubation temperatures. The basis for the new test was the detection of hydrogen sulfide produced by the hydrogen sulfide producing bacteria which are usually associated with the coliform group. The positive results are indicated by the appearance of a brown to black color in the contents of the fermentation tube within 18 to 24 hours of incubation at 35 (+OR-) .5(DEGREES)C. For this study 158 water samples of different sources have been used. The results were analyzed statistically with the paired t-test and the one-way analysis of variance. No statistically significant difference was noticed between the two methods, when tested 35 (+OR-) .5(DEGREES)C, in detecting fecal pollution in drinking water. The new test showed more positive results with raw surface water, which could be due to the presence of hydrogen sulfide producing bacteria of non-fecal origin like Desulfovibrio and Desulfomaculum. The survival of the hydrogen sulfide producing bacteria and the coliforms was also tested over a 7-day period, and the results showed no significant difference. The two methods showed no significant difference when used to detect fecal pollution at a very low coliform density. The results showed that the new test is mostly effective, in detecting fecal pollution in drinking water, when used at 35 (+OR-) .5(DEGREES)C. The new test is effective, simple, and less expensive when used to detect fecal pollution in drinking water and raw surface water at 35 (+OR-) .5(DEGREES)C. The method can be used for qualitative and/or quantitative analysis of water in the field and in the laboratory. ^

Methane and hydrogen sulfide in porewater of sediment cores from the upwelling area off Namibia

Porewater concentrations of sulfate, methane, and other relevant constituents were determined on four sediment cores from the high productivity upwelling area off Namibia which were recovered from the continental slope at water depths of 1300 and 2000 m. At all four stations a distinct sulfate-methane transition zone was observed several meters below the seafloor in which both sulfate and methane are consumed. Nutrient porewater concentration profiles do not show gradient slope changes at the depths of the transition zones. Flux calculations carried out on the basis of the determined porewater profiles revealed that anaerobic methane oxidation accounts for 100% of deep sulfate reduction within the sulfate-methane transition zone and consumes the total net diffusive sulfate flux. A significant contribution of organic carbon oxidation to the reduction of sulfate at these depths could, therefore, be excluded. We state that porewater profiles of sulfate with constant gradients above the transition zones are indicative for anaerobic methane oxidation controlling sulfate reduction.

Some hydrophysical and hydrochemical parameters of the upper part of the hydrogen sulfide zone in the Black Sea, September 11-22, 1994

Features of spatial variability of hydrogen sulfide in the northeastern part of the Black Sea are estimated. Some technical aspects of H2S concentration determination in the anoxic zone are discussed: in its upper part at H2S concentration <30 µmol/l, the photometric method is recommended, while for deeper layers the iodometric method should be used. With linearity of vertical distribution of hydrogen sulfide and ammonium taken into account their vertical gradients are estimated as 0.49+/-0.04 µmol/m and 0.19+/-0.06 µmol/m respectively. It is shown that the upper boundary of the H2S layer corresponds to the isopycnal surface with Sigma_t = 16.19+/-0.05 arbitrary units. Special attention is paid to relationship of hydrogen sulfide distribution with hydrophysical features in the region under study, in particular in the coastal zone. It is shown that hydrodynamic conditions control spatial distribution of hydrogen sulfide. On the basis of isopycnal treatment of the H2S field existence of a coastal convergence zone is proved, and peculiarities are recognized of vertical circulation in the main Black Sea gyre and coastal anticyclonic eddies; here hydrogen sulfide serves as a tracer of hydrophysical mixing processes.

Concentration of hydrogen sulfide in waters of the Black Sea in the layer of its coexistence with oxygen

About 100 parallel determinations of hydrogen sulfide by the volumetric and photometric methods were made in the layer of coexistence of oxygen with hydrogen sulfide (C layer). Thiosulfates were determined simultaneously. Regardless of locations of the stations, determinations by two methods coincided for the entire range of depths of occurrence of the C layer upper boundary. Within the C layer hydrogen sulfide readings obtained by these two independent methods agreed; thiosulfates were not found by direct measurements. Difference in the readings appears at the lower boundary of the C layer and below it, accompanied by appearance of thiosulfates. It is therefore concluded that it is correct to determine the upper boundary of the C layer by the iodometric method and to use concentration of hydrogen sulfide obtained by this method in the C layer to calculate rate of chemical oxidation of hydrogen sulfide in quasistationary processes.