Efficacy and safety of high-dose esomeprazole-amoxicillin dual therapy for Helicobacter pylori rescue treatment: a multicenter, prospective, randomized, controlled trial.

BACKGROUND: High-dose dual therapy (HDDT) with proton pump inhibitors (PPIs) and amoxicillin has attracted widespread attention due to its favorable efficacy in eradicating Helicobacter pylori (H. pylori). This study aimed to compare the efficacy and safety of high-dose PPI-amoxicillin dual therapy and bismuth-containing quadruple therapy for H. pylori rescue treatment. METHODS: This was a prospective, randomized, multicenter, non-inferiority trial. Patients recruited from eight centers who had failed previous treatment were randomly (1:1) allocated to two eradication groups: HDDT (esomeprazole 40 mg and amoxicillin 1000 mg three times daily; the HDDT group) and bismuth-containing quadruple therapy (esomeprazole 40 mg, bismuth potassium citrate 220 mg, and furazolidone 100 mg twice daily, combined with tetracycline 500 mg three times daily; the tetracycline, furazolidone, esomeprazole, and bismuth [TFEB] group) for 14 days. The primary endpoint was the H. pylori eradication rate. The secondary endpoints were adverse effects, symptom improvement rates, and patient compliance. RESULTS: A total of 658 patients who met the criteria were enrolled in this study. The HDDT group achieved eradication rates of 75.4% (248/329), 81.0% (248/306), and 81.3% (248/305) asdetermined by the intention-to-treat (ITT), modified intention-to-treat (MITT), and per-protocol (PP) analyses, respectively. The eradication rates were similar to those in the TFEB group: 78.1% (257/329), 84.2% (257/305), and 85.1% (257/302). The lower 95% confidence interval boundary (-9.19% in the ITT analysis, - 9.21% in the MITT analysis, and -9.73% in the PP analysis) was greater than the predefined non-inferiority margin of -10%, establishing a non-inferiority of the HDDT group vs. the TFEB group. The incidence of adverse events in the HDDT group was significantly lower than that in the TFEB group (11.1% vs. 26.8%, P  < 0.001). Symptom improvement rates and patients' compliance were similar between the two groups. CONCLUSIONS: Fourteen-day HDDT is non-inferior to bismuth-containing quadruple therapy, with fewer adverse effects and good treatment compliance, suggesting HDDT as an alternative for H. pylori rescue treatment in the local region. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04678492.

Effective therapeutic regimens in two South Asian countries with high resistance to major Helicobacter pylori antibiotics.

Background: Nepal and Bangladesh have a high prevalence of Helicobacter pylori with high resistance rates to clarithromycin, metronidazole, and levofloxacin. Here, we evaluated the susceptibility and genetic mutations of 5 alternative antibiotics against isolates from both countries to obtain an effective treatment regimen for H. pylori eradication. Methods: We used the agar dilution method to determine the minimal inhibitory concentration of 5 alternative antibiotics against 42 strains from Nepal and 56 from Bangladesh and performed whole genome mutation analysis. Results: No resistance to furazolidone or rifabutin and a high susceptibility of sitafloxacin (95.2% in Nepal and 98.2% in Bangladesh) were observed. In contrast, resistance to rifaximin (52.4% in Nepal and 64.3% in Bangladesh) was high. Moreover, resistance to garenoxacin was higher in Bangladesh (51.6%) than in Nepal (28.6%, P = 0.041), most likely due to its correlation with levofloxacin resistance (P = 0.03). Garenoxacin and rifaximin were significantly correlated in Bangladesh (P = 0.014) and occurred together with all sitafloxacin-resistant strains. Mutations of gyrA could play a significant role in garenoxacin resistance, and double mutations of A87 and D91 were associated with sitafloxacin resistance. Analysis of the rpoB gene demonstrated well-known mutations, such as V657I, and several novel mutations, including I2619V, V2592 L, T2537A, and F2538 L. Conclusions: Rifabutin can be cautiously implemented as therapy for H. pylori infection due to its interaction with the tuberculosis endemic in Bangladesh. The high susceptibility of furazolidone and sitafloxacin suggests their possible future application in Nepal and Bangladesh.

Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines.

Several pharmaceutical agents produce ethanol intolerance, which is often depicted as disulfiram-like reaction. As in the case with disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases. In the present study, chloramphenicol, furazolidone, metronidazole, and quinacrine, which are reported to produce a disulfiram-like reaction, as well as disulfiram, were administered to Wistar rats and the hepatic activities of alcohol and aldehyde dehydrogenases (1A1 and 2) were determined. The expression of aldehyde dehydrogenase 2 was further assessed by Western blot analysis, while the levels of brain monoamines were also analyzed. Finally, blood acetaldehyde was evaluated after ethanol administration in rats pretreated with disulfiram, chloramphenicol, or quinacrine. The activity of aldehyde dehydrogenase 2 was inhibited by disulfiram, chloramphenicol, and furazolidone, but not by metronidazole or quinacrine. In addition, although well known for metronidazole, quinacrine also did not increase blood acetaldehyde after ethanol administration. The protein expression of aldehyde dehydrogenase 2 was not affected at all. Interestingly, all substances used, except disulfiram, increased the levels of brain serotonin. According to our findings, metronidazole and quinacrine do not produce a typical disulfiram-like reaction, because they do not inhibit hepatic aldehyde dehydrogenase nor increase blood acetaldehyde. Moreover, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Therefore, the ethanol intolerance produced by these agents, either aldehyde dehydrogenase is inhibited or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications.

In vitro activity of therapeutic drugs against Histomonas meleagridis (Smith, 1895).

Histomoniasis or blackhead is a life-threatening disease of turkeys that is caused by a flagellated protozoan, Histomonas meleagridis. The development of an assay to measure the sensitivity of drugs traditionally used against this parasite, as reputed to be effective against other protozoan parasites, is described. The in vitro minimum lethal concentrations (MLC), time for drug efficacy, and parasite viability after removal of residual drugs were determined. Three of the 10 tested drugs, fenbendazole, albendazole, and sulfadiazine, were found to be ineffective against H. meleagridis. Nifursol, the only compound still authorized as a feed additive in Europe, is an inhibiting agent but is not lethal in vitro. Roxarsone, an arsenical derivate similar to nitarsone (the only authorized drug in United States), is effective at high concentration (200 microg/mL) after a long exposure (48 h). The lethal activity of dimetridazole, metronidazole, ronidazole, tinidazole, and furazolidone in vitro was demonstrated. Dimetridazole (MLC = 25 microg/mL after 6 h of exposure), metronidazole (MLC = 50 microg/mL after 24 h), and furazolidone (MLC = 50 microg/mL after 24 h) are rapidly effective at low concentrations. These results confirm the effectiveness of dimetridazole, a drug that has been used in the treatment and prevention of blackhead. In May 2002 this compound was removed as feed additive in Europe.

Antigiardial drugs.

Giardia intestinalis is a world-wide cause of intestinal infection. Treatment of this debilitating disease is usually accomplished using one of several drugs. Metronidazole is the treatment of choice, but benzimidazoles are now being used more frequently. Other treatments include quinacrine, paromomycin and furazolidone. Even though these drugs are all used to treat the same disease, their modes of action differ in all cases. However, resistance is increasing and new alternatives are being sought. New wave antigiardials all appear to have their roots in natural herbal remedies. This mini-review looks at the current treatments available, their efficacy, side effects and different modes of action and addresses a possible way forward using natural products.

Cellular and molecular remodeling in a heart failure model treated with the beta-blocker carteolol.

Broad-breasted white turkey poults fed furazolidone developed dilated cardiomyopathy (DCM) characterized by ventricular dilatation, decreased ejection fraction, beta1-receptor density, sarcoplasmic reticulum (SR) Ca2+-ATPase, myofibrillar ATPase activity, and reduced metabolism markers. We investigated the effects of carteolol, a beta-adrenergic blocking agent, by administrating two different dosages (0.01 and 10.0 mg/kg) twice a day for 4 wk to control and DCM turkey poults. At completion of the study there was 59% mortality in the nontreated DCM group, 55% mortality in the group treated with the low dose of carteolol, and 22% mortality in the group treated with the high dose of carteolol. Both treated groups showed a significant decrease in left ventricle size and significant restoration of ejection fraction and left ventricular peak systolic pressure. Carteolol treatment increased beta-adrenergic receptor density, and the high carteolol dose restored SR Ca2+-ATPase and myofibrillar ATPase activities, along with creatine kinase, lactate dehydrogenase, aspartate transaminase, and ATP synthase activities, to normal. These results show that beta-blockade with carteolol improves survival, reverses contractile abnormalities, and induces cellular remodeling in this model of heart failure.

[Furazolidone resistance of E. coli from chicken intestines after prophylactic treatment with bioptivet GB in animal feed]. / Furazolidonresistenz von E. coli aus dem Geflügeldarm nach prophylaktischer Gabe des Fütterungsarzneimittels bioptivet GB.

This study describes the influence of bioptivet GB on minimum inhibitory concentrations (MIC) for furazolidone of the intestinal E. coli flora of young broiler chickens after prophylactic treatment. From day 6 until day 15 one group of 50 birds received a diet containing 326 ppm furazolidone, another group of 75 birds served as non medicated control. Investigated E. coli had been isolated from cloacal swabs and from caecal contents. MIC of 1581 E. coli strains were determined by agar dilution test. MIC of furazolidone for the investigated strains ranged from 2 micrograms/ml to 64 micrograms/ml. For classification as "resistant" or "susceptible" limits of 16 micrograms/ml and 8 micrograms/ml respectively were used. Strains obtained from undosed birds mainly had MIC values of 4 micrograms/ml or 8 micrograms/ml, i.e. two or three times higher than MIC of E. coli ATCC 25 922, MIC values of 16 micrograms/ml or more were recorded only among isolates obtained from chickens which had received the drug. Administration of bioptivet GB resulted in a statistically significant increase in the average MIC. Statistically higher average MIC were recorded among isolates from cloacal swabs only during application of the drug. For strains from caecal contents, the effect became obvious only at the end of the experiment.

Effects of furazolidone or nitrofurazone on the concentrations of hypothalamic amines and plasma luteinizing hormone (LH) and prolactin (PRL), levels in young turkeys.

1. Furazolidone (30 mg/kg) given orally for 14 days produced significant increases in the hypothalamic concentrations of noradrenaline, adrenaline and dopa. The amine concentrations returned to normal one week after withdrawal of the drug. 2. Nitrofurazone (30 mg/kg) given orally for 14 days did not affect significantly the hypothalamic amine concentrations. 3. Nitrofurazone (30 mg/kg, 14 days) increased significantly the plasma concentration of prolactin (PRL) and decreased luteinizing hormone (LH). The concentrations of the two hormones returned to normal one week after the drug withdrawal. Furazolidone (7.5, 15 or 30 mg/kg) did not influence the concentrations of either hormone. 4. Furazolidone (30 mg/kg, 14 days) did not influence the release of LH or PRL after treatment of LHRH or TRH, respectively. Nitrofurazone at the same dose, however, reduced the increases in LH and PRL concentrations induced by LHRH and TRH, respectively.

Antibiotic resistance in Escherichia coli causing generalized infections in chickens in the UK in 1982: the relationship between the results of in vitro and in vivo furazolidone sensitivity tests.

Compared with a similar survey conducted ten years previously, a survey conducted in 1982, eleven years after the implementation of legislation forbidding the routine use of feeds containing 'therapeutic' antibiotics, revealed a decreased incidence of resistance to tetracyclines, furazolidone and sulphonamides in Escherichia coli strains causing generalized infections in chickens in the UK; the decrease was particularly marked in the case of tetracycline resistance, 17.9% of strains in 1982 being resistant to this antibiotic compared with 31.2% in 1972. Giving furazolidone to groups of chickens inoculated intramuscularly with O2:K1 strains of E. coli of differing degrees of furazolidone sensitivity indicated that great care is required in the performance and interpretation of laboratory tests for sensitivity to this antibiotic. Infections caused by strains that required as little as 1.25 micrograms/ml of furazolidone to inhibit their multiplication in laboratory tests responded poorly to furazolidone treatment; those that were inhibited by less responded well, better than to treatment with tetracycline, chloramphenicol, ampicillin or trimethoprim.

Mutagenicity screening of feed additives in the microbial system.

18 feed additives were tested for DNA-modifying effects by the repair test named "rec-assay" with Bacillus subtillis H17 (rec+) and M45 (rec-), and for mutagenicity with Escherichia coli WP2 hcr and 5 Salmonella typhimurium tester strains with the use of a top-agar overlay method. Carbadox, furazolidone, panazon and zoalene were positive in both assays. The former 3 were mutagenic for TA100, TA98 and WP2 hcr, while zoalene was mutagenic for all strains. These 4 compounds did not require a metabolic activation for their mutagenic activities. Nicarbazin was weakly mutagenic for TA1538 and TA98 with and without S9 mix. Amprolium and caprylohydroxamic acid also showed very weak mutagenicities only for TA100 with S9 mix and for WP2 hcr with and without S9 mix, resp. The mutagenic activities of carbadox, furazolidone and panazon for TA100 were reduced only by the addition of S9 mix, but not by S9 fraction or blood, whereas that of zoalene was decreased by any of the 3 factors.

[The effect of antibiotic supplementation on antibiotic resistance, transferable antibiotic resistance, morbidity, and growth in calves (author's transl)]. / Effekten av foderantibiotika på antibiotikaresistens, överförbar antibiotikaresistens, morbiditet och tillväxt hos mellankalv

112 calves, divided into four groups, were given milk substitutes containing tetracycline (high-dosage feed), zinc bacitracin or Lactosat (control) and concentratesw with or without zinc bacitracin (Table I). We have investigated the incidence of antibiotic resistance and transferable antibiotic resistance in E. coli strains isolated from the faces of these calves and checked the growth and state of health in the four groups. Growth was also studies in a further ten feeding series comprising a total of 258 calves. Half this number received zinc bacitracin in milk substitute, the other half were fed milk substitute containing Lactosat, instead of antibiotics (Fig. 8). Tetracycline led to a quick increase of antibiotic-resistant straing (Fig. 4--6). This increase is significant in comparison with the other groups. Significant increases of resistance were also noted to ampicillin and chloramphenicol (Fig. 7), althoug these drugs were not used. A significant increase of the transferable resistance was also observed in the group of calves given tetracycline (Fig. 7) and to 65% at about 31/2 months after the end to 38% within 12 days (Fig. 7) and to 65% at about 31/2 months after the end of tetracycline feeding (Fig. 7). A marked increase of en-bloc transfer was also noted after completion of tetracycline feeding (Fig. 2). Up to slaughter, at the age of 6 months, no better growth was obtained with zinc-bacitracin supplement than with milk substitute without antibiotics but containing Lactosat. During the milking period the results varied between the different feeding series. In some series the mean growth in the zinc-bacitracin group was better than, in some no different from, and in other s poorer than that in the Lactosat group (TableII, Fig. 8). The only demonstrable positive effect of tetracycline supplement was a tendency twwards better health during the period of administration of the drug (Table II...