The Promising Effects of Erdosteine and Vitamin B in the Liver Ischemia/Reperfusion Model in Anesthetized Rats.

Background and Objectives: Erdosteine (Erd) is an antioxidant and anti-inflammatory drug. Vitamin B has been reported to exert anti-inflammatory and antioxidant effects. In this study, we investigated the effect of erdosteine and vitamin B complex on a liver ischemia/reperfusion (I/R) model. Materials and Methods: Thirty-two Wistar Albino male rats weighing 350-400 g were used. The animals were randomly selected and divided into four groups. The groups are as follows: first group (Sham), second group (I/R), third group (I/R + vit B), and fourth group (I/R + vit B + Erd). Rats were subjected to 45 min of hepatic ischemia, followed by a 45 min reperfusion period in the I/R and Vitamin B + Erd groups. An amount of 150 mg/kg/day of erdosteine was given orally for 2 days, and 0.05 mL/kg of i.p. vitamin B complex was given 30 min before the reperfusion. Serum biochemical parameters were measured. Serum Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) were measured, and the Oxidative Stress Index (OSI) was calculated. Hepatic tissue samples were taken for the evaluation of histopathological features. Results: In terms of all histopathological parameters, there were significant differences in the I/R + vit B group and I/R + vit B + Erd group compared with the I/R group (p < 0.01). In terms of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), TNF-alpha, and IL-6 levels, there were significant differences between the I/R group and treatment groups (p < 0.01). The lowest TOS and OSI levels were obtained in the treatment groups, and these groups had statistically significantly higher TAS levels compared with the sham and I/R groups (p < 0.01). Conclusions: As a preliminary experimental study, our study suggests that these agents may have potential diagnostic and therapeutic implications for both ischemic conditions and liver-related diseases. These results suggest that the combination of vit B + Erd may be used to protect against the devastating effects of I/R injury. Our study needs to be confirmed by clinical studies with large participation.

[Acute bronchitis - modern possibilities of mucactive therapy].

AIM: Analysis of the clinical effectiveness and safety of erdosteine use in comparison with standard (real practice) mucoactive therapy in patients with acute bronchitis (АВ) in adults. MATERIALS AND METHODS: The observational program included 100 adult patients with АВ, 50 of them (group 1) received erdosteine, the group 2 also included 50 patients who received acetylcysteine, bromhexine and other mucolytics (real clinical practice). The following were assessed: cough severity, average time for resolution of night and daytime cough, satisfaction with treatment, NO concentration in exhaled air, levels of C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS: The average duration of relief of severe daytime cough requiring continued therapy was: in group 1 - 3.7±0.46 days, night cough - 1.14±0.94 days. In the second group, daytime cough was relieved in 3.8±0.4 days, night cough - 1.08±0.7 days. The duration of mucoactive therapy in group 1 was 5.32±0.82 days, in group 2 this figure was 8.5±1.4 days (p<0.05). The number of АВ patients with a significant reduction in the severity of productive cough (1 point on cough severity scale) on the 6th day from the beginning of treatment in group 1 (erdosteine) amounted to 32 (64%), in group 2 - 27 (54%). Satisfaction with the treatment was higher in the group receiving erdosteine: according to the indicators "very satisfied" and "extremely satisfied" the patients of the group 1 - 42 - were the leaders in comparison with the group 2, where these positions were marked by 28 patients. The level of CRP in patients with АВ in group 1 was 24.7±21.24 mg/l, in group 2 - 16.37±16.5 mg/l, which indicates the viral etiology of the process and no need in the prescription of antimicrobial drugs. For the first time in Russian practice, the following were determined: the level of IL-6, which in the group 1 was 10.3±6.7 pc/ml; in the group 2 - 10.03±3.94 pc/ml; the level of exhaled NO in group 1 was 16.5±5.1 ppb, in group 2 - 14.9±4.6 ppb (the norm is up to 25 ppb). These indicators, against the background of mucoactive therapy, decreased to normal values by 6th day. CONCLUSION: The findings expand our understanding of АВ in adults. New results have been obtained on the role of CRP, IL-6 and NO in exhaled air during АВ. The use of erdosteine was accompanied by a significant mucoactive effect in the form of a pronounced regression of cough in patients with АВ compared to the comparison group in shorter term.

The Effect of Maintenance Treatment with Erdosteine on Exacerbation Treatment and Health Status in Patients with COPD: A Post-Hoc Analysis of the RESTORE Dataset.

Purpose: To explore the effect of erdosteine on COPD exacerbations, health-related quality of life (HRQoL), and subjectively assessed COPD severity. Patients and methods: This post-hoc analysis of the RESTORE study included participants with COPD and spirometrically moderate (GOLD 2; post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted; n = 254), or severe airflow limitation (GOLD 3; post-bronchodilator FEV1 30‒49% predicted; n = 191) who received erdosteine 300 mg twice daily or placebo added to usual maintenance therapy for 12 months. Antibiotic and oral corticosteroid use was determined together with patient-reported HRQoL (St George's Respiratory Questionnaire, SGRQ). Patient and physician subjective COPD severity scores (scale 0‒4) were rated at baseline, 6 and 12 months. Data were analyzed using descriptive statistics for exacerbation severity, COPD severity, and treatment group. Comparisons between treatment groups used Student's t-tests or ANCOVA as appropriate. Results: Among GOLD 2 patients, 43 of 126 erdosteine-treated patients exacerbated (7 moderate-to-severe exacerbations), compared to 62 of 128 placebo-treated patients (14 moderate-to-severe exacerbations). Among those with moderate-to-severe exacerbations, erdosteine-treated patients had a shorter mean duration of corticosteroid treatment (11.4 days vs 13.3 days for placebo, P = 0.043), and fewer patients required antibiotic treatment with/without oral corticosteroids (71.4% vs 85.8% for placebo, P < 0.001). Erdosteine-treated GOLD 2 patients who exacerbated showed significant improvements from baseline in SGRQ total scores and subjective disease severity scores (patient- and physician-rated), compared with placebo-treated patients regardless of exacerbation severity. Among GOLD 3 patients, there were no significant differences between treatment groups on any of these measures. Conclusion: Adding erdosteine to the usual maintenance therapy of COPD patients with moderate airflow limitation reduced the number of exacerbations, the duration of treatment with corticosteroids and the episodes requiring treatment with antibiotics. Additionally, treatment with erdosteine improved HRQoL and patient-reported disease severity.

Reactive Sulfur Compounds in the Fight against COVID-19.

The SARS-CoV-2 coronavirus pandemic outbreak in 2019 resulted in the need to search for an effective and safe strategy for treating infected patients, relieving symptoms, and preventing severe disease. SARS-CoV-2 is an RNA virus that can cause acute respiratory failure and thrombosis, as well as impair circulatory system function. Permanent damage to the heart muscle or other cardiovascular disorders may occur during or after the infection. The severe course of the disease is associated with the release of large amounts of pro-inflammatory cytokines. Due to their documented anti-inflammatory, antioxidant, and antiviral effects, reactive sulfur compounds, including hydrogen sulfide (H2S), lipoic acid (LA), N-acetylcysteine (NAC), glutathione (GSH), and some other lesser-known sulfur compounds, have attracted the interest of scientists for the treatment and prevention of the adverse effects of diseases caused by SARS-CoV-2. This article reviews current knowledge about various endogenous or exogenous reactive sulfur compounds and discusses the possibility, or in some cases the results, of their use in the treatment or prophylaxis of COVID-19.

Erdosteine reduces cytotoxicity induced by alpha- and beta-amanitin, but not gamma-amanitin, in CA3 hepatocyte cultures.

Amanitin poisoning still has no particular, effective antidote. Erdosteine has been shown to protect numerous tissues, particularly those in the liver. This study investigates the potential therapeutic effects of erdosteine on alpha-, beta- and gamma-amanitin-induced hepatotoxicity in in vitro models. Three hours after administering amatoxins at various concentrations (1-50 µg/mL) to the cells of the C3A human hepatocyte cell line, erdosteine was administered in different concentrations (i.e., 1, 10, 50, 100 and 250 µg/mL). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was selected to determine cell viability. When concentrations of 1, 10, 50, 100 and 250 µg/mL of erdosteine were applied to cell lines, the following cell viability rates were obtained: 106%,99%,93%,86% and 86%, respectively, at a 10 µg/mL alpha-amanitin-induced toxicity; 43%,41%,41%,37% and 35%, respectively, at a 25 µg/mL alpha-amanitin-induced toxicity; 44%,42%,41%,39% and 41%, respectively, at a 50 µg/mL alpha-amanitin-induced toxicity; 136%,142%,143%,137% and 120%, respectively, at a 10 µg/mL beta-amanitin-induced toxicity; 113%,107%,107%,106% and 86%, respectively, at a 25 µg/mL beta-amanitin-induced toxicity; 78%,77%,77%,74% and 70%, respectively, at a 10 µg/mL gamma-amanitin-induced toxicity; and 39%,40%,39%,35% and 31%, respectively, at a 25 µg/mL gamma-amanitin-induced toxicity. This study was the first to evaluate the in vitro efficacy of erdosteine in cytotoxicity induced by alpha-, beta- and gamma-amanitin. Non-high (low and medium) doses of erdosteine are capable of nearly entirely preventing toxicity at mild hepatotoxic concentrations caused by amatoxin and partially preventing toxicity at moderate and severe concentrations. The beneficial effects of erdosteine, especially on the toxicity of alpha- and beta-amanitin, are promising.

Erdosteine enhances antibiotic activity against bacteria within biofilm.

Bacterial biofilms form on inert and living surfaces and display high levels of resistance to antibiotics, making it difficult to eradicate biofilm-related infections. Erdosteine, a thiol-based drug used in the treatment of acute and chronic respiratory diseases, has multiple pharmacodynamic properties (mucolytic, anti-inflammatory, antioxidant), suggesting that it may have potential in controlling biofilm-related infections. This in vitro study aimed to evaluate the effects of erdosteine in combination with different antibiotics against methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) biofilms. Biofilm production/mass and bacterial viability were measured using crystal violet absorbance and resorufin resonance, respectively, in young (6 h) and mature (24 h) biofilms incubated with antibiotics [at concentrations from 0 to 200 times the minimum inhibitory concentration (MIC)] for 24 h in the absence or presence of erdosteine (2, 5 and 10 mg/L). In 6-h MRSA biofilms, vancomycin and linezolid displayed concentration-dependent reductions in biofilm mass and viability, which was enhanced in the presence of increasing concentrations of erdosteine. Similar results were seen for amoxicillin/clavulanate and levofloxacin against 6-h MSSA biofilms. Antibiotics alone had reduced efficacy against 24-h biofilms, while the effect of the erdosteine-antibiotic combination was significantly greater against 24-h biofilms (MRSA and MSSA). These results suggest that erdosteine enhances the activity of the antibiotic by facilitating its penetration into biofilms and by disrupting the extracellular polymeric substance matrix, which should be confirmed with further studies. The potential clinical value of erdosteine in treating biofilm-related infections warrants further investigation.

The influence of erdosteine administration on lead-induced oxidative stress in rat muscle.

Lead-exposure is known to disrupt the redox balance of tissues leading to oxidative stress. Due to the fact that a mucolytic drug, erdosteine, exerts also antioxidant properties, we decided to perform a pilot study on rats to evaluate its therapeutic potency in lead poisoning. Male Wistar rats were divided randomly into the following seven groups having 10 animals in each. Group I served as the control group. During 8-week period, rats in groups II-IV, except standard alimentation, received: erdosteine in a dose 350 mg/kg (collateral control group), 1200 ppm of lead acetate in drinking water and placebo, as well as the same doses of lead and erdosteine, respectively. Rats in group V-VII received 1200 ppm of lead acetate in drinking water for the initial 6-week period and then administered: placebo, erdosteine and EDTA for 2 weeks, respectively. The levels of malondialdehyde (MDA) were significantly higher in groups III and V compared to the control group. The activities of catalase (CAT) were significantly higher in groups IV, V, and VI compared to the control group. The activities of glutathione-S-transferase (GST) were significantly lower in group II and significantly higher in groups VI and VII compared to the control group, while the activities of glutathione reductase (GR) were significantly lower in group III and significantly higher in group VI. Erdosteine has an effect of protection against lead-induced oxidative stress which is not worse than that of EDTA.

The protective effects of erdosteine on subacute diazinon-induced oxidative stress and inflammation in rats.

In today's world, pesticides are commonly used to control pests and in advanced agriculture. As an organophosphorus insecticide (OPI), diazinon (DZN) is a commonly used substance. However, the widespread usage of DZN increases the probability of incidence of toxication. This toxication has been reported to be shaped not through cholinergic syndromes that are experienced as a result of acetylcholinesterase inhibition, which is the primary effect of these cases. It is rather shaped by the altering of the facilitation of oxidative stress and inflammatory response. In this study, the protective effect of administering erdosteine (ERDOS) subacute DZN exposure was investigated. A total of 24 male Wistar albino rats were separated into 4 groups (with 6 rats in each group), namely, the control, DZN (15 mg/kg/day), ERDOS (10 mg/kg/day), and DZN + ERDOS (15 mg/kg/day DZN + 10 mg/kg/day ERDOS) groups. These medications were given through oral gavage for 28 days. With the whole blood, plasma, and serum samples taken from the rats, oxidant-antioxidant parameters and cytokine levels were measured. The MDA and NOx levels and SOD and CAT enzyme activities of the DZN group were higher than those of the control group, while the GSH levels and TAC and GPx activities of the DZN group were lower than those of the control group (p < 0.05). It was also found that cytokine (IL-1ß, IL-10, and TNF-α) levels in the DZN group were higher than those in the control group (p < 0.05). On the other hand, the ERDOS implementations were detected to ameliorate the harmful effects of DZN on the oxidant-antioxidant parameters and cytokine levels (p < 0.05). Conclusively, besides the known mucolytic efficacy of ERDOS, it may also be stated to display free radical scavenger, antioxidant, and anti-inflammatory characteristics to inhibit some proinflammatory cytokines that are specifically involved in oxidative stress. Additionally, the ameliorating property of ERDOS can be benefited from in possible DZN-induced toxication cases.

Understanding the Role of the Antioxidant Drug Erdosteine and Its Active Metabolite on Staphylococcus aureus Methicillin Resistant Biofilm Formation.

Increasing numbers of researches have suggested that some drugs with reactive oxygen species (ROS)-mediated mechanisms of action modulate biofilm formation of some pathogenic strains. However, the full contribution of ROS to biofilm development is still an open question. In this paper, the correlations between the antioxidant drug Erdosteine (Er) and its active Metabolite I (Met I), ROS and biofilm development of two strains of methicillin resistant Staphylococcus aureus are presented. Experiments revealed that Er and Met I at 2 and 5 mg/L increased up to three orders of magnitude the number of biofilm-dwelling cells, while the content of ROS within the biofilms was reduced above the 87%, with a major effect of Met I in comparison to Er. Comparative proteomics showed that, 5 mg/L Met I modified the expression of 30% and 65% of total proteins in the two strains respectively. Some proteins involved in cell replication were upregulated, and a nitric oxide-based mechanism is assumed to modulate the biofilm development by changing quorum sensitive pathways. Additionally, several proteins involved in virulence were downregulated in the presence of Met I, suggesting that treated cells, despite being greater in number, might have lost part of their virulence.

Use of Thiols in the Treatment of COVID-19: Current Evidence.

There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients.

Fixed drug eruption and anaphylaxis induced concurrently by erdosteine: a case report.

BACKGROUND: Erdosteine is used as a mucolytic agent and has a low incidence of adverse drug reactions, most of which are gastrointestinal and mild. Moreover, drug antigens rarely induce multiple simultaneous immunologic reactions. Only one previous case report has demonstrated hypersensitivity reaction induced by erdosteine. Here, we report a case of fixed drug eruption and anaphylaxis, which were concurrently induced by erdosteine. The association between the symptoms and erdosteine was proven by a drug provocation test. CASE PRESENTATION: A 35-year-old woman presented with recurrent angioedema and pruritic rash on the hands, which developed within 2 h following the administration of drugs, including erdosteine, for acute upper respiratory infection. Her rash was characterized by well-defined erythematous plaques, which recurred at the same site following the administration of the medications. She also experienced angioedema of the lips. Fixed drug eruption was considered after excluding other possible causes for the presented skin lesions. A drug provocation test confirmed that fixed drug eruption on both hands had occurred after administration of erdosteine, suggesting that erdosteine was the cause of the allergic reaction. However, she also experienced angioedema, isolated wheal, and laryngeal edema; thus, IgE-mediated type I hypersensitivity could also be concurrently occurring with the fixed drug eruption. CONCLUSIONS: We report about a patient who was diagnosed with two different hypersensitivity reactions concurrently induced by erdosteine. We also demonstrate that patients may exhibit multiple simultaneous symptoms that usually arise from overlapping of different hypersensitivity mechanisms. Physicians should be aware of the possibility that some patients who are allergic to certain drugs could exhibit several symptoms caused by different mechanisms of hypersensitivity reactions simultaneously.

Investigation of Cytotoxic Effects of Oxymetazoline on Lungs in a Rat Model of Rhinitis Medicamentosa.

BACKGROUND: Rhinitis medicamentosa, also known as 'rebound congestion,' is inflammation of the nasal mucosa caused by the overuse of topical nasal decongestants. Although local decongestants resolve the initial nasal obstruction, the overuse causes rebound obstruction. However, how the overuse of the decongestant causes rhinitis medicamentosa is not known. OBJECTIVES: Here, we show the intracellular effects of oxymetazoline, commonly used a local decongestant, on the cell death pathways. We also investigated the antioxidative effects of erdosteine suspension (175 mg/5mL), an antioxidative agent. METHODS: Thirty Wistar-albino rats were used to form the rhinitis medicamentosa model. After rhinitis medicamentosa was clinically detected, we removed the whole lungs of animals to perform the molecular analyses of cell death pathways. RESULTS: We found a statistically significant decrease in the expression levels of Atg5 (p=0.021), Atg7 (p=0.013) and Ulk1 (p=0.036) in the oxymetazoline group compared to the control group (p<0.05); however, Caspase 3 expression level was recorded to be significantly increased in the oxymetazoline group, and the expression level of Beclin1 recorded to be substantially increased in the erdosteine group (p=0.001). CONCLUSION: Based on these grounds, we suggest that vasoconstriction in capillary vessels caused by oxymetazoline could lead to a decrease in the blood supply, which triggers autophagy to ensure cellular homeostasis.

Erdosteine salvages cardiac necrosis: Novel effect through modulation of MAPK and Nrf-2/HO-1 pathway.

Isoproterenol (ISO) induced oxidative stress and inflammation is involved in the pathogenesis of myocardial necrosis. To optimize the effect of erdosteine against myocardial necrosis, male albino Wistar rats were divided into eight groups (n = 6), that is, normal, ISO-control, erdosteine pretreatment with ISO. Rats were administered erdosteine orally for 28 days. Two doses of ISO (85 mg/kg), s.c. were given to ISO-C and erdosteine treatment groups on the 27th and 28th day. On the 29th day, hemodynamic parameters were recorded and the heart was excised for further parameters. In ISO-C rats, significantly increased levels of inflammatory markers, pro-oxidants, and structural damage were observed as compared with normal group. Furthermore, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed an increased expression of apoptotic proteins. Erdosteine at 80 mg/kg reversed the deleterious effects of ISO and normalized myocardium. Erdosteine showed anti-inflammatory, antiapoptotic, and antioxidant activities through inhibition of MAPK and Nrf-2/HO-1 pathways. To conclude, erdosteine was found protective in ISO-induced myocardial necrosis through MAPK and Nrf-2/HO-1 pathway.

Use of mucolytics in COPD: A Delphi consensus study.

BACKGROUND: International guidelines recommend mucolytic agents as add-on therapy in selected patients with COPD because they may reduce exacerbations and improve health status. As the evidence varies among mucolytic agents, we used the Delphi method to assess consensus amongst an international panel of COPD experts on mucolytics use in COPD. METHODS: 53 COPD experts from 12 countries were asked to complete an online questionnaire and rate their agreement with 15 statements using a 5-point scale. The mucolytic agents evaluated were carbocysteine, erdosteine and N-acetylcysteine (NAC). Data were collected anonymously and consensus presented using descriptive statistics. RESULTS: The 47 respondents reached consensus on the statements. They agreed that regular treatment with mucolytic agents effectively reduces the frequency of exacerbations, reduces the duration of mild-to-moderate exacerbations, and can increase the time to first exacerbation and symptom-free time in COPD patients. Consensus was consistently highest for erdosteine. The experts agreed that all three mucolytics display antioxidant and anti-inflammatory activity. Erdosteine and NAC were thought to improve the efficacy of some classes of antibacterial drugs. All three mucolytics were considered effective for the short-term treatment of symptoms of acute exacerbations when added to other drugs. The panel agreed that approved doses of mucolytic agents have favorable side-effect profiles and can be recommended for regular use in patients with a bronchitic phenotype. CONCLUSIONS: Consensus findings support the wider use of mucolytic agents as add-on therapy for COPD. However, the differences in pharmacological actions and clinical effectiveness must be considered when deciding which mucolytic to use.

Changes in quality of life and dyspnoea after hospitalization in COVID-19 patients discharged at home.

BACKGROUND: To date, the effects of COVID-19 pneumonia on health-related quality of life (HRQoL) and dyspnoea are unknown. METHODS: In a real-life observational study, 20 patients with COVID-19-related pneumonia received usual care plus erdosteine (300 mg twice daily) for 15 days after hospital discharge following local standard operating procedures. At discharge (T0) and on Day 15 (T1), participants completed the St George's Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale of dyspnoea during daily activity, the BORG scale for dyspnoea during exertion, and Visual Analogue Scale (VAS) for dyspnoea at rest. Paired t-tests compared scores at T0 and T1. RESULTS: The mean (SD) SGRQ total score decreased from 25.5 (15.5) at T0 to 16.9 (13.2) at T1 (p<0.01); 65% of patients achieved a clinically important change of ≥4 points. SGRQ domain scores (symptoms, activity, and impact) were also significantly reduced (all p<0.01). The mean (SD) VAS score decreased from 1.6 (1.7) to 1.4 (2.5); p<0.01. The mean mMRC score decreased significantly (p=0.031) and 30% of patients achieved a clinically important change of ≥1 point. The mean (SD) Borg score increased from 12.8 (4.2) to 14.3 (2.4); p<0.01. CONCLUSION: The present proof of concept study is the first to report HRQoL in patients with COVID-19. During 15 days after hospital discharge, patients reported significant improvements in HRQoL and dyspnoea at rest and during daily activities.

Simultaneous determination of cefixime and erdosteine in combined dosage form using validated spectrophotometric methods.

Four accurate and precise spectrophotometric methods were developed and validated for the simultaneous determination of a binary mixture of cefixime (CEF) and erdosteine (ERD) without previous separation. Method A was first derivative ratio spectrophotometric method (1DD) where the amplitudes at 310 and 315 nm and the amplitude at 248 nm were chosen to simultaneously estimate CEF and ERD, respectively. Method B depends on ratio difference spectrophotometry (RDSM), in which the difference in amplitudes at 325 and 326 nm on the ratio spectrum of the mixture was directly proportional to the concentration of CEF; independent of the interfering component. Similarly, the amplitude difference between 236 and 249 nm on the ratio spectrum was used for the determination of ERD. Method C was based on simultaneous determination of CEF and ERD using classical least squares (CLS) and partial least squares (PLS) chemometric techniques. Method D was the mean centering of ratio spectra (MCR) at 313 and 237 nm for the determination of CEF and ERD respectively. The developed methods were successfully employed to the determination of CEF and ERD in laboratory prepared mixtures and dosage form showing satisfactory recoveries. Methods validation was performed according to the International Conference on Harmonization (ICH) guidelines. The obtained results were statistically compared to those of the reference method, revealing no significant difference with respect to precision and accuracy. Precision and cost effectiveness of the developed methods permit their application in quality control laboratories for the determination of the binary mixture.

Ultrafast liquid chromatographic analysis of erdosteine in human plasma based on fluorimetric detection and precolumn derivatization with 4-bromomethyl-7-methoxycoumarin: Application to pharmacokinetic studies.

In this study, a new analytical method for erdosteine (ERD) in plasma based on high-performance liquid chromatography and a fluorimetric detector, is presented. Precolumn derivatization of ERD with 4-bromomethyl-7-methoxy coumarin (BrMmC) and dibenzo-18-crown-6-ether as a reaction catalyst led to the production of a fluorescent compound. ERD was monitored by fluorescence with an excitation wavelength λext. = 325 nm and emission wavelength λem. = 390 nm. Optimum reaction conditions were carefully studied and optimized. A chromatographic procedure was performed using a C18 column of 150 × 4.6 mm and 3 µm particle size and a mobile phase consisting of methanol:acetonitrile:water (30:30:40, v/v/v) under a flow rate of 0.5 ml min-1 . A calibration plot was established covering analyte concentration range 0.2-3.0 µg ml-1 ; the detection limit was 0.015 µg ml-1 and quantification limit was 0.05 µg ml-1 . Mean recovery was 87.33% and relative standard deviation was calculated to be less than 4.4%. The developed method was successfully used to determine pharmacokinetic preparations of ERD subsequent to administration of a 900 mg dose capsule to a healthy 40-year-old woman volunteer.

Protective effects of Erdosteine on interleukin-1ß-stimulated inflammation via inhibiting the activation of MAPK, NF-κB, and Wnt/ß-catenin signaling pathways in rat osteoarthritis.

Osteoarthritis (OA), a degenerative arthropathy, is featured with progressive degradation of cartilage and a chondrocyte inflammatory response. Erdosteine (ER) showed the anti-oxidant properties and various anti-inflammatory effects in various diseases. However, whether it protects against OA remains unknown. In this study, we explore the potential therapeutic properties of ER on IL-1ß-stimulated rat chondrocytes and its underlying mechanism in vitro and vivo. Cell viability, pro-inflammatory cytokines and the degradation of ECM biomarkers were tested to determine the effects of ER at 10, 20, and 40 µM doses on IL-1ß-induced rat chondrocytes for 24 h in virto. In vivo, intra-articular injections of 50 µl of 100 mg/ml ER twice a week for 8 weeks. The results showed ER significantly suppressed the expressions of IL-1ß-induced the production of inflammatory factors in a dose-dependent pattern (4.30-fold decrease in COX-2, p < 0.05; 4.77-fold decrease in iNOS, p < 0.05 at 40 µM in protein levels). Moreover, ER could attenuate the degradation of ECM in IL-1ß-induced rat chondrocytes by repressing the expression of OA-related factors (2.40-fold decrease in ADAMTS-5, p < 0.05; 3.12-fold decrease in MMP1, p < 0.05; 3.97-fold decrease in MMP3, p < 0.05; and 2.62-fold decrease in MMP-13, p < 0.05 at 40 µM in protein levels). Furthermore, our study revealed that ER could inhibit the activations of IL-1ß-induced MAPK and Wnt/ß-catenin. Besides, ER could suppress the process of IL-1ß-induced P65 from the cytoplasm into the nucleus. In vivo, ER delaied the osteoarthritis progression in rat OA models. Collectively, ER might become a new therapeutic agent for OA.

Effect of Erdosteine on COPD Exacerbations in COPD Patients with Moderate Airflow Limitation.

Background: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine - a muco-active antioxidant that modulates bacterial adhesiveness - reduced the rate and duration of exacerbations in moderate and severe COPD with a history of exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear. Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted) examined exacerbation rate and duration, time to first exacerbation, and exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann-Whitney U-tests, or log rank tests. Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an exacerbation. There was a 47% reduction in the mean exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild exacerbation rate (0.23 vs 0.53 mild exacerbations per-patient per-year, P=0.001). Mean duration of exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe exacerbations. Mean time to first exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P<0.001) and the mean exacerbation-free time was increased by 51 days (279 days for erdosteine vs 228 days for placebo; P<0.001). Conclusion: These results indicate that adding erdosteine to usual COPD maintenance therapy reduces the number of mild, and duration of all, exacerbations in patients with moderate COPD and a history of exacerbations.

Efficacy and safety profile of mucolytic/antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-acetylcysteine.

BACKGROUND: To date there are no head-to-head studies comparing different mucolytic/antioxidant agents. Considering the inconsistent evidence resulting from the pivotal studies on mucolytic/antioxidant agents tested in chronic obstructive pulmonary disease (COPD), and the recent publication of Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD (RESTORE) study, we have performed a meta-analysis to compare the efficacy and safety of erdosteine 600 mg/day, carbocysteine 1500 mg/day, and N-acetylcysteine (NAC) 1200 mg/day in COPD. METHODS: A pairwise and network meta-analyses were performed to assess the efficacy of erdosteine, carbocysteine, and NAC on acute exacerbation of COPD (AECOPD), duration of AECOPD, and hospitalization. The frequency of adverse events (AEs) was also investigated. RESULTS: Data obtained from 2753 COPD patients were extracted from 7 RCTs published between 2004 and 2017. In the pairwise meta-analysis mucolytic/antioxidant agents significantly reduced the risk of AECOPD (RR 0.74 95%CI 0.68-0.80). The network meta-analysis provided the following rank of effectiveness: erdosteine>carbocysteine>NAC. Only erdosteine reduced the risk of experiencing at least one AECOPD (P < 0.01) and the risk of hospitalization due to AECOPD (P < 0.05). Erdosteine and NAC both significantly reduced the duration of AECOPD (P < 0.01). The AEs induced by erdosteine, carbocysteine, and NAC were mild in severity and generally well tolerated. The quality of evidence of this quantitative synthesis is moderate. CONCLUSIONS: The overall efficacy/safety profile of erdosteine is superior to that of both carbocysteine and NAC. Future head-to-head studies performed on the same COPD populations are needed to definitely confirm the results of this meta-analysis. TRIAL REGISTRATION: CRD42016053762 .