Effect of nebulised BromAc® on rheology of artificial sputum: relevance to muco-obstructive respiratory diseases including COVID-19

Respiratory diseases such as cystic fibrosis, COPD, bronchiectasis asthma and COVID-19 are difficult to treat owing to viscous secretions in the airways that evade mucocilliary clearance. Since earlier studies have shown success with BromAc as mucolytic agent for treating a rare disease known as pseudomyxoma peritonei (PMP), we tested the formulation on two gelatinous airway representative sputa models, in order to determine whether similar efficacy exist. The sputum (1.5 ml) lodged in an endotracheal tube was treated to aerosolised N-acetylcysteine, bromelain, or their combination (BromAc) using a nebuliser with 6.0 ml of the agents in phosphate buffer saline, over 25 min. Controls received phosphate buffer saline. The dynamic viscosity was measured before and after treatment using a capillary tube method, whilst the sputum flow (ml/sec) was assessed using a 0.5 ml pipette. Finally, the sequestered agents (concentration) in the sputa after treatment were quantified using standard bromelain and N-acetylcysteine chromogenic assays. Results indicated that bromelain and N-acetylcysteine affected both the dynamic viscosities and pipette flow in the two sputa models, with changes in the former parameter having immense effect on the latter. BromAc showed a greater rheological effect on both the sputa models compared to individual agents. Further, correlation was found between the rheological effects and the concentration of agents in the sputa. Hence, this study indicates that BromAc may be used as a successful mucolytic for clearing airway congestion caused by thick mucinous immobile secretion, however further studies with patient sputum samples using aerosol BromAc is warranted.

Dissolution of Biofilm Secreted by Three Different Strains of Pseudomonas aeruginosa with Bromelain, N-Acetylcysteine, and Their Combinations

Bacterial infection of hernia mesh with the formation of biofilms presents a barrier to antibiotic treatment with subsequent surgical intervention and hospitalization. Hence, in the current study, we examined the effect of BromAc, a mucolytic agent, on the dissolution of biofilm formed by three different strains of Pseudomonas aeruginosa. Pseudomonas aeruginosa was carefully grown on hernia mesh and treated with various concentrations of bromelain, NAC, and their combinations at 37 °C over 4 h in vitro. Then, the biofilm dissolution activities of the agents were evaluated. Moreover, the combination index (CI) was analyzed to determine the synergy of the bromelain and NAC combination. The results indicated that biofilms were more susceptible to degradation by bromelain, whilst NAC showed growth enhancement in two of the strains. However, in combination (BromAc), the three strains were dramatically affected by the agents, with more than 80% debridement fir a suitable combination of bromelain and NAC that was also strain-specific. Hence, the current study shows that the biofilms formed by these three strains of Pseudomonas aeruginosa were adversely affected by a single treatment of BromAc, with more than 80% debridement, indicating that subsequent treatment may abolish the biofilm completely.

The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol

N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC’s effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allosteric modulator of mGluR5 (MTEP 0.1 mg/kg). Thereafter, the cFOS IR-cell expression was analyzed. Secondly, we explored the effect of 120 mg/kg of NAC on the neurochemical and behavioral activation induced by intra-VTA ethanol administration (150 nmol). Our results showed that the high NAC dose stimulated cFOS expression in the NAcc, and that this effect was suppressed in the presence of MTEP, thus suggesting the implication of mGluR5. Additionally, high doses could attenuate the ethanol-induced increase in cFOS-expression in the NAcc, probably due to a phenomenon based on the long-term depression of the MSNs. Additional experiments are required to corroborate our hypothesis.

N-acetylcysteine in substance use disorder: a lesson from preclinical and clinical research

Substance use disorder (SUD) is a chronic brain condition, with compulsive and uncontrollable drug-seeking that leads to long-lasting and harmful consequences. The factors contributing to the development of SUD, as well as its treatment settings, are not fully understood. Alterations in brain glutamate homeostasis in humans and animals implicate a key role of this neurotransmitter in SUD, while the modulation of glutamate transporters has been pointed as a new strategy to diminish the excitatory glutamatergic transmission observed after drugs of abuse. N-acetylcysteine (NAC), known as a safe mucolytic agent, is involved in the regulation of this system and may be taken into account as a novel pharmacotherapy for SUD. In this paper, we summarize the current knowledge on the ability of NAC to reduce drug-seeking behavior induced by psychostimulants, opioids, cannabinoids, nicotine, and alcohol in animals and humans. Preclinical studies showed a beneficial effect in animal models of SUD, while the clinical efficacy of NAC has not been fully established. In summary, NAC will be a small add-on to usual treatment and/or psychotherapy for SUD, however, further studies are required.

The Effect of N-acetylcysteine on Periodontitis: A mini-review of literature

Recently, there is strong evidence for the beneficial role of antioxidants in the treatment of periodontal diseases. A drug that is gaining more and more focus in new research is N-acetylcysteine, an antioxidant that contributes to the increase in glutathione (GSH), used as a mucolytic agent, however, recent studies have shown its significant role in decreasing levels of reactive oxygen species and in the bone resorption process in experimental periodontitis, therefore, this review sought to elucidate whether N-acetylcysteine is effective in the treatment of periodontitis and also in the involved mechanisms already mentioned in the literature. The present study is a mini-review, in which a search was performed on Google Scholar, PubMed and Web of Science and databases for the collection of studies published in the last 10 years (2009-2020). The mini-review included studies that addressed a direct or indirect link between the effects of N-acetylcysteine on periodontitis, studies published in recent years, and in vitro and in vivo studies (animal and / or human models). Seven articles were selected from the following databases: PubMed (03) and Google Scholar (04) were subsequently analyzed. As for the language and the journal, all were published in international Journals and in English. It was concluded that N-acetylcysteine was effective in bone resorption in experimental periodontitis, but further studies are suggested in order to elucidate all the mechanisms involved in the observed results.

Therapeutic possibilities of using an expectorant mucolytic agent with antioxidant properties in COVID-19 infection

Aim: to study the effect of N-acetylcysteine (NAC) on the dynamics of clinical and radiological changes in patients with COVID-19. Patients and Methods: the study included 111 patients with moderate and severe forms of COVID-19 pneumonia of the 2nd and 3rd stage according to computed tomography (CT). The median age was 49,25 years. Group 1 (n=55) received standard therapy: favipiravir, enoxaparin sodium according to the regimen, dexamethasone. Antibacterial therapy was conducted according to the indications. In addition to standard therapy, group 2 (n=56) was prescribed with NAC at a daily dose of 1200 mg, intravenously, divided into two doses. All patients underwent a comprehensive examination: WBC count, C-reactive protein (CRP), ferritin, fibrinogen, multispiral computed tomography and ultrasound of the chest organs were determined at admission, on the 7th-10th day of hospitalization, at discharge and 8 weeks after discharge. Results: initially, patients from both groups were comparable in terms of demographic indicators and condition severity. NAC prescription to the standard therapy showed a more positive trend both in terms of clinical symptoms and laboratory indicators. Respiratory rate, heart rate, and body temperature were statistically significantly lower in group 2 already on the 7th-10th day of follow-up. The levels of CRP, ferritin and fibrinogen also normalized faster in group 2. The periods of stay in the hospital were 15.3 days and 12.2 days, respectively, in patients from groups 1 and 2 (p<0,05). Conclusions: early prescription with N-acetylcysteine to patients with a moderate course of COVID-19 allowed statistically significantly reducing the volume of lung tissue damage, reducing the level of inflammatory markers (CRP, ferritin, fibrinogen) and contributed to an earlier discharge of the patient. KEYWORDS: COVID-19, N-acetylcysteine, pneumonia, acute respiratory distress syndrome, cytokine storm. FOR CITATION: Ignatova G.L., Antonov V.N., Sheklanova E.V. et al. Therapeutic possibilities of using an expectorant mucolytic agent with antioxidant properties in COVID-19 infection. Russian Medical Inquiry. 2021;5(7):473–478 (in Russ.). DOI: 10.32364/2587-6821-2021- 5-7-473-478.

N-Acetyl Cysteine Loaded-Niosomes as a Mucolytic Agent for Acute Diseases and Respiratory Disorders

Today, there is a strong interest in the development of new drug delivery systems using an inactive carrier for pharmaceutics. In recent years, several drug delivery systems have been introduced, such as liposomes, niosomes, transfersomes, and pharmacosomes. N-acetylcysteine, as a mucolytic agent, is prescribed for acute diseases and respiratory disorders, flu, colds, and bronchitis to reduce mucus viscosity. In this study, niosomes n-acetyl cysteine was prepared with a hydration thin film layer method. Niosome formation was confirmed by light and electron microscope images. To determine the average size of niosomes, zeta seizer instruments were used. To evaluate the effects of the medicine on niosomes membrane composition, Fourier transforms infrared spectra were obtained. The best formulation for this study was the Span 60 formula with a 70:30 ratio. An increase in drug concentration was accompanied by a similar rise in niosome capacity. The average size of niosome with different formulations was listed. The release time of the drug was obtained. The FTIR spectroscopy of pure drug, niosome, and niosome with drugs were taken. When the cholesterol was increased from 30% micromole to 50% micromole, niosome average size was increased. The molar ratio 70: 30 of span and cholesterol was more appropriate for the preparation of niosome drug delivery. By adding distill phosphate and acetyl Tri-methyl ammonium bromide to niosomeal compounds, the average vesicle size and the loading percentage were increased.