Acetylcysteine canon 600mg 3g 10 pcs. granules for the preparation of solution for oral administration
pharmachologic effect
Mucolytic agent is a derivative of the amino acid cysteine.
It has a mucolytic effect, increases the volume of sputum, facilitates its discharge due to a direct effect on the rheological properties of sputum. The action of acetylcysteine is associated with the ability of its sulfhydryl groups to break intra- and intermolecular disulfide bonds of acidic mucopolysaccharides of sputum, which leads to depolarization of mucoproteins and a decrease in sputum viscosity. Remains active in the presence of purulent sputum. Increases the secretion of less viscous sialomucins by goblet cells, reduces the adhesion of bacteria to the epithelial cells of the bronchial mucosa. Stimulates mucous cells of the bronchi, the secretion of which is lysed by fibrin. It has a similar effect on the secretions formed during inflammatory diseases of the ENT organs.
It has an antioxidant effect due to the ability of its reactive sulfhydryl groups (SH groups) to bind to oxidative radicals and thus neutralize them.
Acetylcysteine easily penetrates into the cell and is deacetylated to L-cysteine, from which intracellular glutathione is synthesized. Glutathione is a highly reactive tripeptide, a powerful antioxidant and cytoprotector that neutralizes endogenous and exogenous free radicals and toxins. Acetylcysteine prevents exhaustion and helps increase the synthesis of intracellular glutathione, which is involved in the redox processes of cells, promoting the detoxification of harmful substances. This explains the effect of acetylcysteine as an antidote for paracetamol poisoning.
Protects alpha1-antitrypsin (elastase inhibitor) from the inactivating effects of HOCl, an oxidizing agent produced by myeloperoxidase of active phagocytes. It also has an anti-inflammatory effect (by suppressing the formation of free radicals and reactive oxygen-containing substances responsible for the development of inflammation in the lung tissue).
Composition and release form Acetylcysteine canon 600 mg 3 g 10 pcs. granules for the preparation of solution for oral administration
Granules for preparing a solution for oral administration - 1 granule:
- Active substance: acetylcysteine 600 mg;
- Excipients: strawberry flavoring, ascorbic acid, aspartame, sucrose.
3 g - bags made of combined material (10) - cardboard packs.
Description of the dosage form
Granules for the preparation of a solution for oral administration are white or almost white.
Directions for use and doses
Orally for adults and children over 6 years old - 200 mg 2-3 times a day; children aged 2 to 6 years - 200 mg 2 times / day or 100 mg 3 times / day, up to 2 years - 100 mg 2 times / day.
Parenteral: IM for adults - 300 mg 1 time/day, for children - 150 mg 1 time/day.
Administer intravenously (preferably drip or slow stream over 5 minutes) or intramuscularly. Adults - 300 mg 1-2 times/day; children from 6 to 14 years old - 150 mg 1-2 times a day. The daily dose for children under 6 years of age is 10 mg/kg body weight; in children under 1 year of age, intravenous administration of acetylcysteine is possible only for health reasons in a hospital setting. The duration of treatment should be determined based on changes in the patient's condition.
For inhalation and intratracheal use, the dose, frequency of use and course duration are set individually.
Locally - instill 150-300 mg (1.5-3 ml) into the external auditory canal and nasal passages per 1 procedure.
Pharmacokinetics
When taken orally, it is well absorbed from the gastrointestinal tract. It is largely subject to the “first pass” effect through the liver, which leads to a decrease in bioavailability. Binding to plasma proteins up to 50% (4 hours after oral administration). Metabolized in the liver and possibly in the intestinal wall. In plasma it is determined unchanged, as well as in the form of metabolites - N-acetylcysteine, N,N-diacetylcysteine and cysteine ester.
Renal clearance accounts for 30% of the total clearance.
Indications for use Acetylcysteine canon 600 mg 3 g 10 pcs. granules for the preparation of solution for oral administration
Respiratory diseases and conditions accompanied by the formation of viscous and mucopurulent sputum: acute and chronic bronchitis, tracheitis due to bacterial and/or viral infection, pneumonia, bronchiectasis, bronchial asthma, atelectasis due to blockage of the bronchi with a mucus plug, sinusitis (to facilitate the passage of secretions ), cystic fibrosis (as part of combination therapy).
Preparation for bronchoscopy, bronchography, aspiration drainage.
Removal of viscous secretions from the respiratory tract in post-traumatic and postoperative conditions.
For washing abscesses, nasal passages, maxillary sinuses, middle ear, treatment of fistulas, surgical field during operations on the nasal cavity and mastoid process.
Paracetamol overdose.
Application Acetylcysteine canon 600 mg 3 g 10 pcs. granules for the preparation of a solution for oral administration during pregnancy and lactation
Contraindications for use in children under 14 years of age depend on the dosage form and are indicated in the instructions for use of the drug used.
Contraindicated for use during pregnancy and lactation (breastfeeding).
When using acetylcysteine in patients with bronchial asthma, it is necessary to ensure sputum drainage. In newborns, it is used only for health reasons at a dose of 10 mg/kg under the strict supervision of a physician.
special instructions
When using acetylcysteine in patients with bronchial asthma, it is necessary to ensure sputum drainage.
A 1-2 hour interval should be observed between taking acetylcysteine and antibiotics.
Acetylcysteine reacts with some materials such as iron, copper and rubber used in the spray device. In places of possible contact with acetylcysteine solution, parts made of the following materials should be used: glass, plastic, aluminum, chromed metal, tantalum, sterling silver or stainless steel. Silver may tarnish after contact, but this does not affect the effectiveness of acetylcysteine and does not harm the patient.
The compliance of the route of administration and the dosage form used should be strictly observed.
Side effects Acetylcysteine canon 600mg 3g 10 pcs. granules for the preparation of solution for oral administration
From the digestive system: rarely - heartburn, nausea, vomiting, diarrhea, feeling of fullness in the stomach.
Allergic reactions: rarely - skin rash, itching, urticaria, bronchospasm.
Other: rarely - nosebleeds, tinnitus.
From the laboratory parameters: a decrease in prothrombin time is possible due to the administration of large doses of acetylcysteine (monitoring the state of the blood coagulation system is necessary), changes in the results of the test for the quantitative determination of salicylates (colorimetric test) and the test for the quantitative determination of ketones (sodium nitroprusside test).
Drug interactions
The simultaneous use of acetylcysteine with antitussives may increase sputum stagnation due to suppression of the cough reflex.
When used simultaneously with antibiotics (including tetracycline, ampicillin, amphotericin B), their interaction with the thiol group of acetylcysteine is possible.
Acetylcysteine reduces the hepatotoxic effect of paracetamol.
Material and methods
The study included adult patients (n=46) with moderate COVID-associated pneumonia CT stage 2. The patients were treated in a COVID hospital operating on the basis of the University Clinical Hospital No. 4 of the First Moscow State Medical University named after. THEM. Sechenov Ministry of Health of Russia.
The presence of COVID-19 was confirmed by laboratory tests (smear for RNA of the SARS-CoV-2 virus from the upper respiratory tract using PCR) and/or clinical and radiological tests (the presence of a characteristic clinical picture and characteristic signs of polysegmental viral pneumonia COVID-19). When diagnosing and prescribing treatment for COVID-associated pneumonia, we were guided by the temporary methodological recommendations “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” of the Russian Ministry of Health, version 9, October 26, 2020 [1].
Inclusion criteria
The studies included: body temperature >38 °C, respiratory rate (RR) >22/min, shortness of breath during exercise, CT changes typical of a viral lesion (moderate lesion volume (25–50%), CT 2nd degree), blood oxygen saturation (SpO2) <95%, C-reactive protein (CRP) in the blood serum >10 mg/l.
Exclusion criteria
from the study: failure to meet inclusion criteria, failure of the patient to comply with the protocol conditions;
patient refusal to study .
All patients were assessed for demographic indicators, body mass index (BMI), alternative oxygenation index (SpO2/FiO2 - the ratio of blood saturation with oxygen to the fraction of inspired oxygen), symptoms of the disease, objective, laboratory data (complete blood count, CRP, coagulogram) and instrumental (CT chest) studies, concomitant diseases. To detect respiratory failure (RF) and assess the severity of hypoxemia, pulse oximetry was used to measure blood oxygen saturation.
DN was determined according to severity classification based on pulse oximetry (SpO2) values. To assess the nutritional status of patients, BMI was used, which was calculated using the generally accepted formula: BMI = body weight (kg) / height (m2). The oxygenation index SpO2/FiO2 was calculated using the formula:
SpO2/21 + 3 × oxygen flow rate [17].
Pulse oximetry was performed using an MD300C series pulse oximeter (Armed, Russia). CT scan of the lungs was performed on a spiral computed tomograph Aquillion TSX-101A (Toshiba Medical Medical Systems, Japan), slice thickness - 1 mm, upon admission and 10 days after the start of treatment.
Quantitative determination of CRP in blood serum was determined by the latex immunoturbidimetric method (Beckman Coulter analyzer, USA, AU series, using CRP Latex reagents, Russia) on the 1st, 3rd and 10th days of observation.
Fibrinogen was determined in blood plasma (ASK 2-01 Astra analyzer) using kits from NPO Renam, Russia. D-dimers were determined by microlatex agglutination with photometric registration of the reaction (immunoturbidimetry), using ReDimer-latex kits, NPO Renam test, Russia.
A total of 46 people took part in the study, the median age of which was 57 (51; 71) years, BMI - 30 (27.1; 32.3) kg/m2, duration of illness before hospitalization - 7 (6;
days, temperature at the time hospitalization was 37.5 (37.1; 37.8) °C.
2 study groups were randomly formed. Group 1 (control, n=22) received standard treatment [1]: hydroxychloroquine 200 mg, 800 mg/day on day 1, 400 mg/day on days 2–7; azithromycin 500 mg/day for 5 days, enoxaparin sodium 0.4 mg/day subcutaneously, dexamethasone 8–12 mg/day, for CRP ≥60 mg/l - tocilizumab 400 mg/day. Patients of group 2 (n=24) additionally received NAC (Fluimucil, Switzerland) 1200–1500 mg/day intravenous drip No. 8–10. NAC was prescribed simultaneously with the start of standard therapy.
Statistical data processing
was carried out using the IBM SPSS Statistics application package, version 22 (license 20160413–1). Descriptive statistics of the initial quantitative characteristics are presented by the median and interquartile range. In addition to the initial characteristics, the difference in change in each indicator (the difference before and after treatment) and the intensity of the rate of change in the indicator (the difference in change relative to the initial level, expressed as a percentage) were analyzed. Descriptive statistics of the difference and intensity of change are represented by the mean and standard deviation. Comparison of two independent samples (NAC group and control group) for quantitative indicators was carried out using the Mann-Whitney test (U), dependent (before - after treatment) - Wilcoxon test for related samples (W). Comparison of three independent samples by quantitative indicator (at different points in the study) was carried out using the Friedman test, post-hoc comparisons were carried out using the Nemenyi test. Differences in the length of hospitalization of patients (inpatient bed days) in the 2 groups were assessed using the Kaplan-Meier technique and the Taron-Ware test.
Research results
The study groups were comparable in all considered indicators: age - 57 (46; 58) and 66 (52; 71) years, p = 0.08; body mass index (BMI) - 28.8 (26.4; 31.2) and 31.2 (28.5; 32.3) kg/m2, p=0.07; duration of illness before hospitalization - 7 (6; and 7.5 (6; 9) days, p = 0.37; duration of fever - 9 (7; 10) and 9.5 (9; 10) days, p = 0, 28; including by respiratory rate (p=0.11), heart rate (p=0.11), SpO2 level (p=0.42), oxygenation index (SpO2/FiO2) (p=0.39) , CRP concentration (p=0.08), fibrinogen level (p=0.07) and volume of lung lesions according to CT (p=0.06) (Table 1).
As a result of treatment, all parameters considered, with the exception of leukocyte levels, showed statistically significant changes in both groups. But it is worth noting that the analysis revealed intergroup differences in the intensity of changes in a number of indicators (Table 1). In particular, the SpO2 level increased in the control group on average in each patient by 3±1.5% from the initial level, the change is statistically significant (p<0.001), while the increase in the NAC group was on average 4.6± 1.1% (p<0.001), the difference between the growth rates is statistically significant (p=0.001). As a result of different intensity of the increase in SpO2 after treatment, patients in the NAC group became statistically significantly higher than in the control group - 97 (96; 98)% versus 96 (96; 97)% (p = 0.02).
The oxygenation index (SpO2/FiO2) increased by an average of 88±16.6% from the initial level in patients in the NAC group (p<0.001) and by 70±28.9% in the group of patients with standard treatment (p<0.001), the difference between growth rates is statistically significant (p=0.04). As a result, after treatment, SpO2/FiO2 in patients in the NAC group became statistically significantly higher than in the control group (p = 0.03).
The difference in the increase in oxygenation index in patients in the NAC group was statistically significantly higher than in the control group - 175±54.3 versus 144±54.4 (p=0.02) (Fig. 1).
As a result of treatment, the volume of lung lesions, according to CT data (relative to the initial level), significantly decreased in both groups (p<0.001). The average rate of change in this indicator (the difference between the indicator after and before treatment, expressed as % of the indicator values before treatment) in the study groups was 31±8.3% and 17±6.2%, respectively, the differences are statistically significant (p<0.001) .
Noteworthy is the statistically significant difference in the difference in the reduction in the volume of lung lesions according to CT data (p<0.001), the data are presented in Figure 2.
An analysis of the course of the inflammatory process was carried out based on the concentration of CRP. Initially comparable in the study groups, the level of CRP showed a statistically significant (p=0.002) decrease on the 3rd day of treatment only in the NAC group - from 81 (57; 96) mg/l to 44 (40; 57) mg/l. On the 10th day of treatment, there was a statistically significant decrease in the level of CRP in both study groups, the values of the indicator were 6 (4; 13) mg/l in the control group (the decrease was statistically significant relative to the 1st day - p<0.001 and the 3rd day - p<0.001) and 5 (2; 6) mg/l in the NAC group (the decrease is statistically significant relative to the 1st day - p<0.001 and the 3rd day - p=0.002). There were no statistically significant differences in the level of CRP between the study groups during any of the study periods, but there was a statistically significantly more intense rate of decrease in the level of CRP in the NAC group on the 10th day relative to the 1st day than in the control group - 90±10 .2% versus 82±13.9% (p=0.03).
Analysis of the length of hospitalization of patients (number of hospital bed days) showed that the addition of Fluimucil to standard therapy statistically significantly reduces the duration of hospitalization (p<0.001). In the group of patients who received only standard therapy, the median hospital bed days was 13 (11; 16) days, while in the group receiving the drug it was 11 (10; 12) days.
