Pharmacodynamics and pharmacokinetics
Pharmacodynamics
Human recombinant DNase is an artificial, genetically engineered human enzyme
The accumulation of purulent, viscous secretions in the respiratory tract plays a major role in respiratory failure and exacerbation of infections in patients with cystic fibrosis . The secretion has a high content of extracellular DNA, released from dying leukocytes. Dornase alfa hydrolyzes DNA in sputum and reduces its viscosity in cystic fibrosis.
Pharmacokinetics
Systemic absorption of the active substance after inhalation is low. In persons with cystic fibrosis , the content of the drug in the sputum a quarter of an hour after inhalation of 2.5 mg is equal to 3 mcg/ml. Then its concentration in the blood actively decreases.
Cystic fibrosis (CF) is a multi-organ hereditary pathology that occurs with dysfunction of vital organs, primarily the bronchopulmonary and digestive systems. The development of most clinical symptoms of the disease is associated with the production of secretions of increased viscosity with altered physicochemical properties: an increase in the concentration of electrolytes and proteins with a decrease in the aqueous phase. Difficulty in the outflow of viscous secretion leads to its stagnation with subsequent expansion of the excretory ducts of the glands, atrophy of the glandular tissue and progressive fibrosis [1, 2].
The human lungs are sterile below the first bronchial division, despite the constant presence of bacteria and viruses in the air. The cells lining the respiratory tract are covered with a thin layer (30 microns) of fluid containing proteases/antiproteases, oxidants/antioxidants, natural antibiotics (defensins) and antibodies. This system of biologically active substances works in concert to inactivate or destroy pathogens that enter the lungs. In addition, the coordinated work of the ciliary apparatus ensures the mechanical removal of pathogens and foreign particles from the surface of the respiratory tract. Nonspecific defense mechanisms are complemented by immune mechanisms [3].
In patients with CF, the functioning of all parts of the local defense of the lungs is impaired. The formation of an excessively viscous secretion and disruption of the ciliated epithelium lead to a decrease in mucociliary clearance, stagnation of sputum and airway obstruction. High concentrations of chlorides in lung fluid inactivate natural antibiotics (β-defensin-1 and -2, lysozyme, lactoferin, secretory leukoproteinase inhibitor, secretory phospholipase A2, cathelicidin LL-37).
Changes in ion transport and hyperpolarization of the cytoplasmic membrane cause disruption of the protective function of epithelial cells, which lose the ability to bind and internalize pathogenic microorganisms. In addition, the epithelium of the respiratory tract of CF patients is not able to produce sufficient amounts of nitric oxide, which, together with tumor necrosis factor (TNF-a), is an important protective factor in the first stages of bacterial colonization, which inevitably leads to the development of infection [4].
Long-term antigenic load caused by the persistence of staphylococcus, Haemophilus influenzae and especially Pseudomonas aeruginosa in the respiratory tract leads to the development of hypersensitivity with damage to lung tissue and the activation of immune mechanisms. Recurrent viral and bacterial infections in CF patients stimulate chronic inflammation, characterized by excessive accumulation of neutrophils in the respiratory tract. A pronounced inflammatory response in the lower respiratory tract in patients with chronic Pseudomonas aeruginosa infection can be more harmful than the infection and cause destruction of pulmonary structures due to the release of oxygen radicals and proteases, in particular neutrophil elastase in high concentrations [5]. Neutrophil elastase (NPE) is of greatest importance in the pathogenesis of CF among the inflammatory mediators secreted by activated neutrophils. It destroys structural proteins of the lungs, including collagen types I–IV, fibronectin, proteoglycans and elastin. Elastin is an important component of the vascular wall, determining its elasticity, and is also responsible for the extensibility of lung tissue. Elastin breakdown products (desmosines) are found in the urine of CF patients and their levels correlate with the severity of lung damage. UPE stimulates the release of interleukin-8 (IL-8), mobilizing even more neutrophils into the lungs and thus allowing an endless cycle of inflammation leading to the release of UPE. In addition to structural proteins, NFE destroys protective components such as surfactant, natural antibiotics, immunoglobulins, immune complexes, and complement components. In addition, free UPE damages the bronchial epithelium and cells of the immune system, which facilitates bacterial colonization [6]. UPE in sputum and bronchoalveolar fluid is often used as a marker of inflammation in the lungs of patients with CF, and its level usually correlates with the severity of the process, determined by pulmonary function data and/or pulmonary radiographic scores and clinical status. It should be noted that signs of inflammation in the lungs of CF patients can be detected even in the absence of infection. Thus, high levels of IL-8 and increased NPE activity are found in patients younger than 6 months without signs of bacterial infection, which is associated with a defect in the cystic fibrosis transmembrane conductance regulator [7]. According to C. Verhaeghe, a significant increase in the level of pro-inflammatory proteins is observed in the lungs of fetuses with CF [8].
A consistently high level of IL-8 in bronchial secretions attracts neutrophils, which produce free radicals and proteases that damage lung tissue. Unable to suppress the infection, neutrophils soon die, releasing additional amounts of elastase and oxidants. In addition, DNA and fibrous actin of dead neutrophils accumulate in bronchial secretions, further increasing the viscosity of sputum. Thus, pulmonary infection causes an intense inflammatory response in CF patients, which is accompanied by massive destruction of lung tissue, which ultimately leads to the development of pneumofibrosis, bronchiolosis and bronchiectasis, as well as a progressive decrease in external respiratory function [9]. Airway pathology is the main cause of complications and mortality in more than 90% of CF patients.
The pathological viscoelastic properties of bronchial secretions in CF patients are mainly due to the presence of two macromolecules - mucoid glycoproteins and DNA. A high concentration of DNA is one of the main factors in the accumulation of pathologically viscous bronchial secretions, which disrupts their drainage and favors the development of infection. This leads to further release of neutrophils and the production of even larger amounts of DNA.
In 1988, the pharmaceutical company Genentech, Ltd. (USA) an exact copy of the natural human enzyme DNase, which cleaves extracellular DNA, was cloned and reproduced using recombinant technology - recombinant human DNase. The drug dornase alfa (PulmozymR) from the pharmaceutical company F. Hoffmann-La Roche Ltd.” (Switzerland), is a purified solution of recombinant human deoxyribonuclease-1, produced by the pancreas and other tissues. In special studies, dornase alfa caused the hydrolysis of extracellular DNA in the purulent sputum of patients, significantly reduced its viscoelastic properties and improved mucociliary clearance (MCC).
Dornase alfa is prescribed at a dose of 2.5 mg in a 2.5 ml solution daily in the form of inhalations through compressor inhalers and jet nebulizers or electronic nebulizers such as eFlow rapid. For young children, inhalations are carried out through a face mask. The use of a PEP system or flutter as an attachment to a nebulizer makes it possible to combine Pulmozym inhalations with kinesitherapy. In patients with severe CF and in some adult patients, inhalations are carried out twice a day, 2.5 mg.
At the Russian Center for Cystic Fibrosis, from 1999 to 2003, clinical observations and special studies were conducted to study the safety and effectiveness of dornase alfa, in which 108 children from different age groups with moderate and severe CF took part (A.Yu. Voronkova, 2004) .
In the course of the studies, it was proven that older CF patients who received Pulmozym over a two-year period had significantly better clinical and functional indicators: weight-height index (MHI), forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), frequency of respiratory episodes and duration of intravenous therapy courses than patients in the control group (p < 0.05). The most pronounced positive effect from Pulmozym therapy was obtained in the group of patients with moderate severity of lung damage. By the end of therapy, the indicators of pulmonary function and MRI exceeded the starting ones in the moderate and severe groups: FEV1 and FVC - by 1.4 and 2.4%, MRI - by 3.07 and 1.97%, respectively. The frequency of respiratory episodes significantly decreased in the moderate group by 40% and remained the same in the severe group. The duration of courses of intravenous antibiotic therapy was reduced by 24 and 7%, respectively [10].
Particular attention was paid to the younger age group of CF patients (54 patients were under 5 years of age at the start of therapy, the youngest was 3 months old), since the experience of using Pulmozym in children under 5 years of age at the time of the study was minimal. It was in this group of patients that the greatest effect of treatment was obtained, namely: an increase in MRI - by 4%; reduction in the frequency of respiratory episodes - by 38%; reduction in the duration of courses of intravenous antibiotic therapy – by 35%. Data on the safety and effectiveness of the use of the drug Pulmozyme in the younger age group (up to 5 years), obtained during the study and confirmed by subsequent observations, were of great importance when making changes to the instructions for use of the drug [11]. Currently, Pulmozyme can be used at any age. The possibility of using Pulmozym from the first months of a child’s life is especially relevant in light of the national program for screening newborns for CF, the main goal of which is not only the timely identification of patients, but also the early initiation of therapy. Thus, in a group of children from 3 months to 2 years of age, with the use of Pulmozym, already six months after the start of therapy, a decrease in the frequency of respiratory episodes (p < 0.003) and the duration of courses of intravenous antibiotic therapy was noted, and a year later - a significant increase in MRI [12]. During trial administration of Pulmozym to children under 5 years of age, the following adverse events were recorded: pharyngitis, laryngitis, rhinorrhea, hyperthermia, bronchospasm. With symptomatic therapy that lasted for 5–10 days, the existing symptoms were relieved and did not require discontinuation of the drug. Subsequently, no adverse events were identified with long-term use of Pulmozym. We also do not observe long-term consequences of using inhalations of the drug. There were no differences in the safety profile in children under 5 years of age and in the older age group. Children under 5 years of age tolerate therapy with Pulmozyme also well. Of 270 patients under the age of 18 years observed at the Moscow Center for Cystic Fibrosis, only two (less than 1%) showed persistent intolerance to Pulmozym, manifested by bronchospasm.
Along with the mucolytic effect, dornase alfa has a number of non-colytic effects, namely:
- reduces the concentration of NPE and IL-8 in sputum in patients with the mucoid form of Pseudomonas aeruginosa;
- inhibits the formation of a biofilm of mucoid colonies of Pseudomonas aeruginosa, which determines their resistance to antibacterial drugs and the body’s immune reactions [10, 12].
When studying markers of inflammation in 13 patients of an older age group with chronic seeding of P. aeruginosa, observed at the Russian Center for Cystic Fibrosis and taking Pulmozyme for a year, data were obtained on a decrease in protein and NPE content in the sputum, and a decrease in signs of inflammation in the peripheral blood. In the group with the mucoid form of Pseudomonas aeruginosa infection, a significant increase in the anti-inflammatory response of peripheral blood lymphocytes to phytohemagglutinin was noted (p < 0.05). The results obtained showed that treatment with Pulmozyme not only significantly affects the level of inflammatory markers in sputum, but also has a pronounced systemic anti-inflammatory effect. During treatment with Pulmozyme, the degree of sputum contamination with Staphylococcus aureus and P. aeruginosa decreased [10].
Since 1992, when Pulmozyme began to be widely used, a large amount of information has been accumulated in the world on the effectiveness and safety of this recombinant enzyme both in patients with CF and in other lung diseases, such as chronic bronchitis, Kartagener syndrome, chronic obstructive pulmonary disease, lobar atelectasis and bronchiectasis [13–15].
Indications for the use of the drug in the treatment of CF are expanding. Thus, almost 50% of patients with CF suffer from chronic rhinosinusitis and/or nasal polyposis; in 100% of patients, computed tomography of the upper respiratory tract reveals certain changes. This pathology significantly reduces the quality of life of patients and contributes to a more severe course of CF. Since 2005, reports have been published in the literature on the successful use of the drug Pulmozyme for chronic rhinosinusitis in patients with CF when administered intranasally [16–18]. The optimal delivery method is pulsating administration of an aerosol of the drug through the PARI SINUS inhalation device.
Unfortunately, in a certain group of patients with CF it is not possible to obtain the maximum mucolytic effect with the use of Pulmozyme. Studies have shown that this group is characterized by reduced levels of magnesium and potassium ions in sputum. Magnesium and potassium promote the polymerization of sputum G-actin into F-actin. With a deficiency of magnesium and potassium ions in the sputum, the concentration of G-actin increases, which, unlike F-actin, is a DNase inhibitor and, as a result, inhibits the destruction of DNA strands in the sputum of CF patients. Additional oral administration of magnesium preparations significantly increases the level of magnesium in sputum, thereby ensuring the full mucolytic effect of Pulmozyme. At the same time, the level of magnesium in the blood does not change significantly [19]. Factors such as insufficient intake of salts into the body, impaired intestinal absorption, and the influence of antibacterial drugs, such as aminoglycosides, are considered as the reason for the decrease in the concentration of magnesium ions in the sputum of CF patients [20]. It is proposed to determine the concentration of magnesium ions in the sputum of CF patients to predict the effectiveness of Pulmozyme use and correct the identified magnesium deficiency. The study of the problem of magnesium deficiency in CF patients continues.
Thus, early administration of dornase alfa improves, according to our data, pulmonary function, reduces the frequency of exacerbations of the bronchopulmonary process, improves nutritional status, has a positive effect on inflammatory markers, prevents the colonization of mucoid colonies by P. aeruginosa, reduces the frequency and duration of hospitalizations, and reduces the number of days of intravenous antibacterial therapy improves quality of life, so this drug should be included in basic therapy immediately after the diagnosis of CF, including in the first months of life [21]. In order to compensate for the possible insufficient mucolytic effect of Pulmozyme, and also taking into account the participation of various links in the pathogenesis of airway obstruction with viscous secretions, along with Pulmozyme, drugs from other groups are included in mucolytic therapy regimens, such as N-acetylcysteine, ambroxol hydrochloride, hypertonic solutions (5 -7%).
Information about the authors: Sherman Victoria Davidovna – Candidate of Medical Sciences, Researcher at the Cystic Fibrosis Center, Head of the Cystic Fibrosis Department of Children's City Clinical Hospital No. 13 named after. N.F. Filatov MGSC RAMS. Tel., e-mail Nikolay Ivanovich Kapranov – Doctor of Medical Sciences, Professor, Head of the Cystic Fibrosis Center of the Children's City Clinical Hospital No. 13 named after. N.F. Filatov MGSC RAMS. Tel., e-mail: [email protected] Natalia Yurievna Kashirskaya – Doctor of Medical Sciences, Professor, Leading Researcher at the Cystic Fibrosis Center of the Children's City Clinical Hospital No. 13 named after. N.F. Filatov MGSC RAMS. Tel., e-mail: [email protected]
Indications for use
- As part of combination therapy for cystic fibrosis in individuals with a vital forced lung capacity of more than 40% of normal values.
- Therapy of patients with certain lung diseases of a chronic nature ( obstructive chronic pulmonary disease, bronchiectasis, lung malformations, immunodeficiency conditions affecting the lungs, chronic pneumonia ), if the mucolytic effect of the drug, according to the doctor, has benefits for patients.
Use in childhood
During clinical trials, Pulmozyme was used in children aged 3 months to 9 years with cystic fibrosis, in the form of inhalations once a day at a dose of 2.5 mg for 2 weeks. Bronchoalveolar lavage (BAL) was performed within 90 minutes after the first inhalation dose. In the BAL solution, the concentration of DNase in all patients reached a detectable level, but varied significantly - from 0.007 to 1.8 μg/ml. After using the drug for approximately 14 days, the serum concentration of DNase in the blood (mean ± standard deviation) increased in children aged 3 months to 5 years and from 5 to 9 years by 1.1 ± l.6 and 0. 8 ± 1.2 ng/ml, respectively. The relationship of DNase levels in BAL fluid or serum with the occurrence of adverse conditions or the effectiveness of treatment has not been determined.
The observed side effects were similar to those observed in other studies involving children. In the group of children from 3 months to 5 years, compared with older patients, cough (as an undesirable effect), including severe/moderate severity, as well as rhinitis and rash, was most often observed. Experience with the use of Pulmozym in children under 5 years of age is limited, and the effectiveness of therapy has not been studied. Prescribing the drug to patients of this age category is allowed only if the expected improvement in lung function outweighs the risk of developing infection.
Side effects
- Hematopoietic disorders: aplastic anemia, acute lymphocytic leukemia.
- Nervous disorders: migraine, epileptic seizures.
- Sensory disorders: balance disorders, conjunctivitis .
- Circulatory disorders: bradycardia, tachycardia, cardiac arrest.
- Respiratory disorders: bronchitis, pneumonia , respiratory infections, pharyngitis , hoarseness, laryngitis, rhinitis , shortness of breath, deterioration of lung function, decreased respiratory function, hemoptysis, respiratory failure, pulmonary hemorrhage, pneumothorax, cough, laryngeal polyp, alveolitis, enlargement volume of bronchial secretions, hypoxia , productive cough, bronchospasm.
- Digestive disorders: abdominal pain, dyspepsia , liver failure, hematemesis.
- Skin disorders: itching , rash, dermatitis, urticaria, angioedema, purpura.
- Pregnancy and postpartum period: complications during pregnancy, premature birth, spontaneous abortion .
- General disorders: fever , pleural pain, weakness, death, malaise.
Instructions for use (Method and dosage)
Pulmozyme is used by inhalation. It must not be diluted or mixed with other medications or solutions inside the nebulizer. Mixing with other medications may cause adverse functional and structural changes in Pulmozyme.
Typically, 2.5 mg of dornase alfa (without dilution) is administered by inhalation once a day using a jet nebulizer.
In a number of patients over 21 years of age, a better effect of therapy can be achieved by using a daily dose twice a day. Patients should also be advised to take the drug daily without interruption and continue multicomponent therapy, including physical therapy.
If the course of a respiratory infection during treatment with the drug, its use is allowed to continue without risk to the patient.
Release form and composition
The drug is produced in the form of a solution for inhalation: a colorless or slightly yellowish transparent solution (2.5 ml in a colorless plastic ampoule, 6 ampoules in a protective container made of multilayer aluminum foil, 1 protective container in a cardboard box and instructions for use of Pulmozyme).
2.5 ml of solution for inhalation (1 ampoule) contains:
- active substance: dornase alfa* – 2.5 mg;
- additional components: calcium chloride dihydrate, sodium chloride, water for injection.
* 1 mg of dornase alfa corresponds to 1000 Units of Action (AU).
Interaction
The medicine is perfectly compatible with all standard drugs for the treatment of cystic fibrosis (bronchodilators, antibiotics, vitamins, digestive enzymes, analgesics, glucocorticosteroids).
Pulmozyme is an aqueous solution that does not have buffering properties. It is prohibited to dilute or mix it with other drugs or solutions inside the nebulizer . Such mixing can lead to undesirable structural and functional transformations of the drug or other components of the mixture.
Reviews of Pulmozyme
In most cases, patients leave positive reviews about Pulmozyme. It is noted to be highly effective when used as a means of symptomatic treatment of cystic fibrosis and chronic lung diseases. When using a mucolytic, the viscosity of sputum is significantly reduced, the drug promotes its normal discharge, improving lung function. After regular inhalations, many patients experienced shortness of breath and a significant reduction in cough. However, patients note that Pulmozym should be used only as directed and under the supervision of a physician.
The disadvantages of Pulmozim are its high cost and the presence of side effects.
special instructions
When using the drug, it is necessary to carry out constant medical supervision of the patient.
After therapy with the drug, lung function decreases slightly, and sputum production increases.
The effectiveness and safety of the drug Pulmozyme in individuals with a vital forced lung capacity of up to 40% of normal values have not been established.
A single short-term exposure to elevated temperatures (up to 24 hours at 30 °C) does not affect the pharmacological stability of the drug.
Overdose
Cases of dornase alfa overdose have not been reported.
Single inhalations of Pulmozym to animals in doses significantly higher than those usually prescribed to humans (almost 180 times) were well tolerated. In clinical studies, patients with cystic fibrosis used the drug by inhalation at a dose of 20 mg 2 times a day for 6 days and at a dose of 10 mg 2 times a day for 168 days according to an intermittent regimen (2 weeks of treatment after 2 weeks of break). During the study, good tolerability of both dosing regimens was noted.
Systemic toxicity of the drug has not been identified and is not expected due to its low degree of absorption and short half-life; therefore, in the event of an unintentional overdose of Pulmozyme, systemic therapy is not required.
Analogs
Level 4 ATX code matches:
Mukolik
Abrol
Ambrosan
Bronchorus
ACC 100
ACC 200
ACC Long
ACC
Mukolwan
Lazolvan
Bromhexine 8
Bromhexine 8 Berlin-Chemie
Bromhexine
Bronchobos
Carbocisteine
Erdomed
Pectolvan C
Halixol
Ambrobene
Acetylcysteine
Abrol, Ambrobene, Ambrohexal, Ambrolitin, Ambrosan, Ambrosprey, Acestad, Atsetin, ACC, Bromhexine, Lazolvan, Medox, Mukosol, Rinatiol, Flavamed, Erdomed and others.
