Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment

Glioblastoma is the most malignant and frequently occurring type of brain tumors in adults. Its treatment has been greatly hampered by the difficulty to achieve effective therapeutic concentration in the tumor sites due to its location and the blood–brain barrier. Intranasal administration has emerged as an alternative for drug delivery into the brain though mucopenetration, and rapid mucociliary clearance still remains an issue to be solved before its implementation. To address these issues, based on the intriguing properties of proteins secreted by mussels, polyphenol and catechol functionalization has already been used to promote mucopenetration, intranasal delivery and transport across the blood–brain barrier. Thus, herein we report the synthesis and study of complex 1, a Pt(IV) prodrug functionalized with catecholic moieties. This complex considerably augmented solubility in contrast to cisplatin and showed a comparable cytotoxic effect on cisplatin in HeLa, 1Br3G and GL261 cells. Furthermore, preclinical in vivo therapy using the intranasal administration route suggested that it can reach the brain and inhibit the growth of orthotopic GL261 glioblastoma. These results open new opportunities for catechol-bearing anticancer prodrugs in the treatment for brain tumors via intranasal administration.

Endoscopic findings of dental implant found in the infundibulum showing the mucociliary clearance of the maxillary sinus

Significance statement: A 53-year-old man with left facial pain was referred to our hospital. Nasal endoscopy revealed a purulent discharge at the left middle meatus and bulging of the uncinate process. Computed tomography demonstrated that the dental implant was blocking the left maxillary ostium. Functional endoscopic sinus surgery was performed under general anesthesia. After removal of the uncinate process, a yellowish purulent discharge in the left maxillary sinus discharged from the maxillary sinus. The presence of the dental implant in the infundibulum shows the direction of mucociliary clearance from the nasal sinus. This case indicates how our sinus clears a foreign body, and the direction in which the foreign body is removed.

Immunoglobulin A Mucosal Immunity and Altered Respiratory Epithelium in Cystic Fibrosis

The respiratory epithelium represents the first chemical, immune, and physical barrier against inhaled noxious materials, particularly pathogens in cystic fibrosis. Local mucus thickening, altered mucociliary clearance, and reduced pH due to CFTR protein dysfunction favor bacterial overgrowth and excessive inflammation. We aimed in this review to summarize respiratory mucosal alterations within the epithelium and current knowledge on local immunity linked to immunoglobulin A in patients with cystic fibrosis.

An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure

Adverse outcome pathways (AOPs) help to organize available mechanistic information related to an adverse outcome into key events (KEs) spanning all organizational levels of a biological system(s). AOPs, therefore, aid in the biological understanding of a particular pathogenesis and also help with linking exposures to eventual toxic effects. In the regulatory context, knowledge of disease mechanisms can help design testing strategies using in vitro methods that can measure or predict KEs relevant to the biological effect of interest. The AOP described here evaluates the major processes known to be involved in regulating efficient mucociliary clearance (MCC) following exposures causing oxidative stress. MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and airway surface liquid (ASL). The AOP network described here consists of sequences of KEs that culminate in the modulation of ciliary beat frequency and ASL height as well as mucus viscosity and hence, impairment of MCC, which in turn leads to decreased lung function.

Precision medicine in bronchiectasis

Bronchiectasis, due to its highly heterogenous nature, requires an individualised approach to therapy. Patients experience symptoms and exacerbations driven by a combination of impaired mucociliary clearance, airway inflammation and airway infection. Treatment of bronchiectasis aims to enhance airway clearance and to address the underlying causes of inflammation and infection susceptibility. Bronchiectasis has multiple causes and so the pathophysiology leading to individual symptoms and exacerbations are different between individuals. Standardised investigations are recommended by international guidelines to identify the underlying causes of bronchiectasis. The process of identifying the underlying biology within an individual is called “endotyping” and is an emerging concept across chronic diseases. Endotypes that have a specific treatment are referred to as “treatable traits” and a treatable traits approach to managing patients with bronchiectasis in a holistic and evidence-based manner is the key to improved outcomes. Bronchiectasis is an area of intense research. Endotyping allows identification of subsets of patients to allow medicines to be tested differently in the future where trials, rather than trying to achieve a “one size fits all” solution, can test efficacy in subsets of patients where the treatment is most likely to be efficacious.

Rhinological tactics in the complex treatment of patients with severe combined cranio-facial trauma who are on mechanical ventilation

Introduction. In recent years, injuries ranked fourth among the main causes of death of the population after diseases of the cardiovascular system, malignant neoplasms and infectious diseases. The clinical course of associated injuries, as a rule, is characterized by a high number of complications, much more than in isolated injuries.Objective. Explore approaches to improving otorynolaryngological tactics from the standpoint of normalizing the functional state of the nasal mucosa, as well as increasing the effectiveness of treatment of patients with severe concomitant trauma on prolonged mechanical ventilation.Materials and methods. In the process of studying the problem of impaired mucociliary clearance of the nasal mucosa, the functional state of the mucous membrane in patients with severe concomitant head trauma undergoing prolonged artificial lung ventilation was analyzed. We studied the state of one of the most important mechanisms of sanitation and local protection of the respiratory tract - mucociliary clearance, which provides the necessary potential for barrier, cleansing and immune functions. A study was made of the thermal effect of the nasal cavity, pH + of the mucous membrane, the study of the frequency of beating of the cilia of the ciliated epithelium and the rate of mucociliary transportResults and discussion. The results of the study showed that the problem of post-traumatic and nosocomial sinusitis in patients with severe concomitant head trauma must be resolved as soon as possible, with the involvement of modern diagnostic and treatment methods, including the proposed method of artificial ventilation of the nose. The severity of the patient's condition, the severity of the injuries received excludes the use of advanced methods of surgical, otorhinolaryngological treatment.Conclusion. 12:30 PMThe use of minimally invasive methods of treatment, precision technical execution, including under endovideo control, polysinusotomy made it possible not to burden the condition of the victims and exclude iatrogenic damage that could entail irreversible changes in the body and condition of the victim.

Application of hypertonic saline in children with acute bronchitis

Introduction. Cough is the most common manifestation of respiratory infections of the upper and lower respiratory tract and indicates impaired mucociliary clearance. The cause of cough must be determined to choose the management tactics for children with cough. The most commonly used mucoactive drugs liquefy sputum as a result of a direct action of the components on the tracheobronchial secretion and/or mucosa of the respiratory tract. Given the mucoactive effect of hypertonic salines, we conducted an open clinical study of the effectiveness of 3% hypertonic saline with hyaluronic acid in acute bronchitis in children.Aim of the study. To evaluate the clinical effect of 3% hypertonic saline with hyaluronic acid in acute bronchitis in children.Materials and methods. Clinical efficacy and safety of 3% hypertonic saline with hyaluronic acid in 50 patients aged 3 to 12 years old with acute bronchitis were evaluated in the dynamics on the 1st, 3rd, 7th days of treatment with the score assessment of symptoms (cough, stuffy nose, auscultation data) and an indication of adverse events (if any).Results. Improvement of condition was noted in most patients by the 3rd day of therapy (mean score 1.88 ± 0.3), temperature normalized in all patients, manifestations of rhinitis decreased. By the 5th day of treatment, the intensity of cough did not exceed 1 point in all patients (0.7 ± 0.14 points). According to the patient’s diary data, by the 7th day of treatment 74% of the children had no cough. On the 7th day of treatment, some children had a rare residual cough (0.36 ± 0.06 points), minor rhinitis (0.16 ± 0.1 points). No rales were heard in the lungs in all patients, rigid breathing was heard in 11 patients (mean score 0.22 ± 0.05).Conclusions. The conducted study demonstrated that 3% hypertonic saline with hyaluronic acid is an effective drug in the treatment of cough in acute bronchitis in children.