Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections

Purpose Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. Methods We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. Results At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. Conclusion Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections. Graphical abstract

Veterinary drug Trametin obtained on the basis of Trametes pubescens xylotroph fungi: its effect on the biosynthesis of interferons and its prophylactic activity against calf respiratory diseases

Given the spread of bacterial and viral diseases in young farm animals, the use of interferons and drugs to stimulate their biosynthesis has gained relevance. In a previous study, we examined the effect of a veterinary drug Trametin produced on the basis of Trametes pubescens (Shumach.: Fr.) Pilat. on the biosynthesis of interferons in the blood of mice. The present work is aimed at studying the biosynthesis dynamics of α- and γ-interferons when using Trametin and studying its prophylactic activity in calves. It is shown that a single oral administration of Trametin in doses ranging from 15 to 60 mg/kg causes a dose-dependent induction and production of γ-interferon in the blood of mice, whose maximum content reaches 1337.0±93.0 pg/mL at 48 h after administering a dose of 30 mg/kg. With a Trametin dose increase from 15 to 30 mg/kg, the level of α-interferon production rises to 1388.0±84.0 pg/mL at 48 h after administration. At a Cycloferon dose of 4.5 mg/kg, the production level of α-interferon and γ-interferon amounts to 1455.47±84.2 and 1447.0±90.0 pg/mL, respectively. The immunostimulatory properties of Trametin are confirmed by a scientific and economic experiment conducted using immunocompromised calves. In our studies, an immunological test of calf blood performed prior to and following the administration of Trimetin and Cycloferon constitutes criteria for the prophylactic activity of these drugs. The prophylactic efficacy of Trametin is confirmed by an increase in phagocytic activity by 10.5%, phagocytic index by 61.8%, and phagocytic number by 52.8%. After Trametin administration, the bactericidal activity of the serum increases by 60%. Cycloferon exhibits a similar immunostimulatory effect. Nonspecific prophylaxis using Trametin is shown to reduce the incidence of bacterial and viral respiratory diseases in young calves and generally improve their immunity.

Characterization of the Role of Extracellular Vesicles Released from Chicken Tracheal Cells in the Antiviral Responses against Avian Influenza Virus

During viral respiratory infections, the innate antiviral response engages a complex network of cells and coordinates the secretion of key antiviral factors, such as cytokines, which requires high levels of regulation and communication. Extracellular vesicles (EVs) are particles released from cells that contain an array of biomolecules, including lipids, proteins, and RNAs. The contents of EVs can be influenced by viral infections and may play a role in the regulation of antiviral responses. We hypothesized that the contents of EVs released from chicken tracheal cells are influenced by viral infection and that these EVs regulate the function of other immune cells, such as macrophages. To this end, we characterized the protein profile of EVs during avian influenza virus (AIV) infection and evaluated the impact of EV stimulation on chicken macrophage functions. A total of 140 differentially expressed proteins were identified upon stimulation with various stimuli. These proteins were shown to be involved in immune responses and cell signaling pathways. In addition, we demonstrated that EVs can activate macrophages. These results suggest that EVs play a role in the induction and modulation of antiviral responses during viral respiratory infections in chickens.

Respiratory Syncytial Virus Resurgence in Italy: The Need to Protect All Neonates and Young Infants

Respiratory syncytial virus (RSV) is the most prevalent cause of viral respiratory infections in children up to the age of 2 years and causes a wide range of clinical manifestations [...]

Application of recommended preventive measures against COVID-19 could help mitigate the risk of SARS-CoV-2 infection during dental practice: Results from a follow-up survey of French dentists

Background During the first-wave of the COVID-19 pandemic, dentists were considered at high-risk of infection. In France, to stop the spread of SARS-CoV-2, a nationwide lockdown was enforced, during which dentists suspended their routine clinical activities, working solely on dental emergencies. This measure has had an indisputable mitigating effect on the pandemic. To continue protecting dentists after suspension of nationwide lockdown, implementation of preventive measures was recommended, including adequate personal protective equipment (PPE) and room aeration between patients. No study has explored whether implementation of such preventive measures since the end of the first-wave has had an impact on the contamination of dentists. Methods An online survey was conducted within a French dentist population between July and September 2020. To explore risk factors associated with COVID-19, univariate and multivariate logistic regression analyses were performed. Results The results showed that COVID-19 prevalence among the 3497 respondents was 3.6%. Wearing surgical masks during non-aerosol generating procedures was a risk factor of COVID-19, whereas reducing the number of patients was a protective factor. Conclusions Considering the similar COVID-19 prevalence between dentists and the general population, such data suggest that dentists are not overexposed in their work environment when adequate preventive measures are applied. Impact Dentists should wear specific PPE (FFP2, FFP3 or (K)N95 masks) including during non-aerosol generating procedures and reduce the number of patients to allow proper implementation of disinfection and aeration procedures. Considering the similarities between COVID-19 and other viral respiratory infections, such preventive measures may also be of interest to limit emerging variants spread as well as seasonal viral outbreaks.

Face Mask: A Novel Material for Protection against Bacteria/Virus

Facemask is defined as a loose-fitting device which creates a physical barrier between the mouth and nose of the individual wearing mask and likely pollutants in the immediate environment. Evolution of severe viral respiratory infectious agents such as pandemic COVID-19, severe acute respiratory syndrome, pandemic influenza and avian influenza has driven the use of protective face masks by public and health workers. In this chapter, characteristics features and uses of different types of masks are discussed. Characteristics of various nonwoven technologies for manufacturing face masks are also discussed. Test methods and recent developments in face masks are briefly covered.

Effect of Relative Humidity in Air on the Transmission of Respiratory Viruses

Viral respiratory infections have plagued mankind over its known history. Unfortunately, there has been a lack of meaningful progress in preventing the spread of viral respiratory infections globally. The central dogma appears to be that viruses are the villains. This framing focuses on a viral load balance (VLB) in the air. It follows that physical dilution through various means have been the primary focus of attempts to reduce the spread of infections. The problem of obesity provides a good example of how paradigm blindness can slow down progress in a field. Obesity has been framed as an energy balance disorder that blames overeating and lack of exercise for weight gain. Reframing obesity as a disorder of fat metabolism and storage caused by the quantity and quality of carbohydrates in the diet, referred to as the carbohydrate-insulin model (CIM), opened an alternative line of questioning with a testable hypothesis. Similarly, we postulate an alternative way to frame the spread of viral respiratory infections that would lead to new insights and potentially new ways to prevent infections. It has long been recognized that viral respiratory infections show a pronounced seasonal variation, referred to as seasonal forging, such that they increase in the winter but decrease or virtually disappear in the summer. In temperate regions, people spend over 90% of their time indoors. This is, therefore, where most respiratory infections are expected to occur. Evidence has been accumulating for decades on the strong correlation between variations in indoor relative humidity (RH) and variations in infection rates. Within a RH Goldilocks zone of 40%-60%, encapsulated viruses like influenza and SARS are optimally inactivated outside the infected host. Below 40% and above 80%, viruses can survive for extended periods in the air or on surfaces. This may explain in part the seasonality of infections as the indoor level of RH in winter is typically about 20% and above 40% in summer in temperate regions. However, the mechanism for the inactivation at midrange RH (in summer) is not well understood. This paper offers a hypothesis that could explain these observations. We have demonstrated that H2O2 and other reactive oxygen species (ROS) are formed spontaneously at the water-air interface of pure water microdroplets. Using only water and a nebulizing gas in the presence of oxygen, we have demonstrated the significant disinfectant potential of pure water microdroplets caused by the activity of H2O2 and other ROS. We postulate that spontaneous H2O2 and ROS formation in viruses containing exhaled microdroplets have a similar virucidal effect at mid-range RH. The droplet evaporation rate is sufficient to concentrate the solutes and provide enough time for reactions to occur at significantly higher rates than in bulk solutions. The concentration of H2O2 has also been shown to be positively correlated to RH. In addition, several other ROS/RNS may be present or formed through interactions with H2O2 that may act as even more effective virucide disinfectants to inactivate the virus. Below RH 40% evaporation happens too rapidly for these reactions to make an impact before the droplet is desiccated, and above RH 80% the solutes remain too diluted. Rapid inactivation of viruses at midrange RH may therefore play a greater role in preventing infections than physical dilution of virus load in the air through excessive mechanical ventilation. Similar to obesity, we suggest that a new paradigm that considers virus infectivity outside the host rather than the virus load balance in the air alone could greatly contribute to our understanding of respiratory infections. The proposed new “Relative Humidity Infectivity” RHI paradigm could explain the causal mechanisms underlying seasonal respiratory infections. This can point to better prevention strategies that avoid further distortion of our indoor environment and create conditions within which humans can thrive and be optimally protected. We need more focus on testing the various hypotheses and more data to determine which of the two paradigms will lead us in the right direction or how to use the best of both in an optimal combination. The stakes cannot be higher, and the potential for eradicating future viral respiratory pandemics with nature-based solutions may be right under our noses, literally.

A case report on Severe Acute Respiratory Infection

Introduction: Severe Acute Respiratory Syndrome is a zootoxic viral respiratory illness caused by the severe acute respiratory syndrome corona virus (SARS-CoV or SARS-The syndrome was the cause of the Severe Acute Respiratory Syndrome outbreak in 2002–2004. The virus was traced back to cave-dwelling horseshoe bats via Asian palm civets in late 2017 by Chinese scientists in Xizang Yi Ethnic Township, Yunnan. SARS was a rare illness; there were 8,422 cases at the end of the pandemic in June 2003, with an 11 percent case fatality rate (CFR) (CoV-1), the initial strain of the SARS corona virus species (SARSr-CoV). Clinical Finding: Swelling over Right. Half of face, Breathlessness. Diagnostic Evaluation: Blood test: Hb – 9.2gm%, Total RBC count- 3.22 millions/cu.mm, HCT- 26.6%, Total WBC count – 6600/cu.mm, Monocytes-02%, granulocytes-85%, lymphocytes-10000 /mcl. HRCT Scan OF Thorax: Multiple ill defined patchy ground glass opacities with consolidation and sepal thickening in bilateral lungs filled s/o infective etiology possibility of atypical viral pneumonia. View of covid positive PCR test; imagine grading corad-6 with CT severity score – 03\25 (Mild). Therapeutic Intervention: Inj.Amphotericin-B 500mg IV, Inj.Piptaz 4.4gm IV x TDS, Inj.levoflox 500 mg x OD, Inj.Clindamycin 300mg x BD, Inj.pantaprazol 40 mg x OD, Inj.Emset 4mg x TDS, Tab. limcee 500 mg x BD. Outcome: After Treatment, the patient shows improvement. His swelling over face decrease, and breathlessness decrease. Conclusion: My patient was admitted in SARI-HDU, AVBRH with complaint of swelling over face Right side, and breathlessness. After getting appropriate treatment his condition was improved.