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PloS One 2022Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In...
RATIONALE
Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.
OBJECTIVES
To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.
METHODS
Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.
RESULTS AND DISCUSSION
Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 μg/L in all samples.
CONCLUSION
Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted.
Topics: Administration, Inhalation; Dry Powder Inhalers; Healthy Volunteers; Humans; Hydroxychloroquine; Powders; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35930536
DOI: 10.1371/journal.pone.0272034 -
Journal of Complex Networks Dec 2021This article proposes a unique approach to bring out the potential of graph-based features to reveal the hidden signatures of wet (WE) and dry (DE) cough signals, which...
This article proposes a unique approach to bring out the potential of graph-based features to reveal the hidden signatures of wet (WE) and dry (DE) cough signals, which are the suggestive symptoms of various respiratory ailments like COVID 19. The spectral and complex network analyses of 115 cough signals are employed for perceiving the airflow dynamics through the infected respiratory tract while coughing. The different phases of WE and DE are observed from their time-domain signals, indicating the operation of the glottis. The wavelet analysis of WE shows a frequency spread due to the turbulence in the respiratory tract. The complex network features namely degree centrality, eigenvector centrality, transitivity, graph density and graph entropy not only distinguish WE and DE but also reveal the associated airflow dynamics. A better distinguishability between WE and DE is obtained through the supervised machine learning techniques (MLTs)-quadratic support vector machine and neural net pattern recognition (NN), when compared to the unsupervised MLT, principal component analysis. The 93.90% classification accuracy with a precision of 97.00% suggests NN as a better classifier using complex network features. The study opens up the possibility of complex network analysis in remote auscultation.
PubMed: 35003751
DOI: 10.1093/comnet/cnab039 -
IEEE Access : Practical Innovations,... 2020The current pandemic associated with the novel coronavirus (COVID-19) presents a new area of research with its own set of challenges. Creating unobtrusive remote...
The current pandemic associated with the novel coronavirus (COVID-19) presents a new area of research with its own set of challenges. Creating unobtrusive remote monitoring tools for medical professionals that may aid in diagnosis, monitoring and contact tracing could lead to more efficient and accurate treatments, especially in this time of physical distancing. Audio based sensing methods can address this by measuring the frequency, severity and characteristics of the COVID-19 cough. However, the feasibility of accumulating coughs directly from patients is low in the short term. This article introduces a novel database (NoCoCoDa), which contains COVID-19 cough events obtained through public media interviews with COVID-19 patients, as an interim solution. After manual segmentation of the interviews, a total of 73 individual cough events were extracted and cough phase annotation was performed. Furthermore, the COVID-19 cough is typically dry but can present as a more productive cough in severe cases. Therefore, an investigation of cough sub-type (productive vs. dry) of the NoCoCoDa was performed using methods previously published by our research group. Most of the NoCoCoDa cough events were recorded either during or after a severe period of the disease, which is supported by the fact that 77% of the COVID-19 coughs were classified as productive based on our previous work. The NoCoCoDa is designed to be used for rapid exploration and algorithm development, which can then be applied to more extensive datasets and potentially real time applications. The NoCoCoDa is available for free to the research community upon request.
PubMed: 34786285
DOI: 10.1109/ACCESS.2020.3018028 -
ERJ Open Research Jan 2021Cough is induced by inhaled prostacyclin analogues including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we...
Cough is induced by inhaled prostacyclin analogues including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved in TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS). Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously. In guinea pigs, cough with inhaled TRE (1.23 µg·kg) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg) to induce cough. TRE cough was blocked with IP and tachykinin NK receptor antagonists but not with EP, EP, EP, DP or bradykinin B antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnoea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects. The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibres in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves.
PubMed: 33614774
DOI: 10.1183/23120541.00592-2020 -
European Journal of Internal Medicine Apr 2023Angiotensin converting enzyme inhibitors (ACEi) have consistently demonstrated improved survival and reduced risk of major cardiovascular events, across the spectrum of... (Review)
Review
Angiotensin converting enzyme inhibitors (ACEi) have consistently demonstrated improved survival and reduced risk of major cardiovascular events, across the spectrum of cardiovascular disease, including hypertension, coronary artery disease, myocardial infarction, and heart failure. The cardioprotective effects of ACEi result from inhibiting the conversion of angiotensin I to angiotensin II, and inhibition of bradykinin degradation. They are generally well tolerated but may cause the onset of a dry cough in some patients. This review presents current evidence on the incidence and mechanisms of cough associated with ACEi use, and then considers how to manage ACEi-related cough in clinical practice. The incidence of ACEi-induced cough in the published literature varies widely due to heterogeneity in the source data and lack of adequate controls. Incidence also varies among individual ACEi with agents such as perindopril, which has a high tissue ACE affinity, associated with a lower rate of cough. Evidence from real-world studies shows that the incidence of ACEi-associated cough is lower than rates reported in clinical trials. Patients who experience any dry cough are often switched to angiotensin- receptor blockers or other classes of antihypertensive drugs, regardless of cough severity. To avoid inappropriate discontinuation of ACEi in clinical practice, an alternative approach in patients with persistent cough is to perform a challenge/re-challenge to determine if re-introduction of ACEi is associated with recurrence of symptoms. Incidence of cough should not be considered a class effect for ACEi, and the patient may benefit by a switch from one ACEi to another. Every effort should be made to enable patients to continue ACEi therapy to reduce adverse cardiovascular outcomes and improve survival.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Cough; Antihypertensive Agents; Hypertension; Angiotensin Receptor Antagonists; Myocardial Infarction
PubMed: 36628825
DOI: 10.1016/j.ejim.2023.01.005 -
Temperature (Austin, Tex.) 2015Temperatures above and below what is generally regarded as "comfortable" for the human being have long been known to induce various airway symptoms, especially in... (Review)
Review
Temperatures above and below what is generally regarded as "comfortable" for the human being have long been known to induce various airway symptoms, especially in combination with exercise in cold climate with temperatures below 0°C, which is naturally since exercise is followed by enhanced ventilation and thus greater amounts of inhaled cold air. The aim was to highlight the knowledge we have today on symptoms from the airways (here also including the eyes) arisen from various temperatures; the mechanisms, the pathophysiology and their clinical significance. The most common eye and airway conditions related to temperature changes are dry eye disease, rhinitis, laryngeal dysfunction, asthma, chronic obstructive pulmonary disease and chronic cough. Transient receptor potential (TRP) ion channels are probably involved in all temperature induced airway symptoms but via different pathways, which are now beginning to be mapped out. In asthma, the most persuasive hypothesis today is that cold-induced asthmatic bronchoconstriction is induced by dehydration of the airway mucosa, from which it follows that provocations with osmotic stimuli like hypertonic saline and mannitol can be used as a surrogate for exercise provocation as well as dry air inhalation. In chronic unexplained cough there seems to be a direct influence of cold air on the TRP ion channels followed by coughing and increased cough sensitivity to inhaled capsaicin. Revelations in the last decades of the ability of several airway TRP ion channels to sense and react to ambient air temperature have opened new windows for the understanding of the pathogenesis in a diversity of airway reactions appearing in many common respiratory diseases.
PubMed: 27227021
DOI: 10.1080/23328940.2015.1012979 -
Medical Archives (Sarajevo, Bosnia and... Feb 2017Cough is one of the most common symptoms that doctor faces in working with pediatric population, and according to some characteristics of cough, doctors can often... (Review)
Review
Cough is one of the most common symptoms that doctor faces in working with pediatric population, and according to some characteristics of cough, doctors can often conclude localization, and sometimes even the nature of the disease that causes it. Cough is not only the physiological defense reaction, but a symptom of a disease. According to duration it can be acute, chronic and recidivist, recurrent and persistent, strong or discreet, caused by changes in body position and changes in outside temperature. Pathoanatomically it is divided into lobar, lobular, alveolar and interstitial, pathogenetically to bronchogenic and hematogenous, as well as in immuno competent and immunocompromised, and clinically on the local and inpatient (72 hours after hospital admission). Considering the contents, cough can be productive-with secretion from the respiratory tract, and unproductive-dry, without secretion. By auscultation bronchial breathing, rattle and crepitus can be heard. The primary diagnostics is radiological, posterior to anterior (P-A) and lateral footage of the chest. Laboratory findings in typical pneumonia, are characterized by leukocytosis, neutrophilia and shift of blood image to the left. Sedimentation is accelerated and C-reactive protein is elevated. The basic bacteriological diagnosis is sputum Gram's stain and culture of sputum. In atypical pneumonia, leukocytes are usually in the normal range, and it is necessary to do serological tests (IgM and IgG antibodies). The role of doctors in primary health care is auscultation differentiation of murmurs with confirmation of doubt if there is pathological findings by laboratory tests and treatment, depending on the type of cough. Treatment is essentially pharmacological, with irrefutable importance of non-pharmacological measures.
Topics: Adolescent; Child; Chronic Disease; Cough; Guidelines as Topic; Humans; Predictive Value of Tests; Primary Health Care; Respiratory Function Tests; Sputum
PubMed: 28428678
DOI: 10.5455/medarh.2017.71.66-68 -
Current Pharmacology Reports 2021COVID-19 represents the biggest health challenge. Although the mortality rate of COVID-19 is low, the high numbers of infected people and those with post-COVID-19... (Review)
Review
COVID-19 represents the biggest health challenge. Although the mortality rate of COVID-19 is low, the high numbers of infected people and those with post-COVID-19 symptoms represent a real problem for the health system. A high number of patients with COVID-19 or people recovered from COVID-19 suffer from a dry cough and/or myalgia. Interestingly, an imbalance in bradykinin was observed in COVID-19 patients, which might be due to the accumulation of bradykinin as a result of a reduction in the degradation of bradykinin. This finding inspired the idea of possible similitude between the dry cough that is induced by angiotensin-converting enzyme inhibitors and the COVID-19-induced dry cough. Both of these types of cough are mediated, at least partially, by bradykinin. They both manifested as a persistent dry cough that is not responded to traditional dry cough remedies. However, several drugs were previously investigated for the treatment of angiotensin-converting enzyme inhibitor-induced dry cough. Here, we hypothesized that such treatment might be useful in COVID-19-induced dry cough and other bradykinin-related symptoms such as generalized pain and myalgia. In this article, evidence was presented to support the use of indomethacin as a potential treatment of COVID-19-induced dry cough. The choice of indomethacin was based on its ability to suppress the cyclooxygenase enzyme while also lowering the level of the inflammatory mediator bradykinin. Furthermore, indomethacin has been shown to be effective in treating angiotensin-converting enzyme inhibitor-induced dry cough. Moreover, indomethacin is a long-established, low-cost, effective, and readily available medication.
PubMed: 33907665
DOI: 10.1007/s40495-021-00257-6 -
Frontiers in Pharmacology 2023Observational studies and meta-analyses have demonstrated a positive correlation between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer....
Observational studies and meta-analyses have demonstrated a positive correlation between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer. However, the findings remain controversial; furthermore, the relationship between ACEI-induced cough and lung cancer development remains unknown. We used Mendelian randomization (MR) to verify the association between ACEI use, ACEI-induced cough, and the risk of lung cancer. We performed a two-sample MR analysis to determine the unconfounded relationships between ACE inhibition, which mimics the effects of ACEIs, and genetic proxies for ACEI-induced cough and lung cancer. Single nucleotide polymorphisms that imitate ACE receptors and ACEI-induced cough were collected and integrated into a meta-analysis of existing genome-wide association studies for various lung cancers. The relationship was quantified using inverse variance weighting, weighted median, and MR-Egger methods. A statistically significant association was observed between ACE inhibition and the risk of small cell lung cancer for Europeans (excluding rs118121655/rs80311894). Associations were identified between ACEI-induced cough and the risk of lung cancer for Europeans, although not for Asians, and between ACEI-induced cough and lung adenocarcinoma (excluding rs360206). Our findings reveal a relationship between ACE inhibition and lung cancer development, as well as a significant association between ACEI-induced cough and a higher risk of lung cancer for Europeans. Patients with hypertension who experience dry cough as a side effect of ACEI use should consider switching to an alternative antihypertensive treatment.
PubMed: 37799968
DOI: 10.3389/fphar.2023.1267924 -
Federal Practitioner : For the Health... Sep 2023
PubMed: 38562160
DOI: 10.12788/fp.0407