Inhaled fosamprenavir for laryngopharyngeal reflux: Toxicology and fluid dynamics modeling
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SUBMITTER: Lesnick A
PROVIDER: S-EPMC10866582 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:ObjectiveMore than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin-mediated laryngeal damage in vivo.MethodsDrug and pepsin binding and inhibition were screened by high-throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis.ResultsHIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC50 in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin-mediated laryngeal damage (i.e., reactive epithelia, increased intraepithelial inflammatory cells, and cell apoptosis). Darunavir gavage elicited mild reactivity and no discernable protection; aerosol protected against apoptosis.ConclusionsFosamprenavir and darunavir, FDA-approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin-mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects.Level of evidenceNA. Laryngoscope, 133:S1-S11, 2023.
| S-EPMC9732152 | biostudies-literature
Project description:BackgroundIt is unknown whether the reflux symptom index (RSI) can replace pH monitoring as a diagnostic tool for laryngopharyngeal reflux (LPR) in Chinese people. The relationships between reflux parameters and LPR symptoms also require further research.MethodsA total of 216 Chinese patients underwent laryngopharyngeal pH monitoring and filled out an RSI questionnaire. Laryngopharyngeal pH monitoring indicated a diagnosis of LPR for patients with 7 or more episodes of reflux or a reflex area index (RAI) of 6.3 or more. The RSI questionnaire indicated a diagnosis of LPR for patients with RSI scores of 14 or higher.ResultsOf the 216 patients, 85 were diagnosed with LPR as assessed by the RSI, and 72 were diagnosed with LPR through laryngopharyngeal pH monitoring. The Cohen's kappa coefficient comparing LPR diagnosis consistency between RSI score and laryngopharyngeal pH monitoring was 0.133 (P=0.007). This indicated the two diagnostic methods were consistent to a low degree; the total consistency rate was only 59.7% (129/216). The sensitivity of the RSI was 48.6% (35/72), and its specificity was 82.5% (94/114). For convenience, we named the nine symptom groups in the RSI sequentially as P1-P9. P1, P2, P3, P5, P6, and P7 were all correlated with at least one reflux parameter (P<0.05), but P4, P8, and P9 were not correlated with any reflux parameters (P>0.05). A total of 72 patients were diagnosed using pH monitoring, the gold standard for LPR diagnosis. The most common symptoms of LPR were found to be P9, P3, P8, P7, and P2 in these patients. The symptoms that most seriously affected patients were P9, P8, P3, P7, and P2.ConclusionsThe consistency in diagnosis of LPR between the RSI and laryngopharyngeal pH monitoring was poor, meaning the RSI is not a suitable LPR initial screening tool and cannot replace pH monitoring. Additionally, reflux symptoms P4, P8, and P9 were not correlated with any reflux parameters. The most prevalent LPR symptom was P9, followed by P3, P8, P7, and P2. The most severe symptom was also P9, followed by P8, P3, P7, and P2.
| S-EPMC7859794 | biostudies-literature
Project description:OBJECTIVES:This study was conducted to investigate the current practices of Asian otolaryngologists for laryngopharyngeal reflux (LPR). METHODS:An online survey about LPR was sent to 2,000 members of Asian otolaryngological societies, and a subgroup analysis was performed between Western and Eastern Asian otolaryngologists. The survey was conducted by the Laryngopharyngeal Reflux Study Group of Young Otolaryngologists of the International Federation of Oto-rhino-laryngological Societies. RESULTS:Among approximately 1,600 Asian otolaryngologists, 146 completed the survey (62 from Western Asian countries, 84 from Eastern Asian countries). A substantial majority (73.3%) of the otolaryngologists considered LPR and gastroesophageal reflux disease to be different diseases. The symptoms thought to be closely related to LPR were coughing after lying down, throat clearing, and globus sensation. The findings thought to be closely related to LPR were posterior commissure granulations and hypertrophy, arytenoids, and laryngeal erythema. The respondents indicated that they mostly diagnosed LPR (70%) after an empirical therapeutic trial of proton pump inhibitors (PPIs). Although multichannel intraluminal impedance-pH (MII-pH) monitoring is a useful tool for diagnosing nonacid or mixed LPR, 78% of Asian otolaryngologists never or very rarely used MII-pH. Eastern Asian otolaryngologists more frequently used once-daily PPIs (64.3% vs. 45.2%, P=0.021), whereas Western Asian otolaryngologists preferred to use twice-daily PPIs (58.1% vs. 39.3%, P=0.025). The poor dietary habits of patients were considered to be the main reason for therapeutic failure by Asian otolaryngologists (53.8%). Only 48.6% of Asian otolaryngologists considered themselves to be adequately knowledgeable and skilled regarding LPR. CONCLUSION:Significant differences exist between Western and Eastern Asian otolaryngologists in the diagnosis and treatment of LPR. Future consensus statements are needed to establish diagnostic criteria and therapeutic regimens.
| S-EPMC7435427 | biostudies-literature
Project description:OBJECTIVES:To investigate the role of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in the development of dental disorders. METHODS:The first outcome was review of the role of reflux in the development of dental disorders in adults. The second outcome was review of the potential pathophysiological mechanisms underlying the association between reflux and dental disorders. Three investigators screened publications for eligibility and exclusion based on predetermined criteria through a literature search conducted on PubMed, Cochrane Library, and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS:From 386 publications, 24 studies were kept for analysis. Objective approaches were used in 16 studies to confirm GERD diagnosis. Pharyngeal reflux episodes (LPR) were considered in 2 studies. No study considered nonacid reflux. The study results supported a higher prevalence of dental erosion and caries in reflux patients compared with healthy individuals. Patients with dental erosion have a higher prevalence of reflux than controls. The pathophysiological mechanisms would involve changes in the saliva physiology. No study investigated the microbiota modifications related to reflux although the findings are supporting the critical role of microbiota change in the development of dental disorders. There is an important heterogeneity between studies about diagnostic methods and clinical outcome evaluation. CONCLUSION:The involvement of reflux in the development of dental disorders is not formally demonstrated and requires future investigations considering pharyngeal acid and nonacid reflux episodes and in particular their potential impact on oral microbiota.
| S-EPMC7428125 | biostudies-literature
Project description:Background and objectivesLaryngopharyngeal reflux (LPR) exhibits nonspecific clinical presentations, and these symptoms may be associated with other conditions such as allergies, including allergic rhinitis and laryngitis. However, there is a gap in the literature regarding the correlation of laryngopharyngeal reflux with allergic rhinitis/laryngitis. Hence, the aim of this study is to explore the correlation between these two conditions.Patients and methodsA total of 126 patients with suggestive manifestations of laryngopharyngeal reflux were included in this study. Patients were classified into LPR positive and negative groups based on the results of a 24-hour oropharyngeal pH monitoring system while allergic rhinitis status was assessed with the score for allergic rhinitis (SFAR).The results of the two groups were compared regarding the sfar score correlation between the ph results and sfar score was explored resultsThe LPR positive group demonstrated significantly higher SFAR scores compared to the negative LPR group (p < 0.0001). In addition, the Ryan score was significantly correlated with the SFAR total score and its symptomatology-related items (r ranged between 0.35 and 0.5). Conclusion. It seems that laryngopharyngeal reflux increases patients' self-rating of allergic manifestations. It appears that there is an association between laryngopharyngeal reflux and allergic rhinitis/laryngitis.
| S-EPMC5885348 | biostudies-literature
Project description:RationaleLaryngopharyngeal reflux (LPR) affects up to 20% of Western populations. Although individual morbidity is usually moderate, treatment costs are high and there are associations with other diseases, including laryngeal cancer. To date, there have been no studies of the mucosal immune response to this common inflammatory disease.ObjectivesTo determine the mucosal immune response to LPR.MethodsWe performed a prospective immunologic study of laryngeal biopsies from patients with LPR and control subjects (n = 12 and 11, respectively), and of primary laryngeal epithelial cells in vitro.Measurements and main resultsQuantitative multiple-color immunofluorescence, using antibodies for lymphocytes (CD4, CD8, CD3, CD79, CD161), granulocytes (CD68, EMBP), monocytic cells (CD68, major histocompatibility complex [MHC] class II), and classical and nonclassical MHC (I, II, beta(2)-microglobulin, CD1d). Univariate and multivariate analysis and colocalization measurements were applied. There was an increase in percentage area of mucosal CD8(+) cells in the epithelium (P < 0.005), whereas other leukocyte and granulocyte antigens were unchanged. Although epithelial MHC class I and II expression was unchanged by reflux, expression of the nonclassical MHC molecule CD1d increased (P < 0.05, luminal layers). In vitro, laryngeal epithelial cells constitutively expressed CD1d. CD1d and MHC I expression were inversely related in all subjects, in a pattern which appears to be unique to the upper airway. Colocalization of natural killer T (NKT) cells with CD1d increased in patients (P < 0.01).ConclusionsThese data indicate a role for the CD1d-NKT cell axis in response to LPR in humans. This represents a useful target for novel diagnostics and treatments in this common condition.
| S-EPMC2643204 | biostudies-literature
Project description:Laryngopharyngeal reflux (LPR) is a prevalent disease affecting a high proportion of patients seeking laryngology consultation. Diagnosis is made subjectively based on history, symptoms, and endoscopic assessment. The results depend on the examiner's interpretation of endoscopic images. There are still no consistent objective diagnostic methods. The aim of this study is to use image processing techniques to quantize the laryngeal variation caused by LPR, to judge and analyze its severity. This study proposed methods of screening sharp images automatically from laryngeal endoscopic images and using throat eigen structure for automatic region segmentation. The proposed image compensation improved the illumination problems from the use of laryngoscope lens. Fisher linear discriminant was used to find out features and classification performance while support vector machine was used as the classifier for judging LPR. Evaluation results were 97.16% accuracy, 98.11% sensitivity, and 3.77% false positive rate. To evaluate the severity, quantized data of the laryngeal variation was used. LPR images were combined with reflux symptom index score chart, and severity was graded using a neural network. The results indicated 96.08% accuracy. The experiment indicated that laryngeal variation induced by LPR could be quantized by using image processing techniques to assist in diagnosing and treating LPR.
| S-EPMC7335083 | biostudies-literature
Project description:The PeptestTM is a non-invasive diagnostic test for measuring the pepsin concentration in saliva, which is thought to correlate with laryngopharyngeal reflux (LPR). The aim of this study was to investigate the diagnostic value of the Peptest in detecting LPR based on 24-h multichannel intraluminal impedance-pH (MII-pH) monitoring using several hypopharyngeal reflux episodes as criterion for LPR. Patients with suspected LPR were examined with the Reflux Symptom Index (RSI), Reflux Finding Score (RFS), fasting Peptest, and MII-pH monitoring. We calculated the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Peptest, RSI, and RFS based on the threshold of one and six hypopharyngeal reflux episodes. Altogether, the data from 46 patients were analyzed. When one hypopharyngeal reflux episode was used as a diagnostic threshold for LPR, the accuracy, sensitivity, specificity, PPV, and NPV were, respectively, as follows: 35%, 33%, 100%, 100%, and 3%, for the Peptest; 39%, 40%, 0%, 95%, and 0%, for the RSI; and 57%, 58%, 0%, 96%, and 0%, for the RFS. The accuracy, sensitivity, specificity, PPV, and NPV of the Peptest for diagnosing gastroesophageal reflux disease (GERD) were 46%, 27%, 63%, 40.0%, and 48%, respectively. A positive Peptest is highly supportive of a pathological LPR diagnosis. However, a negative test could not exclude LPR.
| S-EPMC8268930 | biostudies-literature
Project description:BackgroundObstructive sleep apnea syndrome (OSAS) and laryngopharyngeal reflux (LPR) have been found to coexist in the population. OSAS and LPR also share obesity as an important risk factor. However, the relationship between LPR and OSAS remains unclear. This study aimed to correlate LPR as measured by the Reflux Symptom Index (RSI) and the Reflux Finding Score (RFS) with OSAS.MethodsThis cross-sectional study included sixty-four subjects who underwent anamnesis to complete the RSI and the Epworth Sleeping Scale (ESS). The subjects were then divided into the OSAS and non-OSAS groups based on the Apnea-Hypopnea Index (AHI) obtained through a polysomnography examination. Both groups underwent a flexible fiberoptic nasopharyngolaryngoscopy examination to determine the RFS. LPR was identified based on the RSI and RFS.ResultsThe mean BMI of the OSAS group significantly was higher than the non-OSAS group (p < 0.05). Most of the subjects in the OSAS group exhibited mild-moderate OSAS (AHI 10-29), and severe OSAS occurred in only seven subjects. The mean RSI and RFS values in the OSAS group did not differ significantly from the non-OSAS group (p = 0.34 and p = 0.36, respectively). The proportion of LPR between the mild-moderate OSAS group, the severe OSAS group, and the non-OSAS group did not differ significantly (p = 1.00). RSI and RFS did not significantly correlate with AHI. Based on RSI, the proportion of LPR between the ESS (+) and ESS (-) groups did not significantly differ (adjusted p = 0.062). The proportion of LPR based on RFS was almost equal between the ESS (+) and ESS (-) groups (p = 0.817).ConclusionsThe BMI of the OSAS group was significantly higher than the non-OSAS group. There was no significant difference in RSI and RFS between the OSAS and non-OSAS groups. There was no significant correlation between RSI and AHI, or between RFS and AHI. There was no significant difference in the proportion of RSI between the ESS (+) and the ESS (-) groups.
| S-EPMC9053297 | biostudies-literature
Project description:Laryngopharyngeal reflux (LPR) is characterized by backflow of gastric or gastroduodenal content and gases into the upper aerodigestive tract, which can damage the mucus membranes of the larynx and pharynx. It is associated with a variety of symptoms such as retrosternal burning and acid regurgitation, or other unspecific symptoms such as hoarseness, globus sensation, chronic cough, or mucus hypersecretion. Due to the lack of data and the heterogeneity of studies, diagnosis of LPR is problematic and challenging, as recently discussed. Moreover, the different therapeutic approaches are also discussed controversially in the face of the poor evidence base, and include pharmacologic and conservative dietary measures. Hence, in the following review, the available options for treatment of LPR are critically discussed and summarized for daily clinical use.
| S-EPMC10125953 | biostudies-literature