Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials.

BACKGROUND AND OBJECTIVES: Chronic refractory cough is a challenging condition that requires a thorough evaluation and management approach. P2X3 receptors that are ATP-dependent play an important part in nerve fiber sensitization and pathological pain pathways. We conducted this systematic review and meta-analysis to determine the long-term safety and efficacy of P2X3 receptor antagonist drugs in chronic cough. METHODS: We systematically searched PubMed, Scopus, Web of Science, and Embase to identify all relevant published studies through January 15, 2023 that assessed P2X3 antagonists in chronic cough. The protocol was registered in the PROSPERO database with ID: CRD42023422408. Efficacy outcomes were awake (daytime) cough frequency, night cough frequency, 24-h cough frequency, Cough Severity Diary, and total Leicester Cough Questionnaire score. We used the random-effect model to pool the data using RStudio and CMA software. RESULTS: A total of 11 randomized controlled trials comprising 1350 patients receiving a p2x3 antagonist compared to the placebo group were included in this meta-analysis. A significant decrease in 24-h cough frequency (MD = -4.99, 95% CI [-7.15 to -2.82], P < 0.01), awake (daytime) cough frequency (MD = -7.18, 95% CI [-9.98 to 4.37], P < 0.01), and total Leicester Cough Questionnaire score (MD = 1.74, 95% CI [1.02 to 2.46], P < 0.01) exhibited between the P2X3 antagonist and placebo groups. The frequency of the night cough showed an insignificant difference between the two groups. According to the safety, drug-related adverse events, dysgeusia, hypogeusia, and ageusia significantly increased between the P2X3 antagonist and placebo groups. CONCLUSION: P2X3 receptor antagonists are promising drugs for treating chronic cough by significantly reducing the frequency, severity, and quality. Some potential side effects may include drug-related adverse events such as hypogeusia, ageusia, and dysgeusia.

Drug-induced olfactory and gustatory dysfunction: Analysis of FDA adverse events reporting system.

OBJECTIVES: With the COVID-19 pandemic, there is growing interest and research in olfactory and gustatory dysfunction (OGD). Drug-induced dysfunction is an often overlooked etiology. While several medications include smell or taste disturbance as a side effect, there are no publications describing which medications are most frequently implicated. We aim to describe the patterns of these adverse drug reactions (ADRs) using the FDA Adverse Events Reporting System (FAERS). METHODS: The FAERS database was queried from 2011 to 2021 for terms describing ADRs related to OGD. Terms included anosmia, hyposmia, olfactory test abnormal, olfactory nerve disorder, hallucination olfactory, parosmia, ageusia, hypogeusia, dysgeusia, and taste disorder. We identified the top reported medications associated with general smell dysfunction, general taste dysfunction, reduced smell, and altered smell. RESULTS: From 2011 to 2021, 16,091 ADRs were reported with OGD, of which13,641 (84.8%) and 2,450 (15.2%) were associated with gustatory and olfactory reactions, respectively. Zinc products (370 reports) and fluticasone propionate (214) were most commonly associated with olfactory dysfunction, specifically reduced olfaction. Varenicline (24) and fluticasone propionate (23) were most commonly associated with altered smell. Lenalidomide (490) and sunitinib (468) were most commonly associated with gustatory dysfunction. Antineoplastic and immunomodulating medications accounted for 21.6% and 36.3% of olfactory and gustatory ADRs, respectively. Among this category, immunoglobulin drugs were the most commonly associated with OGD ADRs. CONCLUSION: Gustatory dysfunction is more commonly reported ADR compared with olfactory dysfunction. Immunologic/rheumatologic medications are the leading culprit of reported OGD. With increasing numbers of patients presenting to otolaryngologists for OGD, it is important to consider drug-induced etiology. LEVEL OF EVIDENCE: III.

Brain-derived neurotrophic factor overexpression in taste buds diminishes chemotherapy induced taste loss.

Vismodegib is used in patients suffering from advanced basal cell carcinoma (BCC), but 100% of the patients taking it report dysgeusia and 50% discontinue the treatment. Treatment with neurotrophic factors can stimulate neuronal survival and functional improvement in injured organs. Here, we analysed novel transgenic mouse lines in which brain-derived neurotrophic factor (BDNF) is overexpressed in taste buds, to examine whether higher levels of BDNF would reduce or prevent negative side effects of vismodegib in the taste system. BDNF plays crucial roles for development, target innervation, and survival of gustatory neurons and taste buds. The behavioural test in this study showed that vehicle-treated wild-type mice prefered 10 mM sucrose over water, whereas vismodegib treatment in wild-type mice caused total taste loss. Gustducin-BDNF mice had a significantly increased preference for low concentration of sucrose solution over water compared to wild-type mice, and most importantly the transgenic mice were able to detect low concentrations of sucrose following vismodegib treatment. We evaluated taste cell morphology, identity, innervation and proliferation using immunohistochemistry. All drug-treated mice exhibited deficits, but because of a possible functional upcycled priming of the peripheral gustatory system, GB mice demonstrated better morphological preservation of the peripheral gustatory system. Our study indicates that overexpression of BDNF in taste buds plays a role in preventing degeneration of taste buds. Counteracting the negative side effects of vismodegib treatment might improve compliance and achieve better outcome in patients suffering from advanced BCC.

Oral Adverse Events Following COVID-19 Vaccination: Analysis of VAERS Reports.

Background: Oral adverse events (AEs) following COVID-19 vaccination have been sporadically reported during the previous months, warranting further investigation for their prevalence and suspected relationship with vaccine-elicited immune response. Methods: A retrospective analysis using the Vaccine Adverse Event Reporting System (VAERS) data was conducted to evaluate AEs within the oral cavity (mucosa, tongue, lips, palate, dentition, salivary glands) and AEs involving taste and other sensations. Oral AEs reported after receiving COVID-19 vaccination (test group) and seasonal influenza vaccination (control group) were extracted and cross-tabulated to assess their relative prevalence. Results: Among the 128 solicited (suspected) oral AEs, oral paresthesia (0.872%) was most reported after receiving COVID-19 vaccines, followed by the swelling of lips (0.844%), ageusia (0.722%), oral hypoesthesia (0.648%), swollen tongue (0.628%), and dysgeusia (0.617%). The reported prevalence of oral AEs was higher in the COVID-19 vaccine group than in the seasonal influenza group. The distribution pattern of the most reported oral AEs was similar for both COVID-19 and seasonal influenza vaccines. Female sex, older age (>39 years old), primer doses, and mRNA-based COVID-19 vaccines exhibited a higher reported prevalence of oral AEs. Conclusion: Within the limitations of this study, COVID-19 vaccines were found to be associated with rare oral AEs that are predominantly similar to those emerging following seasonal influenza vaccines. The most commonly reported oral AEs were oral paraesthesia (mouth-tingling), lip swelling, and ageusia, representing various pathophysiologic pathways that remain unclear. Taste-related AEs should be acknowledged in the context of the COVID-19 pandemic and the public should be adequately informed about a potential taste dysfunction after receiving the COVID-19 vaccination. Dentists and dental teams need to be aware of the prevalence, severity, and prognosis of oral AEs to inform their patients and increase public confidence in vaccines.

Use of Favipiravir for the Treatment of Coronavirus Disease 2019 in the Setting of Hospitel.

Objective: In a setting with a limited capacity for hospitalization, "hospitels" have been developed by using hotels as extension healthcare facilities for patients with mild illness. This study examined the clinical evidence of patients with coronavirus disease 2019 (COVID-19) who were treated with favipiravir, the main medication for treating COVID-19, in the hospitel setting in Thailand. Methods: We retrospectively collected demographic and clinical information, medication treatment, and outcome data for all patients who received favipiravir for COVID-19 during admission to a hospitel from April 27, 2021, to July 2, 2021. Risk factors for adults who could not complete treatment in a hospitel and who required hospitel transfer were analyzed. Results: In total, 421 patients were included in the study. Most patients (94.5%) received favipiravir to treat COVID-19 pneumonia. Adjunctive corticosteroids were prescribed to 42.3% of patients. Concerning the treatment outcome, 83.6% of patients completed treatment at a hospitel, and only two deaths occurred. No serious adverse drug reactions were observed. On multivariate analysis, age (odds ratio (OR) = 1.06; 95% confidence interval (CI) = 1.02-1.10, P=0.002), dyspnea (OR = 2.84; 95% CI = 1.25-6.44, P=0.013), loss of taste (OR = 107.63; 95% CI = 1.24-9337.39, P=0.040), corticosteroid use (OR = 12.56; 95% CI = 3.65-43.18, P < 0.001), and an extended duration of favipiravir use (OR = 16.91; 95% CI = 7.29-39.24, P < 0.001) were associated with a higher risk of hospitel transfer. Conclusions: Low rates of hospitel transfer and mortality were observed in mild-to-moderate COVID-19 patients treated with favipiravir at hospitel. Caution might be required in elderly patients, patients with dyspnea or a loss of taste, and patients receiving a 10-day course of favipiravir or adjunctive corticosteroids because these patients might require further management in the hospitel.

Omega 6 polyunsaturated fatty acids in red blood cell membrane are associated with xerostomia and taste loss in patients with breast cancer.

Chemosensory and physical complaints are common disorders in cancer patients under chemotherapy treatments that may affect the food intake, leading to a decreased quality of life. Lipid metabolism is a major pathway of cancer proliferation, where erythrocyte membrane phospholipids and their fatty acid composition are promising tools for monitoring metabolic pathways. Relationship between lipid profile in erythrocyte membrane phospholipids and chemosensory alterations in 44 newly diagnosed patients with breast cancer was here investigated. Smell changes and xerostomia were the most common complaints, with xerostomia as the main influencing factor on the development of other taste disorders. Lipid profiles revealed significant negative correlation between diminution of linoleic acid levels and xerostomia as well as positive correlation between increased arachidonic acid and salty taste. The involvement of these polyunsaturated lipids suggests the importance of oxidative and nutritional conditions of cancer patients, which can affect the molecular status for taste signals.

P2X3-Receptor Antagonists as Potential Antitussives: Summary of Current Clinical Trials in Chronic Cough.

Cough is among the most common complaints for which patients worldwide seek medical attention. In a majority of patients with chronic cough (defined as cough of greater than 8 weeks' duration), successful management results from a thorough evaluation and treatment of underlying causes. In a subgroup of patients, however, cough proves refractory to therapeutic trials aimed at known reversible causes of chronic cough. Such patients are appropriately termed as having refractory chronic cough. At present, safe and effective medications are lacking for this challenging patient population. Currently available therapeutic options are usually ineffective or achieve antitussive effect at the expense of intolerable side effects, typically sedation. Fortunately, the past decade has witnessed great progress in elucidating underlying mechanisms of cough. From that knowledge, aided by the development of validated instruments to measure objective and subjective cough-related end points, numerous antitussive drug development programs have emerged. The most active area of inquiry at present involves antagonists of the purinergic P2X receptors. Indeed, four clinical programs (one in Phase 3 and three in Phase 2) are currently underway investigating antagonists of receptors comprised entirely or partially of the P2X3 subunit as potential antitussive medications. Herein we review the foundation on which P2X receptor antagonists were developed as potential antitussive medications and provide an update on current clinical trials.

Efficacy and safety profile of vismodegib in a real-world setting cohort of patients with advanced basal cell carcinoma in Argentina.

INTRODUCTION AND OBJECTIVES: Vismodegib (Erivedge® ), a hedgehog pathway inhibitor, is approved to treat metastatic or locally advanced basal cell carcinoma (BCC) not suitable for surgery or radiotherapy. Our main objectives were to study the objective response rate (ORR) assessed by treating physicians and safety of vismodegib in a real-world practice setting in Argentina. MATERIAL AND METHODS: This is a prospective cohort study in real-world practice. We included consecutive adult patients treated in Argentina with locally advanced or metastatic BCC not suitable for surgery or radiotherapy. Patients were followed until the end of the study, death, or loss to follow-up, whichever occurred first. Patients received 150 mg vismodegib PO daily. RESULT: We included in the analysis 63 patients who received treatment. Locally advanced BCC was present in 57 (90.4%) and metastatic disease in two (3.2%). ORR was observed in 46 patients (73%; 95% CI: 60.3-83.4), with partial response in 36 (57%; 95% CI: 44-69.5) and complete response in 10 (16%; 95% CI: 7.8-27.2). As to safety, 48 (76.2%) patients had at least one adverse event (AE). The most frequently observed AEs were muscular spasms in 25 (39.6%); dysgeusia in 23 (36.5%); alopecia in nine (14.2%); weight loss in seven (11.1%); and ageusia in (9.5%) patients. Serious AEs were observed in 11 (17%) patients with one episode of deep vein thrombosis and pulmonary embolism resulting in death. CONCLUSION: Our study provides additional evidence of the efficacy and tolerability of vismodegib in patients with locally advanced or metastatic BCC in a real-world practice.

A case of anosmia and hypogeusia as a complication of propofol.

Anesthetics represent an uncommon cause of taste and smell disorders. We describe a case of anosmia and hypogeusia for 6 weeks after recovery from a uterine curettage operation in a 32-year-old woman. The case is unusual because propofol was the only anesthetic used during surgery and anesthesia. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed no abnormality. This case may highly suggest that propofol could induce smell and taste disorders.

Reversible ageusia associated with romidepsin therapy.

PURPOSE: The case of a patient who reported the complete loss of his sense of taste after about 3.5 months of romidepsin therapy is presented. SUMMARY: A man with a 12-year history of treatment-refractory cutaneous T-cell lymphoma (CTCL) developed taste disturbances progressing to ageusia (the absence of taste perception) while receiving romidepsin therapy. He reported a metallic taste during the first round of romidepsin therapy (14 mg/m² given as a four-hour infusion on days 1, 8, and 15 of each four-week cycle); during the ninth infusion, he reported the complete loss of taste sensations. The patient chose to continue romidepsin therapy because of a favorable overall response but requested a reduced frequency of infusions due to unabated ageusia. After implementation of a revised administration schedule (infusions only on days 1 and 8 of each cycle), the man gradually regained his sense of taste, with complete reversal of ageusia once romidepsin use was discontinued after two more cycles. The application of the algorithm of Naranjo et al. to this case yielded a score of 6, indicating a probable association between the taste disturbances and romidepsin use. A literature search identified no other reports of romidepsin-associated ageusia. CONCLUSION: A 67-year-old man reported ageusia during the third cycle of romidepsin therapy for CTCL. Taste sensation began to slowly recover following a reduction in the frequency of romidepsin administration, but therapy was ultimately discontinued partly due to the impact of this adverse reaction on the patient's quality of life.

Anosmia after exposure to a pyrethrin-based insecticide: a case report.

We present the case of a subject developing anosmia, preceded by nasal transient irritation and short lasting phantosmia and torqosmia, upon re-entrance into a room treated with a pyrethrin-based insecticide. The concentration of the insecticide in the room is unknown, but relatively high levels are predicted basing upon the modality of exposure and by the irritation symptoms in the subject. Despite corticosteroids therapy, anosmia has persisted unmodified for more than three years; according to, and based on evidence in the literature on olfactory disturbance prognosis, anosmia in this patient is likely to be permanent. The significance of this case report is related to the current wide use of insecticides containing pyrethrin and pyrethroids and highlights the need for more adequate attention to lowering airborne concentrations of pyrethrins and pyrethroids prior to re-entering the treated rooms. In particular, in a closed space sprayed with pyrethrins and pyrethroids insecticide, any irritant symptoms and/or dysosmia should be immediately considered relevant warning signs, and must be avoided.