Repurposed benzydamine targeting CDK2 suppresses the growth of esophageal squamous cell carcinoma / 医学前沿

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.

Benzydamine inhibits osteoclast differentiation and bone resorption down-regulation of interleukin-1 expression

Bone diseases such as osteoporosis and periodontitis are induced by excessive osteoclastic activity, which is closely associated with inflammation. Benzydamine (BA) has been used as a cytokine-suppressive or non-steroidal anti-inflammatory drug that inhibits the production of pro-inflammatory cytokines or prostaglandins. However, its role in osteoclast differentiation and function remains unknown. Here, we explored the role of BA in regulating osteoclast differentiation and elucidated the underlying mechanism. BA inhibited osteoclast differentiation and strongly suppressed interleukin-1 (IL-1) production. BA inhibited osteoclast formation and bone resorption when added to bone marrow-derived macrophages and differentiated osteoclasts, and the inhibitory effect was reversed by IL-1 treatment. The reporter assay and the inhibitor study of IL-1 transcription suggested that BA inhibited nuclear factor-B and activator protein-1 by regulating IB kinase, extracellular signal regulated kinase and P38, resulting in the down-regulation of IL-1 expression. BA also promoted osteoblast differentiation. Furthermore, BA protected lipopolysaccharide- and ovariectomy-induced bone loss in mice, suggesting therapeutic potential against inflammation-induced bone diseases and postmenopausal osteoporosis.

An Evaluation of the Efficacy of Ketamine Gargle and Benzydamine Hydrochloride Gargle for Attenuating Post Operative Sore Throat: A Prospective Randomized, Placebo Controlled Single- Blind Study

Post-operative sorethroat (POST) is a well-recognized complication in patients with endotracheal intubation for general anaesthesia. Many pharmacological measures for attenuating POST are being used during anaesthesia. In our study we compared the effectiveness of ketamine and benzydamine hydrochloride versus a placebo as preoperative gargle in decresing the incidence and severity of POST in patients undergoing endotracheal intubation for general anaesthesia. Methods: A total of 90 patients aged between 18-60 years of ASA I-II of either sex were randomly assigned into three groups of 30 patients each . Group 1(C) received distilled water,group2(BH) received 15 ml of benzydamine hcl(0.15%) and group 3(K) received preservative free ketamine 40 mg as preoperative gargle 10 min before induction. The incid- ence of POST was recorded at 2,4 and 24 hr post operatively. Results: The three groups were comparable in term of demographic characteristics. The incidence and severity of POST is much more in group 1(C) i.e control group (30%) after 24 hr compared to group 2 (BH) 0% and group 3(K)3.5%. There was no significant difference of POST in group 2(BH) and group 3(K). Conclusion: From our study it can be concluded that both benzydamine and ketamine gargle significantly reduces the incidence and severity of POST compared to ditilled water gargle up to 24 hr in the patients undergoing general anaesthesia with endotracheal intubation. Both the Benzydamine and ketamine gargles are safe, simple and equally effective in reducing POST.

Effects of benzydamine hydrochloride spray on postoperative sore throat associated with double-lumen endobronchial intubation: a double-blind, randomized controlled clinical trial

BACKGROUND: Postoperative sore throat is a common complication of endotracheal intubation; the thicker the endotracheal tube, the higher the frequency of postoperative sore throat. So, we evaluated the effect of benzydamine hydrochloride spray on postoperative sore throat, associated with double-lumen endobronchial intubation. METHODS: Sixty patients undergoing thoracic surgery were scheduled and enrolled for intubation, with a double-lumen endobronchial tube. Of these patients, 30 were sprayed with benzydamine hydrochloride (group B), and 30 with normal saline (group N), 10 minutes before intubation was performed. Patients were randomly assigned to the two groups. Blood pressure and heart rate were recorded before, and after endotracheal intubation. Symptoms of sore throat, hoarseness, and dysphagia were examined one hour, as well as 24 hours, after surgery. RESULTS: Incidence of sore throat was 73.3% and 23.3% (P < 0.001) in groups N and B, respectively, at one hour after surgery. In addition, incidence of sore throat at 24 hours after the operation, was also statistically significant (66.6% and 20.0%, P = 0.001). Frequency of dysphagia at one hour, and 24 hours after surgery, was lower in group B. There were no significant differences in heart rate, blood pressure, and hoarseness at 24 hours after surgery between the two groups. CONCLUSIONS: In cases wherein a double-lumen endobronchial tube was used, an oropharyngeal spray of benzydamine hydrochloride before tracheal intubation, reduced incidence of postoperative sore throat.

Randomized controlled trial to compare oral analgesic requirements and patient satisfaction in using oral non-steroidal anti-inflammatory drugs versus benzydamine hydrochloride oral rinses after mandibular third molar extraction: a pilot study

BACKGROUND: Third molar extraction is associated with considerable pain and discomfort, which is mostly managed with oral analgesic medication. We assessed the analgesic effect of benzydamine hydrochloride, a topical analgesic oral rinse, for controlling postoperative pain following third molar extraction. METHODS: A randomized controlled trial was conducted in 40 patients divided into two groups, for extraction of fully erupted third molar. Groups A received benzydamine hydrochloride mouthwash and group B received normal saline gargle with oral ibuprofen and paracetamol. Oral ibuprofen and paracetamol was the rescue analgesic drug in group A. Patients were evaluated on the 3(rd) and 7(th) post-operative days (POD) for pain using the visual analogue score (VAS), trismus, total number of analgesics consumed, and satisfaction level of patients. RESULTS: The VAS in groups A and B on POD3 and POD7 was 4.55 ± 2.54 and 3.95 ± 1.8, and 1.2 ± 1.64 and 0.95 ± 1.14, respectively and was statistically insignificant. The number of analgesics consumed in groups A and B on POD3 (5.25 ± 2.22 and 6.05 ± 2.43) was not statistically different from that consumed on POD7 (9.15 ± 5.93 and 10.65 ± 6.46). The p values for trismus on POD3 and POD7 were 0.609 and 0.490, respectively and those for patient satisfaction level on POD3 and POD7 were 0.283 and 0.217, respectively. CONCLUSIONS: Benzydamine hydrochloride oral rinses do not significantly reduce intake of oral analgesics and are inadequate for pain relief following mandibular third molar extraction.

Anafilaxia a cloridrato de benzidamina: relato de caso / Anaphylaxis to benzydamine hydrochloride: a case report

Reações de hipersensibilidade a medicamentos (RHM) podem induzir manifestações clínicas heterogêneas, desde leves até graves. São classificadas em imunológicas ou alérgicas quando mediadas por anticorpos ou linfócitos T, e não imunológicas quando decorrentes de efeitos farmacológicos da droga, incluindo inibição da enzima cicloxigenase (Cox). Os dois grupos mais frequentemente implicados nas RHM são os anti-inflamatórios não esteroidais (AINEs), e os antibióticos betalactâmicos. O manejo adequado das reações aos AINEs depende da identificação do mecanismo fisiopatológico envolvido, que permitirá classificar em reator seletivo (indivíduo que reage a um único fármaco e a outros com estrutura química similar), ou reator múltiplo ou intolerante cruzado (aquele que reage a múltiplos fármacos de estrutura química não relacionada). O cloridrato de benzidamina (CBZ) é um AINE de uso frequente e relativamente seguro, sem descrições de reações graves associadas ao seu uso. Atua inibindo as enzimas Prostaglandina Endoperoxidase H Sintase 1 e/ou 2, e a Fosfolipase A2. Em pacientes com história de reações aos AINEs, o teste de provocação é a ferramenta diagnóstica padrão ouro para confirmar ou excluir a reatividade cruzada a outros AINEs e definir um fármaco alternativo seguro. Descreveremos um caso raro de anafilaxia ao CBZ durante teste de provocação oral.

Hypersensitivity drug reactions (HDRs) may induce mild to severe heterogeneous clinical manifestations. They are classified as immunological or allergic when mediated by antibodies or T lymphocytes, and non-immunological when resulting from pharmacological effects of the drug, including inhibition of the cyclooxygenase (Cox) enzyme. The two groups of drugs most frequently implicated in HDRs are non-steroidal anti-inflammatory drugs (NSAIDs) and beta-lactam antibiotics. Appropriate management of NSAID reactions depends on identification of the pathophysiological mechanism involved, which will allow to classify the patient as selective reactor (patient reacting to a single drug and others with similar chemical structure) or multiple or cross-intolerant reactor (patient reacting to multiple drugs with unrelated chemical structure). Benzydamine hydrochloride (BZH) is a frequently used, relatively safe NSAID for which descriptions of severe reactions are not available. BZH acts inhibiting the enzymes prostaglandin endoperoxide H synthase (PGHS) 1 and/ or 2 and phospholipase A2. In patients with a history of NSAID reactions, the challenge test is the gold standard diagnostic tool to confirm or exclude cross-reactivity to other NSAIDs, and to define a safe alternative drug. In this paper, we describe a rare case of anaphylaxis to BZH during an oral drug provocation test.

Benzydamine Oral Spray Inhibiting Parasympathetic Function of Tracheal Smooth Muscle

OBJECTIVES: Benzydamine is a nonsteroidal anti-inflammatory agents agent with anti-inflammatory and local anesthesia properties that is available in the entire world as an oral spray for oral mucositis patients who are suffering from radiation effects. The effect of benzydamine on oral mucositis in vivo is well known; however, the effect of the drug on tracheal smooth muscle has rarely been explored. During administration of the benzydamine for oral symptoms, it might affect the trachea via oral intake or inhalation. METHODS: We examined the effectiveness of benzydamine on isolated rat tracheal smooth muscle. The following assessments of benzydamine were performed: effect on tracheal smooth muscle resting tension; effect on contraction caused by 10(-6)M methacholine as a parasympathetic mimetic; and effect of the drug on electrically induced tracheal smooth muscle contractions. RESULTS: Addition of methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of benzydamine at doses of 10(-5)M or above elicited a significant relaxation response to 10(-6)M methacholine-induced contraction. Benzydamine could inhibit electrical field stimulation-induced spike contraction. It alone had a minimal effect on the basal tension of trachea as the concentration increased. CONCLUSION: This study indicated that high concentrations of benzydamine might actually inhibit parasympathetic function of the trachea. Benzydamine might reduce asthma attacks in oral mucositis patients because it could inhibit parasympathetic function and reduce methacholine-induced contraction of tracheal smooth muscle.

Uso abusivo de benzidamina no Brasil: uma abordagem em farmacovigilância / Use abusive of benzydamine in Brazil: an overview in pharmacovigilance

O uso abusivo de medicamentos tem sido objeto de crescente interesse em saúde pública e geralmente veiculado na imprensa brasileira. Dentre os medicamentos, objeto de abuso e que causam dependência física e/ou psíquica, incluemse os barbitúricos, benzodiazepínicos, analgésicos opióides e anfetaminas. Os analgésicos, antitérmicos e antiinflamatórios não esteroidais, apesar de não fazerem parte dessa relação de fármacos, estão, geralmente, associados ao uso recreativo ou fins não terapêuticos. O objetivo deste ensaio é apresentar informações sobre o uso abusivo de benzidamina no Brasil. Trata-se de um estudo descritivo do tipo exploratório, em que foram utilizadas diferentes estratégias metodológicas adotadas na prática de regulação em farmacovigilância. O uso abusivo desse fármaco foi constatado na literatura científica, imprensa e internet. Em função da facilidade na compra de medicamentos sujeitos à prescrição médica, entre outros fatores, devem-se exigir meios e formas para monitorar a comercialização e utilização de medicamentos, assegurando seu uso seguro e racional, incluindo o fortalecimento da farmacovigilância no Brasil.

The abusive drug use has been object of increasing concern in public health and is commonly issued in the Brazilian press. Amongst medicines, those that are abuse substances and cause physical and/or psychic dependence, barbiturates, benzodiazepines, opioid analgesics and amphetamines are included. Analgesics, antipyretics and non-steroidal anti-inflammatory drugs, even not making part of this list, are generally associated with recreational use or non therapeutical purpose. The objective of this essay is to present information on the abusive use of benzydamine in Brazil. The present study is an exploratory essay in which different methodological strategies adopted in the regulatory practice of pharmacovigilance have been used. The abusive use of this drug was evidenced in scientific literature, press releases and on the internet. Considering the facility of purchasing drugs under medical prescription, among other factors, it must be demanded ways to assess the marketing and use of medicines, and assure its safe and rational use, including the strengthening of pharmacovigilance in Brazil.

Recreational use of benzydamine as a hallucinogen among street youth in Brazil / Uso recreacional de benzidamina como alucinógeno entre adolescentes em situação de rua no Brasil

OBJECTIVE: To describe the recreational use of benzydamine, an anti-inflammatory drug, among street youth in Brazil. METHOD: Design: a descriptive, cross sectional survey. Setting: 93 welfare services for the street youth in 27 Brazilian capitals. Participants: 2807 street youth, 10 to 18 years old. Main outcome measures: demographic characteristics, drug use pattern (lifetime use, use in the past 30 days, frequency, and characteristics of use in the past month) and effects of benzydamine through the use of a questionnaire. RESULTS: 78 reported lifetime recreational benzydamine use (67 cases identified only in three capitals). Among the 30 respondents reporting drug use in the last month (the month preceding the survey), 66.7 percent (n = 20) used the drug on 4 or more days (in the month preceding the survey). The most frequently (50 percent) pleasure effects reported were hallucination and nonspecific sensory changes described as "trips". Unwanted effects were reported by 75 percent of respondents, they were especially nausea and vomiting (21.4 percent). In the majority of the cases, drug was obtained from drugstores without a medical prescription. CONCLUSION: This study identifies the recreational use of benzydamine among street youth, mainly in the Northeast of Brazil, and also indicates the need for special controls on the dispensation of this substance.

OBJETIVO: Descrever o uso recreacional de benzidamina, um medicamento antiinflamatório, entre adolescentes em situação de rua no Brasil. MÉTODO: Desenho: descritivo, transversal. Local: 93 instituições assistenciais para crianças e adolescentes em situação de rua nas 27 capitais do Brasil. Participantes: 2.807 crianças e adolescentes em situação de rua, com idade entre 10 e 18 anos. Principais medidas de interesse: características demográficas, padrão de uso (uso na vida, uso nos últimos 30 dias, frequência e características de uso no mês anterior à pesquisa) e efeitos da benzidamina usando um questionário. RESULTADOS: 78 relataram uso recreacional na vida de benzidamina (67 casos identificados somente em três capitais). Entre os 30 entrevistados que relataram uso recente da substância (no mês que precedia a investigação), 66,7 por cento (n = 20) tomaram o medicamento em quatro dias ou mais no mês. Os efeitos desejados mais frequentemente reportados foram alucinações e alterações sensoriais inespecíficas como "viagem" (50 por cento). Efeitos indesejados foram citados por 75 por cento dos entrevistados, principalmente náuseas e vômitos (21,4 por cento). Na maioria dos casos, o medicamento foi obtido de drogarias sem apresentação de prescrição médica. CONCLUSÃO: Os resultados observados neste estudo identificam o uso recreacional de benzidamina entre crianças e adolescentes em situação de rua, especialmente no Nordeste do Brasil, e indicam a necessidade de controle especial sobre a dispensação desta substância.