COVID-19 in Dental Practice Is Prevented by Eugenol Responsible for the Ambient Odor Specific to Dental Offices: Possibility and Speculation.

Dental professionals routinely work in proximity to patients even when either or both of them have suspected or confirmed COVID-19. The oral cavity also serves as a reservoir for SARS-CoV-2 because the virus is present in and replicates in oral secretions (saliva and gingival crevicular fluid), oral tissues (salivary gland and periodontal tissue), and oral microenvironments (gingival sulcus and periodontal pocket). Despite a high risk of SARS-CoV-2 infection, the prevalence of COVID-19 in dentists, dental hygienists, dental assistants, and their patients was similar to that in the general population even during the pandemic. We propose that eugenol, which is responsible for the ambient odor specific to dental offices, could contribute to prevention of COVID-19 in dental settings. Eugenol is not only released from dental materials (filling, cement, and sealer) but is also aerosolized by dental procedures (grinding, polishing, and restoration). Such eugenol has been suggested to possess the potential to inhibit the infectivity and replication of SARS-CoV-2, the entry of SARS-CoV-2 into human cells by binding specifically to the viral spike protein, and the protease indispensable for SARS-CoV-2 replication. It has been shown that aerosolized eugenol acts on airborne viruses to reduce their loads. This review highlights a hypothesis that the environment of dental offices impregnated with eugenol suppresses SARS-CoV-2 airborne transmission and SARS-CoV-2 contagion between dental professionals and patients, preventing COVID-19 in dental practice. Anti-COVID-19 eugenol might give insights into the safe delivery of dental treatment and oral care in the COVID-19 era.

COVID-19 Oral Sequelae: Persistent Gustatory and Saliva Secretory Dysfunctions after Recovery from COVID-19.

Diverse manifestations have been recognized to last for a long time in patients infected with SARS-CoV-2. However, understanding of oral sequelae after recovery from COVID-19 is relatively poor compared to that of oral symptoms in the acute phase of COVID-19 and other COVID-19 sequelae. The aim of the present study was to characterize persistent gustatory and saliva secretory dysfunctions and to speculate on their pathogenic mechanisms. Articles were retrieved by searching scientific databases with a cutoff date of September 30, 2022. The literature search indicated that ageusia/dysgeusia and xerostomia/dry mouth are reported by 1-45% of COVID-19 survivors at follow-ups of 21-365 days and by 2-40% of COVID-19 survivors at follow-ups of 28-230 days, respectively. The prevalence of gustatory sequelae partly depends on difference in ethnicity, gender, age, and disease severity of subjects. Co-occurring gustatory and saliva secretory sequelae are pathogenically related to either or both of the following: expression of SARS-CoV-2 cellular entry-relevant receptors in taste buds and salivary glands, and SARS-CoV-2 infection-induced deficiency in zinc that is essential for normality of taste perception and saliva secretion. Given the long-term oral sequelae, hospital discharge is not the end of the disease; therefore, careful attention should be continuously paid to oral conditions of post-COVID-19 patients.

Treatments of COVID-19-Associated Taste and Saliva Secretory Disorders.

Since the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, treating taste and saliva secretory disorders associated with coronavirus disease 2019 (COVID-19) has become a critical issue. The aim of the present study was to update information on treatments applicable to such oral symptoms and discuss their pathogenic mechanisms. The literature search indicated that different treatments using tetracycline, corticosteroids, zinc, stellate ganglion block, phytochemical curcumin, traditional herbal medicine, nutraceutical vitamin D, photobiomodulation, antiviral drugs, malic acid sialagogue, chewing gum, acupuncture, and/or moxibustion have potential effects on COVID-19-associated ageusia/dysgeusia/hypogeusia and xerostomia/dry mouth/hyposalivation. These treatments have multiple modes of action on viral cellular entry and replication, cell proliferation and differentiation, immunity, and/or SARS-CoV-2 infection-induced pathological conditions such as inflammation, cytokine storm, pyroptosis, neuropathy, zinc dyshomeostasis, and dysautonomia. An understanding of currently available treatment options is required for dental professionals because they may treat patients who were infected with SARS-CoV-2 or who recovered from COVID-19, and become aware of their abnormal taste and salivary secretion. By doing so, dentists and dental hygienists could play a crucial role in managing COVID-19 oral symptoms and contribute to improving the oral health-related quality of life of the relevant patients.

The Oral Cavity Potentially Serving as a Reservoir for SARS-CoV-2 but Not Necessarily Facilitating the Spread of COVID-19 in Dental Practice.

Intraoral tissues, secretions, and microenvironments may provide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the conditions necessary for viral cellular entry and inhabitation. The aim of the present study is to overview the oral cavity that potentially serves as a reservoir for SARS-CoV-2, and then discuss the possibility that such oral cavity facilitates the spread of coronavirus disease 2019 (COVID-19) in dental practice. Articles were retrieved from PubMed/Medline, LitCovid, ProQuest, Google Scholar, and preprint medRxiv databases. Results of the literature search indicated that SARS-CoV-2 host cell entry-relevant receptor and virus/cell membrane fusion mediators are expressed in major and minor salivary glands, tongue, taste bud, periodontal tissue, and dental pulp, which would be a target and reservoir for SARS-CoV-2. SARS-CoV-2 is present in saliva and gingival crevicular fluid of COVID-19 patients. These secretions would contaminate dental aerosol and droplet with SARS-CoV-2. SARS-CoV-2 inhabits periodontal pocket, gingival sulcus, and dental caries lesion, which could provide SARS-CoV-2 with a habitat. SARS-CoV-2 ribonucleic acid is preserved in dental calculus, which may inform of the previous infection with SARS-CoV-2. Despite involvement of the oral cavity in SARS-CoV-2 transmission and infection, to date, there have been no clusters of COVID-19 in dental practice. Dental settings are much less likely to facilitate the spread of COVID-19 compared with general medical settings, which may be explained by the situation of dentistry that the number of patients to visit dental offices/clinics was decreased during the COVID-19 pandemic, the characteristics of dentistry that dental professionals have maintained high awareness of viral infection prevention, adhered to a strict protocol for infection control, and been using personal protective equipment for a long time, the experimental results that dental devices generate only small amounts of aerosol responsible for the airborne viral transmission, irrigant from the dental unit contributes to the aerosol microbiota much rather than saliva, and the commonly used evacuation or suction system effectively reduces aerosol and droplet generation, and the possibility that human saliva exhibits the antiviral activity and the property to inhibit SARS-CoV-2 infection. It is considered that dental treatment and oral health care can be delivered safely in the COVID-19 era.

Membrane Interactivity of Capsaicin Antagonized by Capsazepine.

Although the pharmacological activity of capsaicin has been explained by its specific binding to transient receptor potential vanilloid type 1, the amphiphilic structure of capsaicin may enable it to act on lipid bilayers. From a mechanistic point of view, we investigated whether capsaicin and its antagonist capsazepine interact with biomimetic membranes, and how capsazepine influences the membrane effect of capsaicin. Liposomal phospholipid membranes and neuro-mimetic membranes were prepared with 1,2-dipalmitoylphosphatidylcholine and with 1-palmitoyl-2-oleoylphosphatidylcholine and sphingomyelin plus cholesterol, respectively. These membrane preparations were subjected to reactions with capsaicin and capsazepine at 0.5-250 µM, followed by measuring fluorescence polarization to determine the membrane interactivity to modify the fluidity of membranes. Both compounds acted on 1,2-dipalmitoylphosphatidylcholine bilayers and changed membrane fluidity. Capsaicin concentration-dependently interacted with neuro-mimetic membranes to increase their fluidity at low micromolar concentrations, whereas capsazepine inversely decreased the membrane fluidity. When used in combination, capsazepine inhibited the effect of capsaicin on neuro-mimetic membranes. In addition to the direct action on transmembrane ion channels, capsaicin and capsazepine share membrane interactivity, but capsazepine is likely to competitively antagonize capsaicin's interaction with neuro-mimetic membranes at pharmacokinetically-relevant concentrations. The structure-specific membrane interactivity may be partly responsible for the analgesic effect of capsaicin.

Acetaminophen Has Lipid Composition-Dependent Membrane Interactivity That Could Be Related to Nephrotoxicity but Not to Analgesic Activity and Hepatotoxicity.

OBJECTIVE: Although acetaminophen is one of the most widely used over-the-counter drugs, the mechanisms by which this classical drug exerts analgesic, hepatotoxic, and nephrotoxic effects remain unclear. We hypothesized that acetaminophen might act on cellular membranes of nerves, liver, and kidneys. In order to verify this hypothesis, we studied the interactivity of acetaminophen with biomimetic lipid bilayer membranes by comparing with structurally related phenacetin. METHODS: Liposomal membranes (unilamellar vesicles suspended in the buffer of pH 7.4) were prepared with phospholipids and cholesterol to mimic the membrane lipid composition of neuronal cells, hepatocytes, and nephrocytes. They were subjected to reactions with acetaminophen and phenacetin at clinically relevant concentrations, followed by measuring fluorescence polarization to determine their membrane interactivity to modify membrane fluidity. RESULTS: Acetaminophen and phenacetin interacted with neuro-mimetic and hepato-mimetic membranes to increase membrane fluidity at 10-100 µM. Both drugs were more effective in fluidizing hepato-mimetic membranes than neuro-mimetic membranes. Although the relative membrane-interacting potency was phenacetin >> acetaminophen in neuro-mimetic and hepato-mimetic membranes, such membrane effects conflicted with their relative analgesic and hepatotoxic effects. Acetaminophen and phenacetin strongly interacted with nephro-mimetic membranes to increase membrane fluidity at 2-100 µM and 0.1-100 µM, respectively. Phenacetin interacted significantly with nephro-mimetic membranes at lower concentrations (<2 µM) than acetaminophen, which was consistent with their relative nephrotoxic effects. CONCLUSION: In comparison with phenacetin, lipid composition-dependent membrane interactivity of acetaminophen could be related to nephrotoxicity but not to analgesic activity and hepatotoxicity.

Gustatory and Saliva Secretory Dysfunctions in COVID-19 Patients with Zinc Deficiency.

Given the ever-progressing studies on coronavirus disease 2019 (COVID-19), it is critical to update our knowledge about COVID-19 symptomatology and pathophysiology. In the present narrative review, oral symptoms were overviewed using the latest data and their pathogenesis was hypothetically speculated. PubMed, LitCovid, ProQuest, and Google Scholar were searched for relevant studies from 1 April 2021 with a cutoff date of 31 January 2022. The literature search indicated that gustatory dysfunction and saliva secretory dysfunction are prevalent in COVID-19 patients and both dysfunctions persist after recovery from the disease, suggesting the pathogenic mechanism common to these cooccurring symptoms. COVID-19 patients are characterized by hypozincemia, in which zinc is possibly redistributed from blood to the liver at the expense of zinc in other tissues. If COVID-19 induces intracellular zinc deficiency, the activity of zinc-metalloenzyme carbonic anhydrase localized in taste buds and salivary glands may be influenced to adversely affect gustatory and saliva secretory functions. Zinc-binding metallothioneins and zinc transporters, which cooperatively control cellular zinc homeostasis, are expressed in oral tissues participating in taste and saliva secretion. Their expression dysregulation associated with COVID-19-induced zinc deficiency may have some effect on oral functions. Zinc supplementation is expected to improve oral symptoms in COVID-19 patients.

Characterization and Pathogenic Speculation of Xerostomia Associated with COVID-19: A Narrative Review.

Patients with coronavirus disease 2019 (COVID-19) have become known to present with different oral symptoms. However, xerostomia remains poorly recognized compared with taste dysfunction. For better understanding of COVID-19 symptomatology, xerostomia associated withCOVID-19 was characterized and its possible pathogenesis was speculated by a narrative literature review. Scientific articles were retrieved by searching PubMed, LitCovid, ProQuest, Google Scholar, medRxiv and bioRxiv from 1 April 2020 with a cutoff date of 30 September 2021. Results of the literature search indicated that xerostomia is one of prevalent and persistent oral symptoms associated with COVID-19. In contrast to taste dysfunction, the prevalence and persistence of xerostomia do not necessarily depend on ethnicity, age, gender and disease severity of patients. COVID-19 xerostomia is pathogenically related to viral cellular entry-relevant protein expression, renin-angiotensin system disturbance, salivary gland inflammation, zinc deficiency, cranial neuropathy, intercurrent taste dysfunction, comorbidities and medications. Despite a close association with COVID-19, xerostomia, dry mouth and hyposalivation tend to be overlooked unlike ageusia, dysgeusia and hypogeusia. Although mouth dryness per se is not life-threating, it has an impact on the oral health-related quality of life. More attention should be paid to xerostomia in COVID-19 patients and survivors.

Oral Symptoms Associated with COVID-19 and Their Pathogenic Mechanisms: A Literature Review.

Since the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, management of coronavirus disease 2019 (COVID-19) has been challenging for healthcare providers. The oral cavity is referred to as a target of SARS-CoV-2. The aim of this study was to review oral symptoms specific to COVID-19 patients from the point of view of symptom prevalence and pathogenesis and to speculate the pathogenic mechanisms underlying them. Scientific articles were retrieved by searching PubMed/MEDLINE, Google Scholar, medRxiv, and bioRxiv from 3 February 2020 to 31 December 2020, and they were reviewed by title, abstract, and text for relevance. The literature search indicated that COVID-19 patients frequently present with gustatory dysfunction, xerostomia, and oral mucosal lesions, while their prevalence is likely to vary by country, age, gender, and disease severity. Gustatory dysfunction and xerostomia appear at an early stage of SARS-CoV-2 infection and last relatively long. One of possible pathogenic mechanisms of both symptoms is attributed to the expression of viral cellular entry-relevant receptors in taste cells and salivary glands. Dental professionals who can first become aware of oral symptoms associated with COVID-19 will play a more active role in and make a greater contribution to diagnosis and prevention of COVID-19.

Anesthetic Agents of Plant Origin: A Review of Phytochemicals with Anesthetic Activity.

The majority of currently used anesthetic agents are derived from or associated with natural products, especially plants, as evidenced by cocaine that was isolated from coca (Erythroxylum coca, Erythroxylaceae) and became a prototype of modern local anesthetics and by thymol and eugenol contained in thyme (Thymus vulgaris, Lamiaceae) and clove (Syzygium aromaticum, Myrtaceae), respectively, both of which are structurally and mechanistically similar to intravenous phenolic anesthetics. This paper reviews different classes of phytochemicals with the anesthetic activity and their characteristic molecular structures that could be lead compounds for anesthetics and anesthesia-related drugs. Phytochemicals in research papers published between 1996 and 2016 were retrieved from the point of view of well-known modes of anesthetic action, that is, the mechanistic interactions with Na⁺ channels, γ-aminobutyric acid type A receptors, N-methyl-d-aspartate receptors and lipid membranes. The searched phytochemicals include terpenoids, alkaloids and flavonoids because they have been frequently reported to possess local anesthetic, general anesthetic, antinociceptive, analgesic or sedative property. Clinical applicability of phytochemicals to local and general anesthesia is discussed by referring to animal in vivo experiments and human pre-clinical trials. This review will give structural suggestions for novel anesthetic agents of plant origin.

Discrimination of Stereoisomers by Their Enantioselective Interactions with Chiral Cholesterol-Containing Membranes.

Discrimination between enantiomers is an important subject in medicinal and biological chemistry because they exhibit markedly different bioactivity and toxicity. Although stereoisomers should vary in the mechanistic interactions with chiral targets, their discrimination associated with the mode of action on membrane lipids is scarce. The aim of this study is to reveal whether enantiomers selectively act on chiral lipid membranes. Different classes of stereoisomers were subjected at 5-200 µM to reactions with biomimetic phospholipid membranes containing ~40 mol % cholesterol to endow the lipid bilayers with chirality and their membrane interactions were comparatively evaluated by measuring fluorescence polarization. All of the tested compounds interacted with cholesterol-containing membranes to modify their physicochemical property with different potencies between enantiomers, correlating to those of their experimental and clinical effects. The rank order of membrane interactivity was reversed by changing cholesterol to C3-epimeric α-cholesterol. The same selectivity was also obtained from membranes prepared with 5α-cholestan-3ß-ol and 5ß-cholestan-3α-ol diastereomers. The opposite configuration allows molecules to interact with chiral sterol-containing membranes enantioselectively, and the specific ß configuration of cholesterol's 3-hydroxyl group is responsible for such selectivity. The enantioselective membrane interaction has medicinal implications for the characterization of the stereostructures with higher bioactivity and lower toxicity.

Anesthetic effects changeable in habitual drinkers: Mechanistic drug interactions with neuro-active indoleamine-aldehyde condensation products associated with alcoholic beverage consumption.

Clinicians often experience the reduced efficacy of general and local anesthetics and anesthesia-related drugs in habitual drinkers and chronic alcoholics. However, the mechanistic background underlying such anesthetic tolerance remains unclear. Biogenic indoleamines condense with alcohol-derived aldehydes during fermentation processes and under physiological conditions to produce neuro-active tetrahydro-ß-carbolines and ß-carbolines, many of which are contained not only in various alcoholic beverages but also in human tissues and body fluids. These indoleamine-aldehyde condensation products are increased in the human body because of their exogenous and endogenous supply enhanced by alcoholic beverage consumption. Since tetrahydro-ß-carbolines and ß-carbolines target receptors, ion channels and neuronal membranes which are common to anesthetic agents, we propose a hypothesis that they may pharmacodynamically interact at GABAA receptors, NMDA receptors, voltage-gated Na(+) channels and membrane lipid bilayers to attenuate anesthetics-induced positive allosteric GABAA receptor modulation, NMDA receptor antagonism, ion channel blockade and neuronal membrane modification, thereby affecting anesthetic efficacy. The condensation products may also cooperatively interact with ethanol that induces adaptive changes and cross-tolerance to anesthetics and with dopamine-aldehyde adducts that act on GABAA receptors and membrane lipids. Because tetrahydro-ß-carbolines and ß-carbolines are metabolized to lose or decrease their neuro-activities, induction of the relevant enzymes by habitual drinking could produce an inter-individual difference of drinkers in susceptibility to anesthetic agents. The present hypothesis would also provide a unified framework for different modes of anesthetic action, which are inhibited by neuro-active indoleamine-aldehyde condensation products associated with alcoholic beverage consumption.

Membrane Interactions of Phytochemicals as Their Molecular Mechanism Applicable to the Discovery of Drug Leads from Plants.

In addition to interacting with functional proteins such as receptors, ion channels, and enzymes, a variety of drugs mechanistically act on membrane lipids to change the physicochemical properties of biomembranes as reported for anesthetic, adrenergic, cholinergic, non-steroidal anti-inflammatory, analgesic, antitumor, antiplatelet, antimicrobial, and antioxidant drugs. As well as these membrane-acting drugs, bioactive plant components, phytochemicals, with amphiphilic or hydrophobic structures, are presumed to interact with biological membranes and biomimetic membranes prepared with phospholipids and cholesterol, resulting in the modification of membrane fluidity, microviscosity, order, elasticity, and permeability with the potencies being consistent with their pharmacological effects. A novel mechanistic point of view of phytochemicals would lead to a better understanding of their bioactivities, an insight into their medicinal benefits, and a strategic implication for discovering drug leads from plants. This article reviews the membrane interactions of different classes of phytochemicals by highlighting their induced changes in membrane property. The phytochemicals to be reviewed include membrane-interactive flavonoids, terpenoids, stilbenoids, capsaicinoids, phloroglucinols, naphthodianthrones, organosulfur compounds, alkaloids, anthraquinonoids, ginsenosides, pentacyclic triterpene acids, and curcuminoids. The membrane interaction's applicability to the discovery of phytochemical drug leads is also discussed while referring to previous screening and isolating studies.

A proposed core curriculum for dental English education in Japan.

BACKGROUND: Globalization of the professions has become a necessity among schools and universities across the world. It has affected the medical and dental professions in terms of curriculum design and student and patient needs. In Japan, where medicine and dentistry are taught mainly in the Japanese language, profession-based courses in English, known as Medical English and Dental English, have been integrated into the existing curriculum among its 83 medical and 29 dental schools. Unfortunately, there is neither a core curriculum nor a model syllabus for these courses. METHODS: This report is based on a survey, two discussion forums, a workshop, and finally, the drafting of a proposed core curriculum for dental English approved by consensus of the participants from each university. RESULTS: The core curriculum covers the theoretical aspects, including dental English terms and oral pathologies; and practical aspects, including blended learning and dentist-patient communication. It is divided into modules and is recommended to be offered for at least two semesters. CONCLUSIONS: The core curriculum is expected to guide curriculum developers in schools where dental English courses are yet to be offered or are still in their early development. It may also serve as a model curriculum to medical and dental schools in countries in Asia, Europe, Africa, and Central and South America, where English is not the medium of instruction.

Characteristic interactivity of landiolol, an ultra-short-acting highly selective ß1-blocker, with biomimetic membranes: Comparisons with ß1-selective esmolol and non-selective propranolol and alprenolol.

Although ß1-blockers have been perioperatively used to reduce the cardiac disorders associated with general anesthesia, little is known about the mechanistic characteristics of ultra-short-acting highly selective ß1-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and non-selective ß1-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with ß1-selective landiolol and esmolol and non-selective propranolol and alprenolol at 0.5-200 µM. The membrane interactivity and the antioxidant activity were determined by measuring fluorescence polarization and by peroxidizing membrane lipids with peroxynitrite, respectively. Non-selective ß1-blockers, but not selective ones, intensively acted on 1,2-dipalmitoylphosphatidylcholine (DPPC) liposomal membranes and cardiomyocyte-mimetic membranes to increase the membrane fluidity. Landiolol and its inactive metabolite distinctively decreased the fluidity of DPPC liposomal membranes, suggesting that a membrane-rigidifying effect is attributed to the morpholine moiety in landiolol structure but unlikely to clinically contribute to the ß1-blocking effect of landiolol. Propranolol and alprenolol interacted with lipid raft model membranes, whereas neither landiolol nor esmolol. All drugs fluidized mitochondria-mimetic membranes and inhibited the membrane lipid peroxidation with the potency correlating to their membrane interactivity. Landiolol is characterized as a drug devoid of the interactivity with membrane lipid rafts relating to ß2-adrenergic receptor blockade. The differentiation between ß1-blocking selectivity and non-selectivity is compatible with that between membrane non-interactivity and interactivity. The mitochondrial membrane fluidization by landiolol independent of blocking ß1-adrenergic receptors is responsible for the antioxidant cardioprotection common to non-selective and selective ß1-blockers.

Interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol: mechanistic and clinical implications for anesthetic and cardiotoxic effects.

Despite a long history in medical and dental application, the molecular mechanism and precise site of action are still arguable for local anesthetics. Their effects are considered to be induced by acting on functional proteins, on membrane lipids, or on both. Local anesthetics primarily interact with sodium channels embedded in cell membranes to reduce the excitability of nerve cells and cardiomyocytes or produce a malfunction of the cardiovascular system. However, the membrane protein-interacting theory cannot explain all of the pharmacological and toxicological features of local anesthetics. The administered drug molecules must diffuse through the lipid barriers of nerve sheaths and penetrate into or across the lipid bilayers of cell membranes to reach the acting site on transmembrane proteins. Amphiphilic local anesthetics interact hydrophobically and electrostatically with lipid bilayers and modify their physicochemical property, with the direct inhibition of membrane functions, and with the resultant alteration of the membrane lipid environments surrounding transmembrane proteins and the subsequent protein conformational change, leading to the inhibition of channel functions. We review recent studies on the interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol. Understanding the membrane interactivity of local anesthetics would provide novel insights into their anesthetic and cardiotoxic effects.

Endoscopic biliary drainage for children with persistent or exacerbated symptoms of choledochal cysts.

BACKGROUND: Symptoms of choledochal cysts sometimes persist or become exacerbated. As preoperative management for patients with these cysts, we prospectively employed endoscopic drainage, based on the theory that protein plugs cause symptoms by obstructing the pancreatobiliary ducts. METHODS: Children with choledochal cysts underwent endoscopic retrograde cholangiopancreatography (ERCP). When ERCP showed compaction with filling defects in patients with persistent or worsening symptoms (study patients), the placement of a short biliary stent tube was attempted for drainage. The clinical and ERCP findings of the study patients were compared with those of patients who were asymptomatic at ERCP (asymptomatic patients). RESULTS: There were 13 study patients (median age 2.9 years) and 41 asymptomatic patients (4.7 years) enrolled in the study between August 2005 and February 2011. Study patients more frequently had jaundice and elevated transaminase levels. ERCP showed that all study patients had obstruction or compacted filling defects in the common channel or the narrow segment distal to the cyst. Insertion of a stent tube was successful in 11 patients. Symptoms were relieved soon after biliary drainage. Surgery revealed that the obstructing materials were protein plugs, except in one case, which involved fatty acid calcium stones. CONCLUSIONS: These results support the protein plug theory. Endoscopic short-tube stenting is adequate and effective as preoperative management.

Increasing membrane interactions of local anaesthetics as hypothetic mechanism for their cardiotoxicity enhanced by myocardial ischaemia.

While myocardial ischaemia enhances the cardiotoxicity of local anaesthetics, the pharmacological background remains unclear. Cardiolipin (CL) localized in mitochondrial membranes is possibly the site of cardiotoxic action of local anaesthetics and peroxynitrite is produced by cardiac ischaemia and reperfusion. We verified the hypothetic mechanism that local anaesthetics may interact with CL-containing biomembranes to change the membrane biophysical property and their membrane interactions may be increased by peroxynitrite. Biomimetic membranes were prepared with different phospholipids and cholesterol of varying compositions. The membrane preparations were reacted with peroxynitrite of pathologically relevant concentrations and local anaesthetics (bupivacaine and lidocaine) of a cardiotoxic concentration separately or in combination. Changes in membrane fluidity were determined by measuring fluorescence polarization. Peroxynitrite decreased the fluidity of biomimetic membranes at 0.1-10 µM with the relative potency being CL>1-stearoyl-2-arachidonoylphosphatidylcholine>1,2-dipalmitoylphosphatidylcholine-constituting membranes, indicating the lipid peroxidation-induced membrane rigidification determined by the unsaturation degree of membrane lipids. When treated with 0.1-10 µM peroxynitrite, biomimetic membranes were more rigid with elevating the CL content from 0% to 30 mol%, suggesting that CL is a primary target of peroxynitrite. Bupivacaine and lidocaine fluidized at 200 µM biomimetic membranes containing 10 mol% CL and their effects were increased by pre-treating the membranes with 0.1 and 1 µM peroxynitrite. Cardiotoxic bupivacaine and lidocaine increasingly interact with CL-containing mitochondria model membranes which are relatively rigidified by peroxynitrite. Such an increasing membrane interaction may be, at least in part, responsible for the local anaesthetic cardiotoxicity enhanced by myocardial ischaemia.

Cardiotoxic local anesthetics increasingly interact with biomimetic membranes under ischemia-like acidic conditions.

The cardiotoxic effects of local anesthetics increase in cardiac ischemia which is characterized by the tissue pH lowering to 6.5 or less. Apart from the cardiac channel blockade, the membrane interaction has been referred to as another mode of their cardiotoxic action. By using biomimetic membranes, we verified the hypothesis that bupivacaine and lidocaine may increasingly interact with cardiac mitochondrial membranes under ischemia-like acidic conditions. Biomimetic membranes were prepared with different phospholipids and cholesterol to be unilamellar vesicles suspended in buffers of pH 7.4, 6.9, 6.4 or 5.9. Bupivacaine and lidocaine were reacted with the membrane preparations at cardiotoxically relevant concentrations and their membrane interactivities were determined by measuring fluorescence polarization. Both drugs interacted with 100 mol% 1,2-dipalmitoylphosphatidylcholine, peripheral nerve cell-mimetic and cardiomyocyte-mimetic membranes to increase membrane fluidity, although lowering the reaction pH from 7.4 to 5.9 decreased their membrane-fluidizing effects. In cardiomyocyte mitochondria-mimetic membranes containing 20 mol% cardiolipin, however, bupivacaine and lidocaine reversely increased their membrane interactivities at pH 5.9-6.4 compared with pH 7.4. Such increases were greater in anionic phospholipid membranes which consisted of substantial amounts of cardiolipin and phosphatidylserine. Positively charged bupivacaine and lidocaine would form ion-pairs with the negatively charged head-groups of anionic phospholipids under acidic conditions, thereby increasing the induced membrane fluidization. The mitochondrial membrane interactions depending on pH lowering may be, at least in part, responsible for local anesthetic cardiotoxicity enhanced in acidosis associated with cardiac ischemia.