Growth Differentiation Factor-15 Is Considered a Predictive Biomarker of Long COVID in Non-hospitalized Patients.

Mitochondrial dysfunction is associated with various diseases. Mitochondria plays a regulatory role during infection. The association between mitokines and subsequent COVID progression has not been previously studied. The retrospective cohort study aimed to investigate the potential of serum mitokines as long COVID biomarkers in non-hospitalized patients. Patients with confirmed SARS-CoV-2 infection and blood test reports between January 2021 and April 2023 were included. Patients were categorized into two groups, the recovered and long COVID groups, based on fatigue, decline in focus, and pain. Serum levels of growth differentiation factor 15 (GDF-15) and fibroblast growth factor-21 (FGF-21), which are affected by mitochondrial function, along with inflammatory and vascular endothelium markers, were measured using enzyme-linked immunosorbent assays (ELISA). A receiver operating characteristic curve was used to screen the biomarkers. The threshold value of GDF-15 in the acute phase was 965 pg/mL (sensitivity: 71.4%, specificity: 83.3%), indicating that GDF-15 may be associated with the presence of symptoms three months post onset. No association with inflammatory markers and vascular structures was observed. Therefore, elevated GDF-15 levels in the acute phase may act as a predictive biomarker of long COVID.

Contribution of traditional Japanese Kampo medicines, kakkonto with shosaikotokakikyosekko, in treating patients with mild-to-moderate coronavirus disease 2019: Further analysis of a multicenter, randomized controlled trial.

We previously reported the finding of symptom relief in a randomized controlled trial with the combined use of kakkonto and shosaikotokakikyosekko added to conventional treatment in patients with coronavirus disease 2019 (COVID-19). For further evaluation, we performed post hoc analysis focused on symptom disappearance without recurrence, to determine a clearer effect of Kampo medicine. Patients with mild and moderate COVID-19 were randomly allocated to a control group receiving symptomatic therapy or a Kampo group receiving kakkonto (2.5 g) with shosaikotokakikyosekko (2.5 g) three times daily in addition to symptomatic therapy. The data of 161 patients (Kampo group, n = 81; control group, n = 80) were analyzed post hoc for the time to symptom disappearance. Kaplan-Meier and Cox proportional hazard estimates of disappearance of symptoms showed that all and each symptom targeted in this study disappeared faster in the Kampo group than in the control group, although not statistically significant (all symptomatic cases; hazard ratio [HR] 3.73, 95% confidence interval [CI] 0.46-29.98, log-rank p = 0.1763). In a supplemental assessment using covariate adjustment and competing risk analysis, fever disappeared faster in the Kampo group than in the control group (all symptomatic cases, HR 1.62, 95% CI 0.99-2.64, p = 0.0557; unvaccinated cases, HR 1.68, 95% CI 1.00-2.83, p = 0.0498) and shortness of breath disappeared significantly faster in Kampo group than in control group (all symptomatic cases, HR 1.92, 95% CI 1.07-3.42, p = 0.0278; unvaccinated cases, HR 2.15, 95% CI 1.17-3.96, p = 0.0141). These results demonstrate the advantages of Kampo treatment for acute COVID-19.

Predictors for the Development of Hypoxia or Prolonged Acute Symptoms among Non-Hospitalized Mild-to-Moderate Patients with Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic remains a global public health concern. The clinical course and risk of developing severe illness among patients with COVID-19 who are at low-risk of severe COVID-19 remain uncertain. This retrospective cohort study from an isolation facility for low-risk COVID-19 patients in Japan evaluated the potential risks for severe disease with hypoxia (SpO2 ≤ 93%) or experiencing prolonged isolation period longer than 14 days with persistent acute symptoms. The study was performed before the spread of the alpha variant in the country and before the start of a nationwide mass vaccination campaign against COVID-19. Among the 929 participants with reliable outcome data regarding the development of hypoxia, 63 (6.8%) developed severe disease with hypoxia during their stays at the facility. Higher age [adjusted odds ratio (aOR), 1.08; 95% confidence interval (CI), 1.06-1.10] and male sex (aOR, 4.70; 95% CI, 2.39-9.22) were associated with this outcome. As for the experience of prolonged isolation period, higher age (aOR, 1.02; 95% CI, 1.01-1.04), atopic diseases (aOR, 1.69, 95% CI, 1.09-2.64), presence of cough at onset (aOR, 1.64; 95% CI, 1.09-2.48), and prescription of oral antibiotics before positive test results for COVID-19 (aOR, 2.37; 95% CI, 1.33-4.22) were associated with this outcome. In summary, 5-10% of low-risk COVID-19 patients later develop hypoxia. Older age and male sex were associated with both the development of hypoxia and prolonged acute symptoms. The unnecessary prescription of antibiotics before COVID-19 diagnosis may prolong COVID-19 symptoms.

Conventional and Kampo Medicine Treatment for Mild-to-moderate COVID-19: A Multicenter, Retrospective, Observational Study by the Integrative Management in Japan for Epidemic Disease (IMJEDI Study-observation).

Objective Patients in whom coronavirus disease 2019 (COVID-19) was suspected or confirmed between January 1, 2020, and October 31, 2021, were enrolled from Japanese hospitals in this multicenter, retrospective, observational study. Methods Data on the treatment administered (including conventional and Kampo medicine) and changes in common cold-like symptoms (such as fever, cough, sputum, dyspnea, fatigue, and diarrhea) were collected from their medical records. The primary outcome was the number of days without a fever (with a body temperature <37°C). The secondary outcomes were symptomatic relief and the worsening of illness, defined as the presence of a condition requiring oxygen inhalation. The outcomes of patients treated with and without Kampo medicine were compared. Patients We enrolled 962 patients, among whom 528 received conventional and Kampo treatment (Kampo group) and 434 received conventional treatment (non-Kampo group). Results Overall, after adjusting for the staging of COVID-19 and risk factors, there were no significant between-group differences in the symptoms or number of days being afebrile. After performing propensity score matching and restricting the included cases to those with confirmed COVID-19 who did not receive steroid administration and initiated treatment within 4 days from the onset, the risk of illness worsening was significantly lower in the Kampo group than in the non-Kampo group (odds ratio=0.113, 95% confidence interval: 0.014-0.928, p=0.0424). Conclusion Early Kampo treatment may suppress illness worsening risk in COVID-19 cases without steroid use. Further randomized controlled studies are needed to confirm the clinical benefit of Kampo medicine for COVID-19.

Multicenter, randomized controlled trial of traditional Japanese medicine, kakkonto with shosaikotokakikyosekko, for mild and moderate coronavirus disease patients.

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom's relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan-Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03-3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference -0.13, 95% CI -0.27-0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020].

Refractory Chest Pain in Mild to Moderate Coronavirus Disease 2019 Successfully Treated with Saikanto, a Japanese Traditional Medicine.

Coronavirus disease 2019 (COVID-19) causes a variety of pain symptoms in the acute phase. Severe chest pain suddenly occurs even without abnormalities on examination and is sometimes refractory to analgesics. Such pain is a clinical concern in care facilities with limited resources, and this is the first report on the use of saikanto for its treatment. In Miyagi Prefecture, Japan, COVID-19 patients with mild symptoms were admitted to a hotel that operated as an isolation facility, and their symptoms were observed. In this article, we report four cases in which chest pain comorbid with mild to moderate COVID-19 was successfully treated with saikanto, a traditional Japanese (Kampo) medicine. The patients presented with chest pain and underwent medical examination at the facility. Two patients had severe chest pain refractory to acetaminophen. Critical cardiopulmonary diseases were ruled out in all the patients, and three patients had features of pneumonia on chest radiograph. Medications, including saikanto, were administered to the patients. The patients' chest pain and other symptoms improved 1-4 days after the administration of saikanto, and they left the care facility without hospitalization. The cause of the chest pain experienced by these patients is unclear, but we speculate that it could be minimal pleural inflammation or neuropathy. Previous pharmacological studies have suggested anti-inflammatory and analgesic properties of the crude drugs that constitute saikanto. This case report suggests that saikanto could be a treatment option for chest pain refractory to analgesics in patients with mild to moderate COVID-19.

Kampo Medicine Promotes Early Recovery From Coronavirus Disease 2019-Related Olfactory Dysfunction: A Retrospective Observational Study.

Background: Olfactory dysfunction is a common symptom in patients with coronavirus disease 2019, and it significantly deteriorates patients' quality of life. Effective treatments remain unknown. Purpose: To assess the effect of Japanese traditional (Kampo) medicine on coronavirus disease 2019-related olfactory dysfunction. Study Design: Retrospective observational study. Methods: In total, 87 patients aged ≥18 years with coronavirus disease 2019 and severe dysosmia or anosmia (Numeric Rating Scale, ≥7) at isolation facilities in Miyagi Prefecture, Japan, were enrolled from October 2020 to March 2021. Patients were divided into the Kampo group (N = 52) and the control group (N = 35) based on the treatment received. Changes in Numeric Rating Scale scores were evaluated at the first visit and 2 weeks after. Results: The median reduction in the olfactory dysfunction score at both 1 and 2 weeks after the first visit was significantly greater in the Kampo group (6 and 8, respectively; p = 0.03) than in the control group (3 and 7, respectively; p = 0.04). We defined improvement in olfactory dysfunction as a median reduction in the olfactory dysfunction score of ≥5. Multiple logistic regression analysis demonstrated that only Kampo treatment was significantly associated with improvement in olfactory dysfunction. Conclusion: This study suggests that Kampo medication promotes early recovery from coronavirus disease 2019-related olfactory dysfunction.

Response to Glucocorticoid Therapy in Patients with Mild to Moderate Coronavirus Disease 2019 at a Japanese Care Facility.

The fifth wave of the coronavirus disease 2019 (COVID-19) pandemic caused by delta variant infection depleted medical resources, and the Japanese government announced glucocorticoid use for outpatients. An appropriate outpatient-glucocorticoid treatment for COVID-19 has not been established; therefore, we created treatment manuals with indications for glucocorticoid administration in a care facility adequately equipped to manage patients with mild to moderate COVID-19. Thirty-eight patients (24 males, 14 females; mean age 40.5 ± 11.8 years) were treated with glucocorticoids from August 1 to October 1, 2021 [COVID-19 staging, mild (n = 1), moderate I (n = 19), and moderate II (n = 18)]. Patients were treated with 6.6 mg/day d.i.v. or 6 mg/day p.o. dexamethasone, or 20-30 mg/day p.o. prednisolone. The median (25th-75th percentile) number of days from the date of onset to glucocorticoid administration was 8.0 days (7.0-11.25 days). While 24 patients were hospitalized, the condition of 14 improved without hospitalization. The median number of days from glucocorticoid administration to hospitalization was 1.0 day (range, 1.0-1.0 day). In the non-hospitalized patients, the median number of days of glucocorticoid administration was 5.0 days (5.0-5.25 days). The mean number of days from glucocorticoid administration to discharge from the care facility for non-hospitalized patients was 8.4 ± 3.3 days. The adverse reactions among non-hospitalized patients included insomnia (n = 1) and mild liver dysfunction (n = 3). The present method of glucocorticoid administration can be safely used for patients with COVID-19 in care facilities.

Kampo Medicine Treatment for Advanced Pancreatic Cancer: A Case Series.

Aims: The present report aims to investigate the use of Kampo medicine for advanced pancreatic cancer patients in order to prolong survival. Methods: We retrospectively reviewed medical records of patients with pancreatic cancer who presented to our Shimizu Clinic from 2000 to 2020. Patients who survived at least twice as long as the initial prognostic estimate were selected and their treatment was reviewed. The Kampo formula and crude drugs were selected according to the Kampo diagnosis and treatment strategy, which included qi and blood supplementation; qi, blood and water smoothing; and inflammation (termed "heat") and cancer suppression. Results: Ten patients aged 45-80 years (six males and four females) with stage IV advanced cancer were selected. All patients received hozai, which is a tonic formula, of juzentaihoto (JTT) or hochuekkito (HET) decoction. Anti-cancer crude drugs were included in the decoctions of nine patients. At the first visit, the estimated life expectancy for all patients was no more than 1 year; however, treatment with Western and Kampo medicine led to a relatively long survival period of over 2 years. Three patients were still living at the time of this writing, more than 2, 6, and 14 years after treatment initiation. Conclusion: Our results suggest that Kampo medicine may be useful for disease control and supportive care for patients with advanced pancreatic cancer.

Treatment of COVID-19-Related Olfactory Disorder Promoted by Kakkontokasenkyushin'i: A Case Series.

Olfactory disorders are one of the characteristic symptoms of the coronavirus disease of 2019 (COVID-19), which causes infection and inflammation of the upper and lower respiratory tract. To our knowledge, there are no treatments for COVID-19-related olfactory disorder. Here, we report five olfactory disorder cases in COVID-19, treated using the Japanese traditional (Kampo) medicine, kakkontokasenkyushin'i. We treated five patients with mild COVID-19 at an isolation facility using Kampo medicine, depending on their symptoms. Patients with the olfactory disorder presented with a blocked nose, nasal discharge or taste impairment. Physical examination using Kampo medicine showed similar findings, such as a red tongue with red spots and sublingual vein congestion, which presented as blood stasis and inflammation; thus, we prescribed the Kampo medicine, kakkontokasenkyushin'i. After administration, the numeric rating scale scores of the smell impairment improved within 3 days from 9 to 3 in case 1, from 10 to 0 in case 2, from 9 to 0 in case 3, from 5 to 0 in case 4, and from 9 to 0 within 5 days in case 5. Following the treatment, other common cold symptoms were also alleviated. Kakkontokasenkyushin'i can be used for treating nasal congestion, rhinitis, and inflammation in the nasal mucosa. The olfactory disorder in COVID-19 has been reportedly associated with inflammation and congestion, especially in the olfactory bulb and olfactory cleft. Kakkontokasenkyushin'i may be one of the treatment alternatives for the olfactory disorder with rhinitis in patients with COVID-19.

Integrative therapy for advanced pancreatic cancer using Kampo and western medicine: A case report.

A 45-year-old male patient diagnosed as stage IVa pancreatic cancer received anti-cancer treatment with chemotherapy and radiotherapy. During the treatment, he complained of nausea, appetite loss, and fatigue. He received a Kampo diagnosis of qi deficiency, blood stasis, and heat with phlegm; consequently, qi supplementation, smoothing blood, and relieving fever were initiated using Juzentaihoto and Keppuchikuoto. After this treatment, the symptoms showed remarkable improvement. However, computed tomography revealed multiple lung nodules. We prescribed crude drugs with anti-cancer effects, including Scutellaria barbata and Oldenlandia diffusa. These drugs led to slowed development of lung metastases that could be surgically resected. He survived for 7 years after the advanced diagnosis without loss of quality of life. Kampo medicine may be useful for disease control and supportive care in advanced pancreatic cancer patients.

Kampo Medicine for Various Aging-Related Symptoms: A Review of Geriatric Syndrome.

With the continued growth of the aging population in Japan, geriatric syndrome (GS), which is associated with aging-related symptoms, has become a social problem. GS is caused by physiological and pathological aging and may manifest various symptoms. Physicians use multidisciplinary approaches to provide treatment for individual GS symptoms. Kampo medicine, a Japanese traditional medicine that uses multiple pharmacologically active substances, is useful for many syndromes, conditions, disorders, and diseases associated with GS. Evidence of the effectiveness of Kampo medicine for GS has accumulated in recent years. The effects of Kampo treatment for symptoms related to functional decline of the cardiovascular, respiratory, and digestive systems, cognitive impairment and related disorders, pain and other sensory issues, among others, support the use of Kampo medicine for the management of GS. The role of Kampo medicine for GS is summarized in this review.

Exploratory study of clinical effectiveness and safety of TJ-116 bukuryoingohangekobokuto for anxiety and postoperative water brash in esophageal cancer patients (TJ116E).

BACKGROUND: Patients with esophageal cancer suffer from anxiety in the perioperative period surrounding esophagectomy; this may increase the risk of postoperative complications. In particular, postoperative aspiration pneumonia carries a high risk of hospital mortality. Bukuryoingohangekobokuto (BRIHK) is a traditional Japanese medicine formula used to treat anxiety, the feeling of a foreign body in the esophagus, and water brash. We hypothesize that BRIHK might be effective for both anxiety and water brash in perioperative patients with esophageal cancer. The aim of this study is to evaluate the efficacy and safety of BRIHK compared to a placebo for anxiety and water brash in perioperative esophageal cancer patients. METHOD/DESIGN: This will be a single-center, single blind, placebo-controlled randomized clinical trial. Twenty-four patients with esophageal cancer undergoing radical resection surgery will be registered to participate, then randomly and blindly assigned to the BRIHK treatment group or control group. Patients will be administered BRIHK or the placebo from 2 weeks before to 6 weeks after surgery. Primary outcome measures will be anxiety and depression (assessed using the Hospital Anxiety and Depression Scale), and water brash (assessed using the 10-item Eating Assessment Tool, Esophagus and Stomach Surgery Symptom Scale, and videofluoroscopy swallowing measurement). Incidences of aspiration pneumonia will be noted and abdominal gas volume, inflammatory markers, and nutrition status will be evaluated. DISCUSSION: This investigative study will provide clinical evidence of BRIHK administration for anxiety and water brash, which might improve mental distress and reduce postoperative mortality. TRIAL REGISTRATION: The protocol and progress are registered on the Japan Registry of Clinical Trials (jRCT s021190001) and University Hospital Medical Information Network (UMIN000031330). The protocol was approved by the Japanese Ministry of Health, Labour and Welfare certified clinical research review board, Tohoku University (CRB2180001).

[A case of previously undiagnosed methemoglobinemia exhibiting sustained low SpO2 value at the induction of general anesthesia].

A 70-year-old woman was scheduled to undergo surgery for removal of thyroid tumor under general anesthesia. A routine preoperative evaluation confirmed that the patient was stable with no signs of cyanosis and dyspnea. However, during pre-oxygenation as well as mechanical ventilation with 100% oxygen, she showed sustained low SpO2 values (i.e., 91%). Arterial blood gas analysis at FIO2 of 1.0 showed an oxygen partial pressure (PaO2) of 297 mmHg. Unexpectedly, the analysis revealed methemoglobinemia (MetHb concentration: 15%) causing a discrepancy between the low SpO2 and normal PaO2 values in this patient. Methemoglobinemia is an uncommon cause of cyanosis; however, anesthesiologists should be aware that some drugs used during perioperative period (e.g., local anesthetics) can cause methemoglobinemia. While our case was a mild one and the patient recovered with no complications, methemoglobinemia levels above 30% could cause tissue hypoxemia and, thereby, requiring a treatment with methylene blue or ascorbic acid.

Blood lactate/ATP ratio, as an alarm index and real-time biomarker in critical illness.

OBJECTIVE: The acute physiology, age and chronic health evaluation (APACHE) II score and other related scores have been used for evaluation of illness severity in the intensive care unit (ICU), but there is still a need for real-time and sensitive prognostic biomarkers. Recently, alarmins from damaged tissues have been reported as alarm-signaling molecules. Although ATP is a member of the alarmins and its depletion in tissues closely correlates with multiple-organ failure, blood ATP level has not been evaluated in critical illness. To identify real-time prognostic biomarker of critical illness, we measured blood ATP levels and the lactate/ATP ratio (ATP-lactate energy risk score, A-LES) in critically ill patients. METHODS AND RESULTS: Blood samples were collected from 42 consecutive critically ill ICU patients and 155 healthy subjects. The prognostic values of blood ATP levels and A-LES were compared with APACHE II score. The mean ATP level (SD) in healthy subjects was 0.62 (0.19) mM with no significant age or gender differences. The median ATP level in severely ill patients at ICU admission was significantly low at 0.31 mM (interquartile range 0.25 to 0.44) than the level in moderately ill patient at 0.56 mM (0.38 to 0.70) (P<0.01). Assessment with ATP was further corrected by lactate and expressed as A-LES. The median A-LES was 2.7 (2.1 to 3.3) in patients with satisfactory outcome at discharge but was significantly higher in non-survivors at 38.9 (21.0 to 67.9) (P<0.01). Receiver operating characteristic analysis indicated that measurement of blood ATP and A-LES at ICU admission are as useful as APACHE II score for prediction of mortality. CONCLUSION: Blood ATP levels and A-LES are sensitive prognostic biomarkers of mortality at ICU admission. In addition, A-LES provided further real-time evaluation score of illness severity during ICU stay particularly for critically ill patients with APACHE II scores of ≥20.0.

Potential inadequacy of automatic tube compensation to decrease inspiratory work load after at least 48 hours of endotracheal tube use in the clinical setting.

BACKGROUND: Endotracheal tubes (ETTs) impose a substantial respiratory work load on mechanically ventilated patients. Automatic tube compensation (ATC) should overcome this flow-dependent resistive work load; however, ETT resistance can be increased by tracheal secretions or ETT deformities. Our bench study investigated whether ATC provides effective respiratory work load relief in used ETTs. METHODS: We enrolled 20 critically ill patients requiring mechanical ventilation for longer than 48 hours. After extubation, we collected the used ETTs and measured the pressure-time products (PTPs) by using a bellows-in-a-box lung model that simulated spontaneous breathing, at a respiratory rate of 10 breaths/min, inspiratory time of 1.0 s, and tidal volumes (V(T)) of 300 mL, 500 mL, and 700 mL. The ventilator was set at ATC 100% with PEEP of 5 cm H(2)O and F(IO(2)) of 0.21. The flow and airway pressure at the proximal (P(aw)) and distal (P(tr)) ends of the ETT were recorded, and the PTP integrated from P(tr) analyzed. RESULTS: PTP values increased with V(T) during ATC. Even at 100% ATC the ventilator did not completely compensate for the PTP imposed by the ETT. In used ETTs, peak flow and peak P(aw) were lower and PTP values were greater than in new ETTs. As V(T) increased, the percentage difference in the PTP values between the new and used ETTs increased. CONCLUSIONS: ATC does not necessarily compensate for an ETT-imposed respiratory work load. ETT configuration changes and tracheal secretions can increase ETT resistance and decrease the ability of ATC to compensate for the increased respiratory work load.

[Comparison of thoracoscopic and open repair of esophageal atresia with tracheoesophageal fistula].

BACKGROUND: With the increasing use of endoscopic surgery in children, several papers report the comparison between the thoracoscopic and open repair of the neonatal esophageal atresia with tracheoesophageal fistula (EA/TEF). Most of them focus on the duration and outcome of the surgery with few focusing on the neonatal tolerance to the thoracoscopic procedure and intraoperative anesthetic management. METHODS: We retrospectively reviewed the repair surgery of EA/TEF performed during 2001 and 2006 in our institution and compared thoracoscopic repair (thoracoscopy group, n=5) with open repair (open group, n=7). The right main bronchus was blocked with Fogarty catheter in thoracoscopic repair, but not in open repair. Thoracoscopic repair was performed with insufflation of carbon dioxide (3-5 mmHg). RESULTS: The thoracoscopy group had a higher incidence of intraoperative hypercapnia and acidosis and required higher inspired oxygen fraction. On admission to ICU Pa(CO2) was in the normal range in both groups and there was no difference in the duration of mechanical ventilation and ICU stay. CONCLUSIONS: Hypercapnia and acidosis were severer in thoracoscopy group. Careful perioperative adjustment of inspired oxygen fraction and ventilator setting is required.

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on scratching behavior in mice.

The present study was performed to study the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on scratching behavior in hairless mice, which are highly sensitive to pruritogens (mediators causing itching), except for histamine, and are suitable for time-course studies due to their hairless skin. TCDD is a well-known environmental pollutant that causes skin diseases with itching; therefore, we examined whether TCDD induced itching. Oral administration of TCDD caused no increase in scratching behavior when used alone, whereas TCDD in combination with distilled water or acetone/olive oil application caused a significant increase in scratching behavior. Furthermore, nerve growth factor (NGF) content in the skin increased significantly. A single administration of chlorpheniramine (histamine H1 receptor antagonist), tranilast (chemical mediator release inhibitor) and olopatadine (histamine H1 receptor antagonist) had no effect on scratching behavior induced by TCDD in combination with acetone/olive oil application. With repeated administration for 7 days, chlorpheniramine and tranilast had no effect on scratching behavior, whereas olopatadine significantly inhibited scratching behavior. In addition, only olopatadine significantly inhibited NGF content in the skin. From these findings, it can be concluded that TCDD is not a pruritogen but causes alloknesis (itchy skin) with the simultaneous use of trivial external stimulation. In addition, it was found that drugs which decreased skin NGF contents may inhibit this scratching behavior.

Effect of histamine H4 receptor antagonist on allergic rhinitis in mice.

The aim of this study was to clarify the effect of histamine H(4) receptor antagonist, JNJ7777120 (1-[(5-Chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine) on allergic rhinitis in mice. We measured allergic symptoms (sneezing and nasal rubbing), serum total IgE and the levels of cytokines in nasal lavage fluid. Histamine H(4) receptor antagonist, JNJ7777120, caused the dose-dependent inhibition of nasal symptoms by single and repeated intranasal administrations; however, JNJ7777120 caused no inhibition of serum total IgE by single and repeated intranasal administrations. Therefore, we investigated the effect of JNJ7777120 by oral administration. JNJ7777120 also caused a significant inhibition of nasal symptoms by both single and repeated oral administrations. In addition, repeated oral administration of JNJ7777120 caused significant inhibition of serum total IgE. Furthermore, JNJ7777120 caused a significant decrease in the levels of IL-4 and a significant increase in the levels of IFN-gamma in nasal lavage fluid. These results indicated that histamine H(4) receptor is closely related with allergic rhinitis and is important in the pathogenesis of allergic rhinitis. From these results, it can be concluded that histamine H(4) receptor antagonist might be a new strategy to treat allergic rhinitis with immunomodulatory function.

Role of histamine H(4) receptor in allergic conjunctivitis in mice.

We investigated the character of histamine H(1) receptor and H(4) receptor in allergic conjunctivitis. Histamine is the most important mediator in allergic conjunctivitis. We measured eye scratching behavior and allergic-like symptoms score, that is, hyperemia and edema in ICR mice, and examined which receptors intimately involved in allergic conjunctivitis. Histamine caused a dose-dependent eye scratching behavior and allergic-like symptoms. Histamine H(1) receptor antagonist (levocabastine) and H(4) receptor antagonist (JNJ7777120) inhibited eye scratching behavior and histamine H(1) receptor antagonist inhibited allergic-like symptoms induced by histamine. Additionally, combination of levocabastine and JNJ7777120 caused more potent inhibition in allergic conjunctivitis. On the other hand, both selective histamine H(1) receptor agonist (HTMT) and selective H(4) receptor agonist (4-methylhistamine) induced a dose-dependent eye scratching behavior and allergic-like symptoms. JNJ7777120 inhibited the effect of HTMT. However, levocabastine caused no inhibition on the response of 4-methylhistamine. H(4) receptor was closely related with allergic conjunctivitis. H(4) receptor antagonists may be effective in allergic conjunctivitis which showed no inhibition by histamine H(1) receptor antagonists.