Adipose tissue-derived stem cells suppress coronary arteritis of Kawasaki disease in vivo.

BACKGROUND: Kawasaki disease (KD) is a systemic inflammatory disease resulting in an acute febrile syndrome commonly affecting children younger than 5 years. Coronary arteritis in KD is occasionally non-responsive to several treatments. Recently, adipose tissue-derived stem cells (ADSCs) have been shown to have anti-inflammatory, immunosuppressive, and tissue-repair characteristics and are considered a useful treatment for inflammatory disease. The present study aimed to elucidate whether the administration of ADSCs can suppress KD-associated vasculitis in vivo. METHODS: Candida albicans water-soluble fraction is often used to model KD via the induction of severe coronary arteritis. Kawasaki disease model mice were intravenously administered ADSCs and phosphate-buffered saline (PBS). On day 29, the mice were sacrificed and hearts from mice in each group were dissected. This was followed by serum collection. Cardiac tissue sections were subjected to histopathological examination to evaluate the inflammatory area. The levels of pro-inflammatory cytokines in the serum were analyzed at days 15 and 29. The survival rates of both groups were compared. RESULTS: The mean inflammatory area in coronary arteritis was significantly lower in the ADSC group compared to the PBS group (P < 0.01). Furthermore, the levels of pro-inflammatory cytokines, such as IL-1ß, IL-12, IL-17, RANTES, INF-γ, and TNF-α, in the ADSC group were significantly lower than those in the PBS group. Moreover, the ADSC group had a significantly higher survival rate than the PBS group. CONCLUSIONS: These findings highlight that ADSCs have anti-inflammatory and immune regulatory functions that could provide novel cell-based therapeutic strategies for severe KD.

The Inhibitory Effect of S-777469, a Cannabinoid Type 2 Receptor Agonist, on Skin Inflammation in Mice.

We investigated the effects of S-777469 (1-[[6-Ethyl-1-[4-fluorobenzyl]-5-methyl-2-oxo-1, 2-dihydropyridine-3-carbonyl]amino]-cyclohexanecarboxylic acid), a novel cannabinoid type 2 receptor (CB2) agonist, on 1-fluoro-2,4-dinitrobenzene (DNFB)-induced ear inflammation and mite antigen-induced dermatitis in mice. The oral administration of S-777469 significantly suppressed DNFB-induced ear swelling in a dose-dependent manner. In addition, S-777469 significantly alleviated mite antigen-induced atopic dermatitis-like skin lesions in NC/Nga mice. A histological analysis revealed that S-777469 significantly reduced the epidermal thickness and the number of mast cells infiltrating skin lesions. We demonstrated that S-777469 inhibited mite antigen-induced eosinophil accumulation in skin lesions and an endogenous CB2 ligand, 2-arachidonoylglycerol (2-AG)-induced eosinophil migration in vitro. Moreover, we confirmed that 2-AG levels significantly increased in skin lesions of mite antigen-induced dermatitis model. Together, these results suggest that S-777469 inhibits skin inflammation in mice by blocking the activities of 2-AG.

Effectiveness of ethinylestradiol/drospirenone for premenstrual symptoms in Japanese patients with dysmenorrhea: Open-label pilot study.

AIM: A combined oral contraceptive containing ethinylestradiol 20 µg plus drospirenone 3 mg (EE20 + DRSP) in a 24/4 regimen has been shown to alleviate the symptoms of premenstrual syndrome and premenstrual dysphoric disorder. This study was conducted to evaluate the efficacy of EE20 + DRSP in Japanese patients with premenstrual symptoms. MATERIAL AND METHODS: A multicenter, prospective, open-label, single-arm, phase IV study was performed in Japanese women with dysmenorrhea and premenstrual symptoms. They were treated with EE20 + DRSP to alleviate the symptoms of dysmenorrhea for six treatment cycles. Premenstrual symptoms were evaluated using a Premenstrual Symptoms Questionnaire at baseline and after three and six cycles of EE20 + DRSP. The degree of dysmenorrhea was also evaluated using a visual analog scale at baseline and after one, three, and six cycles of EE20 + DRSP. RESULTS: Forty-eight patients were treated with EE20 + DRSP. Most of the premenstrual symptoms were alleviated significantly by three and six cycles of EE20 + DRSP treatment. EE20 + DRSP treatment significantly improved the severity of premenstrual symptoms. We also confirmed the effectiveness of EE20 + DRSP for the treatment for dysmenorrhea. CONCLUSION: This study showed that EE20 + DRSP could be a useful treatment strategy for premenstrual symptoms in Japanese women.

Characterization and quantification of diacylglycerol species in biological extracts after one-step derivatization: a shotgun lipidomics approach.

Diacylglycerols (DAGs) are important intermediates of lipid metabolism and cellular signaling. It is well-known that the mass levels of DAG are altered under disease states. Therefore, quantitative analysis of DAGs in biological samples can provide critical information to uncover underlying mechanisms of various cellular functional disorders. Although great efforts on the analysis of individual DAG species have recently been made by utilizing mass spectrometry with or without derivatization, cost-effective and high throughput methodologies for identification and quantification of all DAG species including regioisomers, particularly in an approach of shotgun lipidomics, are still missing. Herein, we described a novel method for directly identifying and quantifying DAG species including regioisomers present in lipid extracts of biological samples after facile one-step derivatization with dimethylglycine based on the principles of multidimensional mass spectrometry-based shotgun lipidomics. The established method provided substantial sensitivity (low limit of quantification at amol/µL), high specificity, and broad linear dynamics range (2500-fold) without matrix effects. By exploiting this novel method, we revealed a 16-fold increase of total DAG mass in the livers of ob/ob mice compared to their wild type controls at 4 months of age (an insulin-resistant state) versus a 5-fold difference between 3 month old mice (with normal insulin). These results demonstrated the importance and power of the method for studying biochemical mechanisms underpinning disease states.

Use of tocilizumab to treat arthritis associated with mixed connective tissue disease complicated by ovarian teratoma: a case report.

Mixed connective tissue disease (MCTD) is characterized by mixed features of systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis and is rare in children. Here, we report a case of MCTD in a 10-year-old girl who presented at our hospital with arthralgia, Raynaud's phenomenon, and fatigue. Blood tests were positive for anti-U1-ribonucleoprotein (RNP) antibodies and for rheumatoid factors (RFs) IgG-RF and anti-galactose-deficient IgG. Levels of myogenic enzymes and hypergammaglobulinemia were elevated. Macrophages were prominent in bone marrow, with scattered phagocytic macrophages. MCTD was diagnosed based on the patient's symptoms and laboratory findings. Methylprednisolone pulse therapy combined with oral tacrolimus was administered, which led to resolution of symptoms. Three months after pulse therapy, arthralgia worsened and methotrexate was administered. Arthralgia improved but did not resolve. Magnetic resonance imaging performed to investigate the hip pain revealed a mature ovarian teratoma, which was surgically removed. Because the pain persisted and interfered with her daily life, she was treated with tocilizumab for joint pain relief, which decreased the pain level. Tocilizumab is a candidate for additional treatment of juvenile idiopathic arthritis-like arthritis associated with childhood-onset MCTD.

A syringotropic variant of cutaneous sarcoidosis: presentation of 3 cases exhibiting defective sweating responses.

BACKGROUND: Although nodular collections of epithelioid histiocytes and multinuclear cells can be present at all levels of the dermis in cutaneous sarcoidosis, sarcoidal granulomas characterized by marked syringotropism of epithelioid histiocytes have not been previously reported to our knowledge. OBJECTIVE: We sought to determine whether syringotropic sarcoidosis bears characteristic clinical and histologic features and exhibits defective sweating responses. METHODS: We investigated the clinical, histologic, and immunohistochemical features of syringotropic sarcoidosis, and sweating responses to thermal stress in 3 patients. RESULTS: Multiple erythematous patches/plaques predominantly affected the extensor aspect of the lower legs and thighs. Immunohistochemical analyses of the sweat glands surrounded by syringotropic granulomas exhibited profoundly decreased expression of dermcidin and aquaporin 5, both of which are constitutively expressed in sweat glands of control subjects, suggesting functional defects. Indeed, sweating responses to thermal stress were markedly decreased in the involved area, as compared with those in the uninvolved area and in healthy control subjects. LIMITATIONS: There were a limited number of cases in our study. CONCLUSION: A syringotropic variant of cutaneous sarcoidosis might be a distinct entity clinically and histologically or represent an abortive variant.

Successful coil embolization for life-threatening hemorrhage in childhood leukemia induction therapy.

An 11-year-old boy was experienced severe life-threatening hemorrhage from a branch of the superior mesenteric artery (SMA) after acute lymphoblastic leukemia induction therapy. The patient had a history of attention deficit hyperactivity disorder (ADHD), diagnosed at 3 years of age. Subsequent to discontinuing his psychotropic medication, the patient's mental status deteriorated and treatment with midazolam for 3 weeks was necessary to allow the completion of the leukemia induction regimen. On day 51, although there was no indication of thrombocytopenia or a coagulation disorder, the patient began to hemorrhage suddenly from anal with resulting hypovolemic shock, and large-volume blood transfusion was initiated. Although upper and lower endoscopy failed to determine the location of the hemorrhage, angiography enabled us to determine that it was a branch of the SMA (the middle colic artery #6), and selective arterial embolization was used to arrest the bleeding. There could have been underlying causes, such as, a probable malformation or aneurysm in that area, although there was no indication before or after the event. This is a rare case of arterial hemorrhage from a branch of the SMA that occurred in a pediatric patient idiopathically during the induction therapy of leukemia.

Serum KL-6 and surfactant protein D in children with 2009 pandemic H1N1 influenza infection.

BACKGROUND: A global pandemic influenza A (H1N1) outbreak occurred in 2009. Rapid progress of respiratory distress is one of the characteristic features of pandemic influenza A (H1N1) infection. The physiologic mechanism causing hypoxia in pandemic influenza A (H1N1) infection, however, has not been elucidated. METHODS: The serum levels of KL-6 and surfactant protein D (SP-D) were evaluated in 21 cases of pandemic influenza A (H1N1) infection associated with chest radiographic abnormality in order to estimate alveolar involvement. The clinical features were also analyzed. RESULTS: All of the patients had high fever, and rapidly progressed to respiratory distress within several days of disease onset. Despite mild radiographic abnormality in these patients, dyspnea was severe and they had low blood oxygen saturation levels. Many of the patients had a history of allergic diseases including asthma. Serum KL-6 and SP-D levels on admission were 191 ± 69 U/mL and 32.6 ± 18.9 ng/mL, respectively. These two levels were still below the upper normal limit 1 week later. There were no clear relationships between specific clinical symptoms and KL-6 or SP-D levels. All patients were treated with oseltamivir and/or zanamivir, and improved without mechanical ventilation management. CONCLUSION: KL-6 and SP-D elevation were not significant in pandemic influenza A (H1N1) infection associated with chest radiographic abnormality. In pandemic influenza A (H1N1) infection, alveolar involvement was estimated to be little, and severe respiratory distress was probably caused by obstruction of peripheral bronchi.

Long-term remission of unusual plasmoacanthoma on the nasal canthus achieved by intralesional corticosteroid injection: Insights into the pathogenesis and treatment planning based on a literature review.

Plasmoacanthoma (PA) is a verrucous tumor predominantly developing on periorificial areas, which has been considered as an unusual subtype of plasmacytosis circumorificialis. Because of its rarity and clinical resemblance to several verrucous dermatological disorders, accurate diagnosis of PA is quite challenging. Herein, we present an extremely unusual case of PA which arose on both sides of the nasal canthus and was successfully treated with intralesional corticosteroid injections. To elucidate clinicopathological features of this condition, a literature review was also attempted. A 78-year-old woman visited us with a 2-year history of eruptions affecting both sides of the nasal canthus. At a local clinic, the diagnosis and treatment had been unsuccessful due to non-specific histological findings, leading to the referral to our institute. On physical examination, verrucous and lobulated reddish plaques were observed. In histology, psoriasiform epidermal change and dense plasma cell infiltration in the dermis were detected. The diagnosis of PA was made. After 5-monthly intralesional triamcinolone acetonide injections, the lesions became hardly noticeable with no evidence of recurrence. A literature review found five PA cases. PA predominantly arose on the periorificial area, mostly in or around the mouth, except one case which developed on the extra-oral or perioral area. Intralesional corticosteroid injection has been preferably performed, which frequently achieved successful remission. Chronic inflammation has been reported as a preceding condition. Abundance of plasma cells in the lacrimal glands and conjunctiva, together with pre-existing allergic conjunctivitis and habitual scratching, might have contributed to PA development in our case. Histopathological detection of psoriasiform epidermal change and dense dermal plasma cell infiltration is indispensable for the diagnosis of PA. For accurate diagnosis, optimization of treatment, and further accumulation of extra-oral/perioral PA cases, a skin biopsy needs to be proactively performed on verrucous lesions on relatively unfamiliar orifice sites.

Development of a human immunodeficiency virus type 1-based lentiviral vector that allows efficient transduction of both human and rhesus blood cells.

Human immunodeficiency virus type 1 (HIV-1) vectors transduce rhesus blood cells poorly due to a species-specific block by TRIM5alpha and APOBEC3G, which target HIV-1 capsid and viral infectivity factor (Vif), respectively. We sought to develop a lentiviral vector capable of transducing both human and rhesus blood cells by combining components of both HIV-1 and simian immunodeficiency virus (SIV), including SIV capsid (sCA) and SIV Vif. A chimeric HIV-1 vector including sCA (chiHIV) was superior to the conventional SIV in transducing a human blood cell line and superior to the conventional HIV-1 vector in transducing a rhesus blood cell line. Among human CD34(+) hematopoietic stem cells (HSCs), the chiHIV and HIV-1 vectors showed similar transduction efficiencies; in rhesus CD34(+) HSCs, the chiHIV vector yielded superior transduction rates. In in vivo competitive repopulation experiments with two rhesus macaques, the chiHIV vector demonstrated superior marking levels over the conventional HIV-1 vector in all blood lineages (first rhesus, 15 to 30% versus 1 to 5%; second rhesus, 7 to 15% versus 0.5 to 2%, respectively) 3 to 7 months postinfusion. In summary, we have developed an HIV-1-based lentiviral vector system that should allow comprehensive preclinical testing of HIV-1-based therapeutic vectors in the rhesus macaque model with eventual clinical application.

Busulfan produces efficient human cell engraftment in NOD/LtSz-Scid IL2Rgamma(null) mice.

Xenografting immunodeficient mice after low-dose irradiation has been used as a surrogate human hematopoietic stem cell (HSC) assay; however, irradiation requires strict and meticulous animal support and can produce significant mortality rates, limiting the usefulness of this model. In this work, we examined the use of parenteral busulfan as an alternative conditioning agent. Busulfan led to dose-dependent human HSC engraftment in NOD/LtSz-scid/IL2Rgamma(null) mice, with marked improvement in survival rates. Terminally differentiated B and T lymphocytes made up most of the human CD45+ cells observed during the initial 5 weeks post-transplant when unselected cord blood (CB) products were infused, suggesting derivation from existing mature elements rather than HSCs. Beyond 5 weeks, CD34+-enriched products produced and sustained superior engraftment rates compared with unselected grafts (CB CD34+, 65.8% +/- 5.35%, vs. whole CB, 4.27% +/- 0.67%, at 24 weeks). CB CD34+ group achieved significantly higher levels of engraftment than mobilized CD34+-enriched peripheral blood (PB CD34+). At 8 weeks, all leukocyte subsets were detected, yet human red blood cells (RBCs) were not observed. Transfused human red cells persisted in the chimeric mice for up to 3 days; an accompanying rise in total bilirubin suggested hemolysis as a contributing factor to their clearance. Recipient mouse-derived human HSCs had the capacity to form erythroid colonies in vitro at various time points post-transplant in the presence of human transferrin (Tf). When human Tf was administered singly or in combination with anti-CD122 antibody and human cytokines, up to 0.1% human RBCs were detectable in the peripheral blood. This long evasive model should prove valuable for the study of human erythroid cells.

5% dimethyl sulfoxide (DMSO) and pentastarch improves cryopreservation of cord blood cells over 10% DMSO.

BACKGROUND: Cell number and viability are important in cord blood (CB) transplantation. While 10% dimethyl sulfoxide (DMSO) is the standard medium, adding a starch to freezing medium is increasingly utilized as a cytoprotectant for the thawing process. Similar to hetastarch, pentastarch has the advantages of faster renal clearance and less effect on the coagulation system. STUDY DESIGN AND METHODS: We compared a lower DMSO concentration (5%) containing pentastarch with 10% DMSO and performed cell viability assay, colony-forming units (CFUs), and transplantation of CB cells in NOD/SCID IL2Rγ(null) mice. RESULTS: CB cells in 5% DMSO/pentastarch had similar CD34+, CD3+, and CD19+ cell percentages after thawing as fresh CB cells. CB cells in 5% DMSO/pentastarch had higher viability (83.3±9.23%) than those frozen in 10% DMSO (75.3±11.0%, p<0.05). We monitored cell viability postthaw every 30 minutes. The mean loss in the first 30 minutes was less in the 5% DMSO/pentastarch group. At the end of 3 hours, the viability decreased by a mean of 7.75% for the 5% DMSO/pentastarch and 17.5% for the 10% DMSO groups. CFUs were similar between the two cryopreserved groups. Frozen CB cells engrafted equally well in IL2Rγ(null) mice compared to fresh CB cells up to 24 weeks, and CB cells frozen in 5% DMSO/pentastarch engrafted better than those in 10% DMSO. CONCLUSION: Our data indicate that the lower DMSO concentration with pentastarch represents an improvement in the CB cryopreservation process and could have wider clinical application as an alternate freezing medium over 10% DMSO.

Genetic and Antigenic Characterization and Retrospective Surveillance of Bovine Influenza D Viruses Identified in Hokkaido, Japan from 2018 to 2020.

Influenza D virus (IDV), which is a new member of the Orthomyxoviridae family, is potentially involved in bovine respiratory diseases (BRDs). Bovine IDVs (BIDVs) from Japan have been distributed nationwide since 2010 and are genetically distinct from foreign IDVs. We isolated BIDVs from three BRD outbreaks, in Hokkaido during 2018-2020, to understand their genetic and antigenic characteristics. Retrospective surveillance was performed using sera collected throughout the last decade in Hokkaido to investigate BIDV existence. Three BIDVs were isolated using cell culture. Comparative and phylogenetic analyses using sequence data of the three BIDVs and IDVs from Japan and other countries available in GenBank demonstrated that Japanese BIDVs, including the three BIDV isolates, were genetically distinct from other IDVs. Genotype classifications based on the rotavirus genotype classification revealed multiple genotypes of RNA segments 1-7. Two BIDVs were of a new genotype, different from those of other Japanese BIDVs. Neutralization assays against two BIDVs with different genotypes using sera collected in acute and recovery phases of BRD revealed differences in cross-reactivity to heterogenous BIDVs. Retrospective surveillance suggested that BIDV existed in Hokkaido, in 2009. Our findings suggest that BIDVs of different genotypes and antigenicity are distributed and maintained in Hokkaido and provide new insights into molecular characteristics and the evolution of IDVs.

Dextran sulfate and stromal cell derived factor-1 promote CXCR4 expression and improve bone marrow homing efficiency of infused hematopoietic stem cells.

Although the homing of hematopoietic stem cells (HSC) to the bone marrow (BM) is a crucial step in hematopoietic development and BM repopulation, the mechanisms underlying these processes have not been fully clarified. Recent studies suggest that interaction between the chemokine receptor CXCR4 and its ligand, stromal cell-derived factor 1 (SDF-1), plays a critical role in these processes. In addition, dextran sulfate increases plasma SDF-1 levels in mice and nonhuman primates. Thus, we examined the effects of preconditioning with SDF-1 and dextran sulfate on the homing efficiency of HSCs following BM transplantation in mice. We found that the preconditioning of donor mice with either SDF-1 or dextran sulfate enhanced the homing efficiency of infused HSCs in vivo. The greatest effects were obtained with dextran sulfate. Moreover, reverse transcriptase polymerase chain reaction analysis demonstrated that SDF-1 and dextran sulfate increased transcription of a variety of homing-related genes, including those for CXCR4, lymphocyte function associated antigen-1, matrix metalloproteinase-9, very late antigen-4/5, and macrophage inflammatory protein-1. We suggest that whereas SDF-1 directly acts to upregulate CXCR4 expression in HSCs, dextran sulfate acts via multiple pathways involved in the induction of various homing-related molecules, in addition to SDF-1. Thus, preconditioning donors with dextran sulfate offers a novel clinical approach for improving the homing and engraftment of HSCs in the BM.

Observation of enhanced thermopower due to spin fluctuation in weak itinerant ferromagnet.

Increasing demand for higher energy efficiency calls for waste heat recovery technology. Thus, facilitating practical thermoelectric generation systems is strongly desired. One option is enhancing the thermoelectric power factor, S 2/r, where S is the Seebeck coefficient and r is the electrical resistivity, although it is still challenging because of the trade-off between S and r. We demonstrate that enhanced S 2/r can be achieved by incorporating magnetic interaction in ferromagnetic metals via the spin fluctuation arising from itinerant electrons. We show that electron-doped Heusler alloys exhibit weak ferromagnetism at T C near room temperature with a small magnetic moment. A pronounced enhancement around T C was observed, with a 20% improvement in the power factor from the case where spin fluctuation is suppressed by applying magnetic field. This result supports the merit of using spin fluctuation to further enhance thermoelectric properties and the potential to further probe correlations and synergy between magnetic and thermoelectric fields.

Safety and Immunogenicity of the Quadrivalent HPV Vaccine in Japanese Boys: a Phase 3, Open-Label Study.

Human papillomavirus (HPV)-associated disease is common among men with HPV infection. A quadrivalent HPV (qHPV) vaccine has demonstrated 85.9% efficacy against HPV6/11/16/18-related, persistent (≥ 6 month) infection in a study of Japanese men aged 16-26 years old. Here, we report the results of an open-label study of the immunogenicity and tolerability of the qHPV vaccine (NCT02576054), conducted to bridge findings from Japanese men to Japanese boys aged 9-15 years old. A total of 100 boys completed a three-vaccination regimen (Day 1, and Months 2 and 6), and 99 boys were included in the primary analysis population. The rate of seroconversion at one month after vaccine Dose 3 (Month 7) was high for each type of HPV (anti-HPV6/11/16/18 seroconversion rates [95% CI]: 94.9% [85.5%, 98.3%], 99.0% [94.4%, 100.0%], 99.0% [94.5%, 100.0%], and 99.0% [94.4%, 100.0%], respectively). Moreover, anti-HPV6/11/16/18 geometric mean titers were 482.9 mMU/mL, 1052.8 mMU/mL, 3878.3 mMU/mL, and 1114.5 mMU/mL, respectively. Immune responses to the qHPV vaccine were non-inferior among Japanese boys included in the current study and compared with young Japanese men from a separate study. Injection-site reactions were the most common adverse events, and administration of the vaccine was well tolerated in Japanese boys.

Therapy-related Secondary Malignancy After Treatment of Childhood Malignancy: Cases from a Single Center.

BACKGROUND: Therapeutic outcomes for childhood malignancy have dramatically improved. However, secondary malignancies are a major concern, as they greatly affect the quality of life of survivors. This retrospective study evaluated the cumulative incidence, clinical features, and outcomes of secondary malignancies at Nippon Medical School Hospital. METHODS: We examined data from 275 cases of primary childhood malignancy diagnosed between 1980 and 2014. Information regarding treatment of the primary malignancy, including irradiation dose, site, and cumulative dose of anticancer drugs, was assessed. We also collected data on secondary malignancy, including patient sex, age at diagnosis, malignancy site, time from primary to secondary malignancy, and outcomes. RESULTS: Secondary malignancies developed in 11 patients and included acute myeloid leukemia (AML) (4), meningioma (4), Ewing sarcoma (1), germ cell tumor (1), and malignant parotid gland tumor (1). The primary malignancies included acute lymphoblastic leukemia (ALL) (9), non-Hodgkin lymphoma (1) and brain tumor (1). In 7 of the 9 ALL patients, chemoradiotherapy was the primary treatment. The meningiomas and 1 solid tumor developed within the radiation field. All AMLs and meningiomas developed within 5 years and after 20 years, respectively, of the primary diagnosis. The 10- and 20-year cumulative incidence rates for secondary malignancy in our hospital were 1.9% and 5.8%, respectively. CONCLUSIONS: Our results revealed that the type of secondary malignancy depends on the interval after the end of treatment for primary malignancy. Meningioma, notably, develops many years after completion of primary malignancy treatment. Early detection during long-term follow-up is therefore essential.

Design, synthesis, and structure-activity relationship of novel opioid kappa-agonists.

By focusing on 4,5-epoxymorphinan, a traditional opioid skeleton but a new structure in the opioid kappa-agonist research field, and by rationally applying the 'message-address concept' and 'accessory site hypothesis,' we discovered a new chemical class opioid kappa-agonist, TRK-820 (1). Its development as an antipruritus is now in the final stage. Here, the full scope of its design, synthesis, and structure-activity relationship are described.