Synthesis of JTT‐501 and its metabolite JTP‐20604 labelled with 13C

JTT‐501 specifically labelled with ¹³C was obtained via a four‐step synthesis at an isotopic enrichment level of 99% and in 14% overall chemical yield starting from 4‐hydroxy‐[ring‐U‐¹³C₆]benzaldehyde (3) . The hydrogenation of [¹³C₆]JTT‐501 over Pd/C gave [¹³C₆]JTP‐20604 in 90% chemical yield. Copyright © 2003 John Wiley & Sons, Ltd.     

Nongastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas: Clinical and therapeutic features of 24 localized patients

Background: Peripheral B-cell lymphoma of the marginal zone (MALT, low-grade), presenting as localized, extranodal disease, usually affects the elderly. The gastrointestinal tract is the most frequently involved extranodal location, representing 70% of all MALT lymphomas. Recently, numerous other extranodal sites involved by MALT lymphomas have also been described.Patients and methods: From January 1990 to October 1995, 24 patients with untreated nongastrointestinal low-grade MALT lymphoma were submitted to treatments ranging from the local approach of radiotherapy and local -interferon (-IFN) administration to chemotherapy. The tumours were located in the lung (seven cases), conjunctiva (four cases), lachrymal gland and orbital soft tissue (four cases), salivary glands (three cases), skin (three cases), breast (two cases)' and thyroid (one case). All patients had low-grade stage IE tumours.Results: Chemotherapy was administered in 11 patients (six with lung, three with salivary gland, one with breast, and one with thyroid locations); radiation therapy was employed in seven patients (three with lachrymal gland, three with skin, and one with breast locations); local -IFN administration was administered in five patients (four with conjunctival, and one with lachrymal gland sites); and surgery was employed in one patient with a lung tumour. All patients achieved complete remissions; three local recurrences and two relapses in other sites were observed. The global five-year survival rate was 100% with a relapse-free survival rate of 79%.Conclusions: These data confirm the significant efficacy of different therapeutic approaches to specific sites inbes obtaining a good remission rate for nongastrointestinal localized low-grade MALT lymphomas.     

起搏预防和终止快速性房性心律失常的疗效观察(附3例报告)

观察AT501起搏器起搏预防和终止快速性房性心律失常的疗效。3例病窦综合征(SSS)患者,同时伴有快速性房性心律失常,置入Medtronic公司生产的AT501起搏器,术后1个月打开三种独立的起搏预防治疗功能和3个可程控的起搏终止治疗功能。经8～10个月的随访,患者的临床症状较术前明显改善,通过9790程控仪回顾心律失常发生事件,发现AT501起搏器对快速性房性心律失常的检测准确率为98%,起搏预防治疗功能和起搏终止治疗功能可减少快速性房性心律失常的发作,其中起搏终止治疗的成功率为56%,在270～360ms快速性房性心律失常检测区成功率为78%,在220～270ms快速性房性心律失常检测区成功率为40%。结论:初步临床应用表明,AT501起搏器置入后通过对起搏器的起搏预防和终止治疗功能合理程控,可安全、有效地减少快速性房性心律失常的发作。     

ABP 501 for the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease, which has a negative impact on the ability to perform activities daily. Tumour necrosis factor α (TNF) is a cytokine with diverse cellular effects, and a key regulator of the inflammatory response. ABP 501 is a biosimilar to adalimumab, a TNF inhibitor.

Areas covered: In this review, we examined ABP 501, as a biosimilar candidate to adalimumab in the treatment of RA focusing on the available data. Current data indicate that ABP 501 is a highly similar alternative to adalimumab in terms of safety, efficacy, tolerability and immunogenicity. ABP 501 has already been approved by health authorities in Europe and the United States of America, as a subcutaneous (s.c.) therapy option for the treatment of patients with RA, but also for the full spectrum approved for its bio-originator adalimumab.

Expert opinion: Current body of evidence suggests that all biologic activities have been demonstrated to be equivalent between ABP 501 and the originator, including binding rates and affinity to TNF, and also the effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, it is fully expected to have same efficacy and safety in all indications.     

Serial changes in markers of disease activity with corticosteroid treatment in sarcoidosis

Serial changes in various markers of disease activity with corticosteroid therapy were assessed in 12 patients with active sarcoidosis. After six weeks of treatment with 40 mg daily of prednisone, all but one patient demonstrated symptomatic and radiographic improvement. For the entire patient group, there were corresponding improvements in forced vital capacity, from 59.2 +/- 5.5 to 70.5 +/- 5.3 percent of the predicted value (p less than 0.001, Student paired t test), serum angiotensin-converting enzyme levels, from 66.0 +/- 12.1 to 28.2 +/- 4.0 U/ml (p = 0.003), 67gallium lung scanning scores, from 3.6 +/- 0.2 to 0.8 +/- 0.3 (p less than 0.001), serum gamma globulin levels, from 2.40 +/- 0.2 to 1.5 +/- 0.1 g/dl (p less than 0.001), and erythrocyte sedimentation rate, from 26.8 +/- 2.7 to 14.8 +/- 3.0 mm per hour (p less than 0.001). Changes in percent of bronchoalveolar lavage fluid lymphocytes were less impressive (from 28.7 +/- 4.9 to 21.2 +/- 5.1, p = 0.034), but the geometric mean number of bronchoalveolar lavage fluid-IgG-secreting cells decreased from 23,861 to 3,830 (p = 0.013). Serial evaluations in five patients treated with decreasing doses of alternate-day prednisone for an additional 10 1/2 months indicated that changes in 67gallium lung scanning scores corresponded most closely to the clinical course in five of five patients. Determination of serum angiotensin-converting enzyme levels also closely paralleled the clinical course in four of five patients, whereas the other parameters measured were more variable markers of clinical response. However, abnormalities of bronchoalveolar lavage fluid-IgG-secreting cells often persisted in the absence of clinically evident disease, and the percentages of bronchoalveolar lavage fluid lymphocytes were frequently normal in patients who responded subsequently to corticosteroids. Larger prospective studies are warranted to more extensively evaluate various measurements of disease activity, especially bronchoalveolar lavage fluid analysis, in sarcoidosis.     

A new antidiabetic agent (JTT-501) rapidly stimulates glucose disposal rates by enhancing insulin signal transduction in skeletal muscle

Summary A newly synthesized antidiabetic agent, JTT-501 is an isoxazolidinedione rather than a thiazolidinedione. An oral dose of JTT-501 (100 mg · kg^–1· day^–1) given to 12-week-old male Zucker fatty rats for 7 days led to the amelioration of both hyperinsulinaemia (40 % of non-treated) and hypertriglyceridaemia (23 % of non-treated) as well as a 2.4-fold increased insulin sensitivity as determined by a euglycaemic insulin clamp. In our study, we further evaluated the acute effect of JTT-501 on both the glucose infusion rates (GIR) and insulin signalling in skeletal muscle. Male Sprague-Dawley (SD) rats aged 10 weeks were injected intravenously with JTT-501 (5 mg/kg) and then a euglycaemic insulin clamp was initiated and glucose infusion rates monitored for 150 min. We found that this treatment increased the glucose infusion rate by 33 % during the last 30 min in SD rats. After the clamp had been initiated for 30 min, the insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activities co-immunoprecipitated with insulin receptor substrate 1 (IRS-1) were also enhanced, resulting in increased glycogen synthase activities in the soleus muscles. Treatment with JTT-501 also enhanced the phosphorylation of insulin receptors and insulin receptor-substrate 1 rapidly as well as the phosphatidylinositol 3-kinase activities, which were stimulated by a bolus injection of insulin. Similarly, JTT-501 stimulated the glucose infusion rate by 30 % and enhanced insulin signalling in Zucker fatty rats. In conclusion, a newly developed isoxazolidinedione, JTT-501, rapidly potentiates the insulin sensitivity of skeletal muscle by enhancing insulin signalling and could be useful for the treatment of insulin-resistant diabetic subjects. [Diabetologia (1999) 42: 151–159] Received: 2 June 1998 and in final revised form: 2 October 1998     

Immunomodulatory aspects in the progression and treatment of oral malignancy

Inflammation substantially affects the risk of oral malignancy. Pro-inflammatory cytokine, interferon (IFN)-γ, confers anti-tumor activity using several different mechanisms. Conversely, higher expression of interleukin (IL)-17 is associated with worse prognosis. Monocyte chemotactic protein (MCP)-1 correlates positively with poor long-term survival of head and neck squamous cell carcinoma (HNSCC) patients. IL-1α affects cancer associated fibroblasts and macrophages, and promote several malignant phenotypes including immune suppression. Some anti-inflammatory cytokines, including IL-10 and transforming growth factor (TGF)-β, relate to pro-tumoral activities.Among immune checkpoint modulators, programmed death (PD-)1 and PD-ligand (L)1 facilitate oral squamous cell carcinoma (OSCC) cell evasion from immune surveillance, and the expression status of these has a prognostic value.OSCCs contain tumor associated macrophages (TAMs) as major stromal cells of their tumor microenvironment. Among the two distinctive states, M2 macrophages support tumor invasion, metastasis and immune suppression. Crosstalk between TAMs and OSCC or cancer-associated fibroblasts (CAF) plays an important role in the progression of OSCC.Clinical trials with blocking antibodies against IL-1α or melanoma-associated antigens have been reported as therapeutic approaches against OSCCs. The most promising approach activating antitumor immunity is the blockade of PD-1/PD-L1 axis. Manipulating the polarization of pro-tumorigenic macrophages has been reported as a novel therapeutic approach.     

Structure-Function Analyses of New SARS-CoV-2 Variants B.1.1.7, B.1.351 and B.1.1.28.1: Clinical,Diagnostic, Therapeutic and Public Health Implications

SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) has accumulated multiple mutations during its global circulation. Recently, three SARS-CoV-2 lineages, B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1), have emerged in the United Kingdom, South Africa and Brazil, respectively. Here, we have presented global viewpoint on implications of emerging SARS-CoV-2 variants based on structural–function impact of crucial mutations occurring in its spike (S), ORF8 and nucleocapsid (N) proteins. While the N501Y mutation was observed in all three lineages, the 501Y.V1 and P.1 accumulated a different set of mutations in the S protein. The missense mutational effects were predicted through a COVID-19 dedicated resource followed by atomistic molecular dynamics simulations. Current findings indicate that some mutations in the S protein might lead to higher affinity with host receptors and resistance against antibodies, but not all are due to different antibody binding (epitope) regions. Mutations may, however, result in diagnostic tests failures and possible interference with binding of newly identified anti-viral candidates against SARS-CoV-2, likely necessitating roll out of recurring “flu-like shots” annually for tackling COVID-19. The functional relevance of these mutations has been described in terms of modulation of host tropism, antibody resistance, diagnostic sensitivity and therapeutic candidates. Besides global economic losses, post-vaccine reinfections with emerging variants can have significant clinical, therapeutic and public health impacts.     

机动门脉动真空灭菌器的科学化管理

本文论述了机动门脉动真空灭菌器在使用中的科学化管理,质量保证(QA)与质量控制(QC)及预防性维修。