No abstract

This study innovatively prepared an effective capsaicin-loaded liposome, a nanoformulation with fewer irritants, for oral administration. The in vitro and in vivo properties of the liposomal encapsulation were investigated and the potential possibility of oral administration evaluated. The liposomal agent composed of phospholipid, cholesterol, sodium cholate and isopropyl myristate was prepared using film-dispersion method. A level A in vitro-in vivo correlation (IVIVC) was established for the first time, which demonstrated an excellent IVIVC of both formulated and free capsaicin in oral administration. Physicochemical characterizations including mean particle size, zeta (ζ) potential and average encapsulation efficiency of capsaicin-loaded liposome were found to be 52.2 ± 1.3 nm, -41.5 ± 2.71 mv and 81.9 ± 2.43 %, respectively. In vivo, liposomal encapsulation allowed a 3.34-fold increase in relative bioavailability compared to free capsaicin. The gastric mucosa irritation studies indicated that the liposomal system was a safe carrier for oral administration. These results support the fact that capsaicin, an effective drug for the treatment of neuropathic pain, could be encapsulated in liposome for improved oral bioavailability. The excellent IVIVC of capsaicin-loaded liposome could also be a promising tool in liposomal formulation development with an added advantage of reduced animal testing.

Background: In RRMM, the median overall survival (OS) of pts with RRMM who progressed after exposure to ≥3 prior therapies is ~13 mo, indicating a high unmet need. LCAR-B38M is a structurally differentiated CAR-T cell therapy containing a 4-1BB co-stimulatory domain and 2 BCMA-targeting single-domain antibodies designed to confer avidity. Earlier results from LEGEND-2 (NCT03090659), a first-in-human phase 1 study using LCAR-B38M CAR-T cells in 74 pts with RRMM conducted in 4 hospitals in China (Jiangsu Provincial People's Hospital; Ruijin Hospital; Changzheng Hospital; and the Second Affiliated Hospital of Xi'an Jiaotong University), showed encouraging efficacy and manageable safety. Key eligibility criteria included RRMM with ≥3 prior lines of therapy. Here, we present long-term follow-up data on safety and efficacy from the Xi'an site. Methods: In the Xi'an site-specific protocol (n=57), lymphodepletion was performed using cyclophosphamide (Cy; 300 mg/m2)alone for 3 days. LCAR-B38M (median CAR+ T cells, 0.5×106 cells/kg; range, 0.07-2.1 × 106) was infused in 3 split infusions. The primary objective was to evaluate the safety of LCAR-B38M; the secondary objective was to evaluate anti-myeloma response of treatment. Adverse events (AEs) were graded using the NCI-CTCAE v4.03, cytokine release syndrome (CRS) was assessed per Lee et al. 2014, and response was evaluated using IMWG criteria. Results: As of the 12/31/18 cutoff date (median follow-up, 19 mo; 95% confidence interval [CI], 17-22), enrollment at Xi'an is complete, and 57 pts have been infused with LCAR-B38M. AEs were reported by all pts: pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts: leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 events; no grade 4/5 CRS was observed. Neurotoxicity was observed in 1 pt (grade 1 aphasia, agitation, seizure-like activity). The median time to onset of CRS was 9 days (range, 1-19) with a median duration of 9 days (range, 3-57); all but 1 CRS events resolved. Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M was not detectable in peripheral blood in 71% of pts at 4 mo; 5 pts showed CAR-T cell persistence for up to 10 months. The overall response rate (partial response [PR] or better) was 88% (95% CI, 76-95), complete response (CR) was achieved by 42 pts (74%; 60-85), very good partial response (VGPR) by 2 pts (4%; 0.4-12), and PR by 6 pts (11%; 4-22). Of pts with CR, 39/42 were minimal residual disease negative (MRD-neg, 8-color flow cytometry). The median time to first response was 1.2 mo. There was no relationship between best response and baseline BCMA expression level or weight-adjusted CAR+ cells infused (Fig 1a,b). At cutoff, the median follow-up was 19 mo [17-22]. Median OS has not yet been reached. The OS rate at 18 mo was 68% (54─79) with a median duration of response (mDOR) of 22 mo (13-29). Of MRD-neg pts with CR, 91% (75-97) are still alive at data cut, with a 27 mo (16-NE) mDOR. Overall, 26 (46%) of 57 all-treated pts and 25 (64%) of 39 MRD-neg pts with CR remain progression-free. The median progression-free survival (PFS) for all-treated pts was 20 mo (10-28); median PFS for MRD-neg pts with CR was 28 mo (20-31). At 18 months, the PFS rate was 50% (36-63) for all pts and 71% (52-84) for MRD-neg pts with CR. Factors contributing to long-term response are shown in Fig 1c,d. Seventeen pts died during the study and the follow-up period: progressive disease (PD; n=11), disease relapse, PD + lung infection, suicide after PD, esophageal carcinoma, infection, and pulmonary embolism and acute coronary syndrome (n=1 each). Of these, 4 did not achieve PR or better; 1 was not evaluable. Conclusions: This study provides evidence that LCAR-B38M is a highly effective therapy for RRMM, regardless of baseline BCMA expression. LCAR-B38M displayed a manageable safety profile consistent with its known mechanism of action and, with a median follow-up of 19 months, demonstrated deep and durable responses in pts with RRMM. A phase 1b/2 clinical study is ongoing in the United States (CARTITUDE-1, NCT03548207, JNJ-68284528), and a phase 2 confirmatory study has initiated in China (CARTIFAN-1, NCT03758417). Figure 1 Disclosures Zhuang: Nanjing Legend Biotech: Employment. Fan:Legend Biotech: Employment, Equity Ownership.

BackgroundWe intended to investigate the long-term clinical characteristics, responses to therapy and survival in patients with lightchain multiple myeloma (MM).MethodsNinety-six patients were enrolled into the study. There were 42 κ-chain MM patients and 54 λ-chain MM patients. All the patients werestage III in the Durie-Salmonstaging system. Among them, 66 patients received Velcade (bortezomib) treatment and the other 30 did not.ResultsThe main symptoms of these patients included bone pain (77.1%), weakness and fatigue (12.5%), foamy urine (8.3%) and extramedullaryplasmocytomas (33.3%). The overall response rate (ORR) was 95.5% in patients treated with Velcade and 60%in the patients without. The median survival times were 23 months in patients treated with Velcade and 12 months in patients without. The median time of progression-free survival (PFS) was nine months in patients treated with Velcade and five months in patients without. The one-year PFS and two-year PFS were 37% and 25%, 27% and 9% for patients treated with Velcade, or without, respectively. The three-year overall survival (OS) and five-year OS were 33% and 24%, 28% and 9% for patients treated with Velcade, or without, respectively. There was no significance in OS between the two groups (P = 0.335). But there was significant difference in PFS between the two groups (P = 0.036).ConclusionsOur long-term study demonstrated that patients with lightchain myeloma appeared to have more aggressive disease courses and poor outcomes, which could be improved by treatment with Velcade.

No abstract

No abstract

Background/Aims: To explore the protective effect of curcumin on renal ischemia-reperfusion injury (RIRI) in rats, and its influence on nephridial tissue’s NO and cGMP levels as well as downstream signaling pathway, to elucidate the possible mechanism of curcumin on RIRI. Methods: 36 Sprague Dawley rats (SD rats) were randomly divided into Sham group, Model group, curcumin (CUR +) Model group, 12 rats per group. They were all given RIRI model preparation by unilateral artery occlusion method. All groups’ β2-MG in urine in 24h, serum Cr and BUN were compared, and UAER were calculated. Nitric oxide synthase (NOS), cGMP-dependent protein kinase (PKG), Caspase-3 expression were all determined by western blot. Nitric oxide (NO), NOS and cGMP levels were also examined by using ELISA. All groups’ nephridial histomorphology and kidney tubules score were evaluated and compared. Results: β2-MG and UAER in urine, serum Cr and BUN, in renal tissue were all elevated in Model of RIRI, indicating the success of animal model of RIRI establishment, and above index in CUR + Model group were all lower than those in Model group. Furthermore, iNOS, NO, cGMP, PKG and Caspase-3 in renal tissue were all increased in Model of RIRI, indicating the NO signaling pathway was activated, which is one of the pathogenesis of RIRI, and above index in CUR + Model group were all lower than those in Model group, suggesting that inactivation of iNOS/NO/cGMP/PKG signaling pathway is one of the reasons that explain the protective effect of curcumin in RIRI. Conclusion: The activation of iNOS/NO/cGMP/PKG signaling pathway and the consequent promoted apoptosis of renal tubules are significantly involved in the pathogenesis of development of RIRI, and curcumin treatment could protect renal tubules against RIRI, at least partially, by suppressing the activated iNOS/NO/cGMP/PKG signaling pathway.

No abstract