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WOS: 000426644800007, PubMed ID: 29396713, Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov., Novartis (CH); Novartis Pharmaceuticals Corporation (US) [Not applicable]

Summary Background Immunotherapy combination treatments can improve patient outcomes. Epacadostat, an IDO1 selective inhibitor, and pembrolizumab, a PD-1 inhibitor, showed promising antitumour activity in the phase 1–2 ECHO-202/KEYNOTE-037 study in advanced melanoma. In this trial, we aimed to compare progression-free survival and overall survival in patients with unresectable stage III or IV melanoma receiving epacadostat plus pembrolizumab versus placebo plus pembrolizumab. Methods In this international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial, eligible participants were aged 18 years or older, with unresectable stage III or IV melanoma previously untreated with PD-1 or PD-L1 checkpoint inhibitors, an ECOG performance status of 0 or 1, and had a known BRAFV600 mutant status or consented to BRAFV600 mutation testing during screening. Patients were stratified by PD-L1 expression and BRAFV600 mutation status and randomly assigned (1:1) through a central interactive voice and integrated web response system to receive epacadostat 100 mg orally twice daily plus pembrolizumab 200 mg intravenously every 3 weeks or placebo plus pembrolizumab for up to 2 years. We used block randomisation with a block size of four in each stratum. Primary endpoints were progression-free survival and overall survival in the intention-to-treat population. The safety analysis population included randomly assigned patients who received at least one dose of study treatment. The study was stopped after the second interim analysis; follow-up for safety is ongoing. This study is registered with ClinicalTrials.gov , number NCT02752074 . Findings Between June 21, 2016, and Aug 7, 2017, 928 patients were screened and 706 patients were randomly assigned to receive epacadostat plus pembrolizumab (n=354) or placebo plus pembrolizumab (n=352). Median follow-up was 12·4 months (IQR 10·3–14·5). No significant differences were found between the treatment groups for progression-free survival (median 4·7 months, 95% CI 2·9–6·8, for epacadostat plus pembrolizumab vs 4·9 months, 2·9–6·8, for placebo plus pembrolizumab; hazard ratio [HR] 1·00, 95% CI 0·83–1·21; one-sided p=0·52) or overall survival (median not reached in either group; epacadostat plus pembrolizumab vs placebo plus pembrolizumab: HR 1·13, 0·86–1·49; one-sided p=0·81). The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus pembrolizumab and 11 (3%) of 352 patients receiving placebo plus pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus pembrolizumab and 32 (9%) of 352 patients receiving placebo plus pembrolizumab. There were no treatment-related deaths in either treatment group. Interpretation Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. Funding Incyte Corporation, in collaboration with Merck Sharp & Dohme.

Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (PP=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18–1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits.

Background: Immunotherapy combination treatments may improve patient outcomes. Epacadostat, an indoleamine 2,3-dioxygenase 1 (IDO1) selective inhibitor, and pembrolizumab, a programmed death protein (PD)-1 inhibitor, showed promising antitumour activity in the phase 1/2 ECHO-202/KEYNOTE-037 advanced melanoma study. Methods: In the phase 3 ECHO-301/KEYNOTE-252 (NCT02752074) study, patients with unresectable stage III or IV melanoma previously untreated with checkpoint inhibitors were stratified by PD-ligand-1 expression and BRAF mutation status, and randomised (1:1) to epacadostat 100 mg twice-daily (BID) plus pembrolizumab 200 mg every 3 weeks (Q3W) or placebo plus pembrolizumab 200 mg Q3W for up to 2 years. Primary endpoints were progression-free survival (PFS) per modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and overall survival (OS). Secondary endpoints included objective response rate (ORR) per modified RECIST v1.1, duration of response (DOR), and safety. We report PFS final and OS interim analyses. Findings: 706 patients were randomised (n=354 epacadostat plus pembrolizumab, n=352 placebo plus pembrolizumab). Median follow-up was 12·4 months. No significant difference was found between epacadostat plus pembrolizumab versus placebo plus pembrolizumab for PFS (median 4·7 vs 4·9 months, respectively; HR=1·00; CI, 0·83-1.21; one-sided p=0·517) or OS (HR=1·13; 95% CI 0·86 1·49; one-sided p=0·807). Twelve-month OS rate was 74% (both groups). ORR was 34·2% (epacadostat plus pembrolizumab) and 31·5% (placebo plus pembrolizumab). Median DOR was not reached (both groups). Grade ≥3 treatment-related adverse events were reported in 21·8% of patients receiving epacadostat plus pembrolizumab; 17·0% receiving placebo plus pembrolizumab. Interpretation: Epacadostat 100 mg BID plus pembrolizumab did not improve PFS or OS versus pembrolizumab alone in unresectable or metastatic melanoma patients. Utility of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. Funding: Incyte Corporation (Wilmington, DE, USA) in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Declaration of Interest: GVL has served as a consultant/advisor for Amgen, Array, Bristol-Myers Squibb, Incyte, Merck Sharp and Dhome, Novartis, Pierre Fabre, and Roche; has received honoraria from Bristol-Myers Squibb, Incyte, Merck Sharp and Dhome, Novartis, and Roche; and personal fees for travel to conferences from Merck Sharp and Dhome and Roche. RD has served as a consultant/advisor for Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma, and Takeda. OH has served as a consultant/advisor for and/or received honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck, Novartis, and Roche; served on speakers bureau for Amgen, Array, Bristol-Myers Squibb, Genentech, Novartis, and Sanofi; and his institution has received research funding from AstraZeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck, Merck Serono, Medimmune, Novartis, Pfizer, and Rinat. TFG has served on advisory boards for Merck and his institution has received research grants from Merck and Incyte. CC has served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, and Merck Sharp and Dhome; served on speakers bureau for Bayer, Bristol-Myers Squibb, Eli Lilly, and Merck Sharp and Dhome; received personal fees and for travel and non-financial support from Boehringer Ingelheim and Bristol-Myers Squibb; and has received research grants from Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medivation, Merck Sharp and Dhome, and Roche. SD received personal fees from Sanofi; non-financial support for travel and research from Bristol-Myers Squibb and Merck Sharp and Dhome; and research grant from Bristol-Myers Squibb. AA has served as a consultant and on speakers bureau for Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Roche. MSC has served as a consultant for Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Pierre Fabre. J-JG has served as a consultant/advisor for and/or received honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck/Pfizer, Merck Sharp and Dhome, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; has served on speakers bureau for Novartis; and received other support for travel from Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Pierre Fabre, and Roche. TMK declares no competing interests. LD has served as a consultant for and received honoraria and research grants from Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Roche. CR has served as a consultant/advisor for and received honoraria from Amgen, Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre, and Roche. JL has served as a consultant for Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Merck Sharp and Dhome, Nektar Therapeutics, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess; his institute has received grants from Achilles Therapeutics, Aveo, Bristol-Myers Squibb, Covance, Immunocore, Merck Sharp and Dhome, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, and Roche; and has received non-financial support from NIHR RM/ICR Biomedical Research Centre for Cancer. JRA is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JM and MJ are employees and stockholders of Incyte. SJD is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. TCM has served as a consultant/advisor for Bristol-Myers Squibb, Incyte, Merck, and Novartis. Ethical Approval: The study was conducted in accordance with the protocol, Declaration of Helsinki, and International Council for Harmonisation guidelines for Good Clinical Practice. The protocol and amendments were approved by the institutional review boards or independent ethics committees of participating institutions. All patients provided written informed consent.

British journal of haematology 176(1), 76-85 (2017). doi:10.1111/bjh.14382, Published by Wiley-Blackwell, Oxford [u.a.]

108Background: In a phase 1/2 study, the combination of E, a selective oral inhibitor of the IDO1 enzyme, plus P, a PD-1 inhibitor, suggested promising antitumor activity with minimal additive toxicity. ECHO-301/KEYNOTE-252 (NCT02752074) is a phase 3, randomized, double-blind study evaluating the efficacy and safety of E + P vs placebo + P in pts with untreated unresectable or metastatic melanoma. Methods: Pts had histologically confirmed unresectable stage III or IV melanoma and were treatment naive for advanced or metastatic disease, except for pts with the BRAF V600 mutation who could have received prior BRAF/MEK therapy. Pts were stratified by PD-L1 expression and BRAF mutation status (BRAF mutant with prior BRAF-directed therapy, BRAF mutant without prior BRAF-directed therapy, and BRAF wild type) and randomized 1:1 to E 100 mg BID + P 200 mg Q3W or matched E placebo + P 200 mg Q3W. Response was assessed per RECIST v1.1 and irRECIST (both by central review). The primary endpoints were PFS per RECIST ...

The bone morphogenetic protein (BMP) type 2 receptor ligand, Bmp2, is upregulated in the peripheral pulmonary vasculature during hypoxia-induced pulmonary hypertension (PH). This contrasts with the expression of Bmp4, which is expressed in respiratory epithelia throughout the lung. Unlike heterozygous null Bmp4 mice ( Bmp4LacZ/+), which are protected from the development of hypoxic PH, mice that are heterozygous null for Bmp2 ( Bmp2+/−) develop more severe hypoxic PH than their wild-type littermates. This is associated with reduced endothelial nitric oxide synthase (eNOS) expression and activity in the pulmonary vasculature of hypoxic Bmp2+/−but not Bmp4LacZ/+mutant mice. Furthermore, exogenous BMP2 upregulates eNOS expression and activity in intrapulmonary artery and pulmonary endothelial cell preparations, indicating that eNOS is a target of Bmp2 signaling in the pulmonary vasculature. Together, these data demonstrate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH and suggest that the protective effects of Bmp2 are mediated by increasing eNOS expression and activity in the hypoxic pulmonary vasculature.

RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944. V received funding from and participated in advisory boards for Incyte Corporation. AMV served as a consultant for Novartis, participated in speakers bureaus for Novartis and Shire, and received research funding from Novartis. MG received travel reimbursements from Amgen, Roche, Novartis, and Shire. TM served as a consultant for Novartis and Janssen-Cilag. SD received honoraria and research funding from Novartis. CNH received honoraria from Sanofi, Novartis, and Baxter; served on speakers bureaus for Sanofi, Novartis, Shire, and Baxter; received research funding from Novartis; and received travel reimbursement from Novartis. KK received honoraria from Novartis. CB received honoraria from Novartis and Shire. FPan received honoraria from Novartis, Bristol-Myers Squibb, and Roche; served as a consultant for Bristol Myers Squibb and Ariad; received research funding from Novartis; and received travel reimbursements from Novartis and Roche. BM served on speakers bureaus for Novartis and Bristol-Myers Squibb. CBM received honoraria and served on a speakers bureau and as a consultant for Incyte Corporation. RM received honoraria and served as a consultant for Novartis and received research funding from Incyte Corporation, Gilead, CTI BioPharma, and Celgene. MMJ and HZ are employees and stockholders of Incyte Corporation. JL, NF, and DH are employees and stockholders of Novartis. J-JK served as a consultant for Novartis, Shire, and Incyte Corporation and received research funding from Novartis and AOP Orphan Pharmaceuticals.

Objectives Polycythemia vera (PV)-related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant. Methods In the previously reported primary analysis, ruxolitinib achieved the primary composite endpoint of hematocrit control and ≥35% reduction in spleen volume at Week 32. The current analysis evaluated patient-reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), and the Patient Global Impression of Change (PGIC). Results Compared with standard therapy, ruxolitinib was associated with greater improvements in global health status/QoL, functional subscales, and individual symptom scores of the EORTC QLQ-C30. At Week 32, more patients in the ruxolitinib arm (44%) achieved a ≥10-point improvement in global health status/QoL vs. standard therapy (9%). Improvements in MPN-SAF symptom scores were consistent with improvements in EORTC QLQ-C30, PSIS, and PGIC scores. Conclusions Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea resistant/intolerant.

Novel sulfonyl chlorides of quinolines and isoquinolines have successfully been prepared. This enabled the preparation of the corresponding sulfonamides via reaction with an amine using the “resin-capture and release” methodology.

Christopher Arthur,1 Jaroslav Cermak,2 Jacques Delaunay,3 Jirí Mayer,4 Grzegorz Mazur,5 Xavier Thomas,6 Agnieszka Wierzbowska,7 Mark M Jones,8 Erhan Berrak,8 Hagop Kantarjian9 1Department of Haematology, Royal North Shore Hospital, Sydney, NSW, Australia; 2Institute of Hematology and Blood Transfusion, Prague, Czech Republic; 3Department of Clinical Hematology, University of Nantes, Nantes, France; 4Department of Internal Medicine, Masaryk University Hospital Brno, Central European Institute of Technology, Brno, Czech Republic; 5Department of Hematology, Wroclaw Medical University, Wroclaw, Poland; 6Department of Hematology, Edouard Herriot Hospital, Lyon, France; 7Copernicus Memorial Hospital, Lodz, Poland; 8Oncology Product Creation Unit, Eisai Inc., Woodcliff Lake, NJ, USA; 9Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: In a Phase III trial, 485 patients (≥65 years) with newly diagnosed acute myeloid leukemia received decitabine 20 mg/m2 intravenously for 5 days every 4 weeks or a treatment choice (supportive care or cytarabine 20 mg/m2 subcutaneously for 10 days every 4 weeks). Materials and methods: We summarized overall and progression-free survival by baseline white blood cell count using two analyses: 5×109/L; ≤10 or .10×109/L. Results: There were 446 deaths (treatment choice, n=227; decitabine, n=219). Median overall survival was 5.0 (treatment choice) versus 7.7 months (decitabine; nominal P=0.037). Overall survival differences between white blood cell groups were not significant; hazard ratios (HRs) favored decitabine. Significant progression-free survival differences favored decitabine for groups 1–5×109/L (P=0.005, HR =0.67), greater than 5×109/L (P=0.027, HR =0.71), and up to 10×109/L (P=0.003, HR =0.72). Conclusion: There was a trend toward improved outcome with decitabine, regardless of baseline white blood cell count. Keywords: decitabine, acute myeloid leukemia, prognosis, leukemia, adult

Background Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. Methods We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. Results The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P

Objective: In a phase III trial, 485 patients aged 65 years or older with newly diagnosed acute myeloid leukemia received decitabine (20 mg/m2 intravenously for 5 days) or treatment of choice (supportive care or cytarabine 20 mg/m2 subcutaneously for 10 days) every 4 weeks. This post hoc analysis investigated potential efficacy and safety indicators and treatment response. Methods: Transfusions, intravenous antibiotics, and dose modifications were tabulated for responders (morphologic complete remission, complete remission with incomplete blood count recovery, or partial response) and nonresponders. Results: Median overall survival was significantly greater for treatment responders than for nonresponders (17.4 months vs 4.3 months; P

3012 Background: The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) facilitates immune tolerance in cancer via T-cell suppression, and IDO1 overexpression is associated with poor survival. Epacadostat, an oral inhibitor of IDO1, has been shown to be well tolerated as monotherapy and in combination with checkpoint inhibitors. ECHO-202/KEYNOTE-037 is a phase 1/2 study evaluating the safety and efficacy of oral epacadostat plus IV pembrolizumab in patients (pts) with advanced tumors. Based on phase 1 outcomes, epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was selected for phase 2 evaluation. This analysis summarizes phase 2 safety experience in the overall population of ECHO-202/KEYNOTE-037 (pooled across tumor types) at an October 29, 2016 data cutoff. Methods: Phase 2 pts were ≥18 years of age with advanced or recurrent melanoma (MEL), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma (UC), triple-negative breast cancer, squamous cell carcinoma of head and neck (SCCHN), ovarian cancer, diffuse large B-cell lymphoma, or microsatellite instability–high colorectal cancer. Results: The overall safety population comprised 244 pts receiving ≥1 study treatment dose. Median age was 63 years, 52% were women, and 91% were white. As of data cutoff, 134 study pts (55%) discontinued study treatment, primarily due to disease progression (n = 97). Median exposure to study treatment was 86 days (range, 1–374 days). TRAEs occurring in ≥5% of pts were fatigue (23%); rash (16%); diarrhea and nausea (7% each); increased alanine aminotransferase, increased aspartate aminotransferase, and pruritus (6% each); and pyrexia (5%). A total of 37 pts (15%) had grade ≥3 TRAEs; the most common grade ≥3 TRAEs were increased lipase (asymptomatic) and rash (3% each). TRAEs led to discontinuation in 3% of pts. Conclusions: Epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was associated with an acceptable safety profile in pts with advanced cancers, supporting continued evaluation of the combination. The phase 3 ECHO-301/KEYNOTE-252 MEL study is ongoing and additional phase 3 studies (NSCLC, UC, RCC, SCCHN) are planned. Clinical trial information: NCT02178722.

9014 Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: < 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS < 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in > 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.

The hypothesis that two known chelators 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and desferrioxamine (DFO) might be more efficient as combined treatment than as monotherapies in removing aluminium from the body was tested in a new acute rat model. Five-week old female rats received chelators: L1 (p.o.), DFO (i.p.) or L1+DFO as 100 or 200 mg/kg dose half an hour after a single i.p. administration of 6 mg Al/kg body weight in the form of chloride. Serum aluminium concentration and urinary aluminium and iron excretions were determined by electrothermal or flame atomic absorption spectrometry. Both chelators were effective only at the higher dose level. While DFO was more effective than L1 in enhancing urinary aluminium excretion, L1 was more effective than DFO in enhancing urinary iron excretion. In the combined treatment group L1 did not increase the DFO effect on aluminium and DFO did not increase the effect of L1 on iron elimination. However, in this group a simultaneous increase in both aluminium and iron elimination was observed. Our results support the usefulness of this animal model for preliminary in vivo testing of aluminium chelators. Urinary values were more useful because of the high variability of serum results. Result of combined chelators treatment should be confirmed in a different experimental model before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for evaluating the efficiency of chelating agents in aluminium toxicity.

Female rats were loaded with lead acetate (5 mg Pb/kg) during 2 weeks (10 times) intraperitoneally. Four-day chelation treatment started 1 week later with CaNa2 ethylenediaminetetraacetate (EDTA, 0.3 mmol/kg i.p. at 4:00 p.m.), and meso- or racemic-2,3-dimercaptosuccinic acid (meso- or rac-DMSA, 0.5 mmol/kg p.o. at 10:00 a.m.). One group was administered EDTA as monotherapy, and two groups received combined treatment with EDTA plus either meso-DMSA or rac-DMSA. Lead was determined in femur, kidneys, and brain. Urinary eliminations of lead, iron, zinc, and copper were also evaluated. With EDTA monotherapy, lead was reduced in kidneys. Combined treatment with EDTA plus meso-DMSA reduced lead in kidneys and brain, and EDTA plus rac-DMSA treatment reduced lead in femur, kidneys, and brain. Urine lead elimination was increased by EDTA monotherapy 10 times, and by both combined treatments 14–15 times. Urine zinc excretion was increased by both EDTA monotherapy and in combined treatment with meso-DMSA 3–4 times, and in combined treatment with rac-DMSA 5–6 times. Both combined treatments increased copper urinary excretion 3–4 times. Best results in reducing tissue lead were obtained when EDTA therapy was combined with rac-DMSA treatment. Since this combination also caused highest urinary trace element elimination, more data are needed before recommending rac-DMSA for use in combined treatment of lead poisoning. J. Trace Elem. Exp. Med. 13:277–284, 2000. © 2000 Wiley-Liss, Inc.

The efficacy of the Al chelating drugs deferoxamine (DFO) and the hydoxypyridones (HPs): 1,2-dimethyl-3-hydroxypyrid-4-one (L1), 1-[3-hydroxy-2-methyl-4-oxopyridyl]-2-ethanesulfonic acid (L6), 1-benzyl-(4-carboxylic acid)-3-hydroxy-2-methyl-4-oxopyridine (Bzcal) and 1-(p-methylbenzyl)-2-ethyl-3-hydroxypyrid-4-one (MeBzEM) in increasing Al excretion and reducing tissue Al accumulation has been compared in adult male rats which had previously received Al nitrate nonahydrate i.p. at 0.16 mmol/kg per day for 2 months. At the end of this period, DFO was injected s.c. and the HPs were given by gavage at 0.89 mmol/kg per day for five consecutive days. Total urines were collected 24 h after each chelator administration. Following chelation treatment animals were killed and samples of brain, bone, liver, kidney, and spleen were collected. DFO administration increased to about 4 x the cumulative urinary Al elimination for 5 days, while the excretion of Al into urine caused by Bzcal, L1, and MeBzEM administration was about twice that of the control group. On the other hand, treatment with Bzcal, DFO, and MeBzEM for 5 days significantly reduced the Al levels in bone by 31, 33, and 29%, and the Al concentrations in brain by 46, 69, and 71%, respectively. These results suggest that oral administrations of MeBzEM and Bzcal can be potential alternatives to parenteral administration of DFO in Al removal.

Comparison of the racemic and meso forms of 2,3-dimercaptosuccinic acid (DMSA) in lead mobilization from lead-loaded albino Wistar rats demonstrates that the racemic form is significantly more effective in reducing femur lead levels. After four oral doses at 0.5 mmol/kg, femur lead levels were reduced to 87% of control values by meso-DMSA and to 50% of control levels by rac-DMSA. Similarly, when the dose was increased to 1.0 mmol/kg, femur lead levels were reduced to 69% of control levels by meso-DMSA and to 45% of control levels by rac-DMSA. A similar pattern was found for renal lead levels. Brain lead concentrations were significantly lower in treated groups than in control groups, but no differences were found between rac- and meso-DMSA. Rac-DMSA is more soluble than meso-DMSA in acetonitrile, ethyl acetate, and ethyl ether. The partition coefficient of rac-DMSA in the n-octanol/water system was found to be about 2.8. These results indicate that rac-DMSA deserves further attention as a possible substitute for meso-DMSA.

Background In a multicenter, randomized, open-label phase III study, patients ≥ 65 years with newly diagnosed AML received decitabine 20 mg/m 2 once daily for 5 days every 4 weeks (n = 242) or treatment choice (supportive care or cytarabine 20 mg/m 2 once daily for 10 days every 4 weeks; n = 243). Decitabine use demonstrated greater response rates ( P = .001) and OS data favored decitabine. Patients and Methods In a post hoc sensitivity analysis of mature data of patients in the intent-to-treat population (N = 485), OS at 3, 6, 12, 18, and 24 months after randomization was estimated for each arm using Kaplan-Meier methods. Age, cytogenetic risk, and Eastern Cooperative Oncology Group performance status were used as stratification factors in the Cox regression model to estimate the hazard ratio. Results A survival advantage was seen with decitabine at each cutoff time point; hazard ratios for OS for decitabine vs. treatment choice were 0.83, 0.71, 0.83, 0.80, and 0.79 at 3, 6, 12, 18, and 24 months, respectively. A trend toward improved OS with decitabine was observed at fixed time points over 2 years. Conclusion Decitabine should be considered as a treatment option for older patients with AML and poor prognostic risk factors.

The relative abilities of a series of acyclic polyamine chelating agents containing only nitrogen donors (N-donors) to induce the urinary excretion of cadmium has been examined in the rat. The compounds examined include triethylenetetramine dihydrochloride (TRIEN), tris(2-aminoethyl)amine trihydrochloride (TREN), tetraethylenepentamine pentahydrochloride (TETRAEN), and pentaethylenehexamine hexahydrochloride (PENTAEN). Sodium N-methyl-D-glucamine-N-carbodithioate (NaG) was used as a positive control compound. The polyamines induced a significant increase in the urinary excretion of cadmium in rats that had been loaded with cadmium at least 4 d prior to the polyamine treatments. A comparison of these with similar data on macrocylic nitrogen donor systems, which form much more stable complexes with cadmium but are also ineffective in enhancing the excretion of cadmium from such aged deposits, suggests that the factors responsible for the relative inefficiency of these compounds may involve either a difficulty in penetrating cellular membranes or a slow rate of reaction with biologically bound cadmium. The occurrence of oliguria and anuria following the administration of the several of the polyamines indicates that their use is accompanied by significant renal damage in cadmium-exposed rats.

The ability of atrial natriuretic peptide (ANP) to prevent cisplatin-induced nephrotoxicity was compared to the protective effect of 3% NaCl. ANP (1 microgram/kg/min), 3% NaCl or peptide buffer vehicle (50 microliters/min) were infused for 45 min to conscious unrestrained rats immediately after cisplatin administration (5 mg/kg i.v.). Measurements taken 72 h after drug treatment indicated that compared to animals receiving cisplatin only, ANP co-treated rats had lower post-treatment plasma creatinine concentrations (0.70 +/- 0.07 vs 1.3 +/- 0.17 mg/dl; P0.05), blood urea nitrogen (BUN) concentrations (44.2 +/- 5.8 vs. 65.5 +/- 2.1 mg/dl; P0.05) and higher post-treatment glomerular filtration rates (GFR) (0.71 +/- 0.18 vs. 0.14 +/- 0.03 ml/min; P0.05). ANP was as effective as 3% NaCl in preventing cisplatin nephrotoxicity in this model. The effect of ANP co-treatment on the anti-tumor activity of cisplatin was also examined using the Walker 256 carcinosarcoma model. ANP treatment did not result in any observable loss in anti-tumor activity. When ANP was administered 72 h after cisplatin treatment, improvement in GFR was observed for the duration of the infusion, confirming the beneficial effect of ANP on cisplatin-damaged kidneys. ANP may have a role in the treatment and prevention of cisplatin nephrotoxicity especially in clinical situations where treatment with a large fluid volume is contraindicated.

Four novel cadmium-chelating agents N,N"di(D-glucosyl)alkanediamine-N,N"-bis(carbodithioates) 4a-e were prepared as disodium salts of the general formula (CH2)nSN(CS2Na)CH 2(CHOH)4CH2OHC2, where n = 7, 8, 10, and 12. They were synthesized by the reductive coupling of 2 mol of alpha-D-(+)-glucose (1)with 1 mol of the corresponding alkanediamines 2a-e followed by reaction with CS2 in a basic medium. The elemental analyses of the Cd complexes 5a, b, d, and e prepared revealed that these bis(carbodithioates) form 1:1 complexes with Cd2+. The in vivo cadmium-mobilizing efficacy of three of the new chelators (4a, b, and d) was determined in rats pretreated ip with CdCl2.H2O containing 2 microCi of 109Cd (74 kBq), and comparable data were obtained on a previously reported member of this series (4c, n = 9), and with BGDTC (sodium N-benzyl-D-glucamine-N-carbodithioate, 6), all given once at 1.0 mmol/kg ip. The compound with n = 12 (4e, C12G2DTC) proved to be too toxic in the preliminary study and was not evaluated further. A single injection of the 4a, b, and d caused a reduction in Cd levels of the whole body to ca. 50% and liver to ca. 12% of control levels. Comparable experimental data on BGDTC resulted in a reduction of whole-body cadmium to only 78% of the control levels and a reduction in liver cadmium to only 56% of control. After one and six injections at the same dosage, the new chelators (4a, b, and d) and C9G2DTC (4c, n = 9) significantly surpassed BGDTC for whole-body and liver Cd depletion but caused only a very modest depletion of renal Cd. While these compounds were designed to allow the two dithiocarbamate groups to coordinate to the same Cd2+ in vivo, the data do not prove that the two > NCS2Na groups bind to the same cadmium ion in vivo. The very rapid reduction in liver cadmium levels following only a single injection indicates that these -2 anions rapidly gain access to intracellular hepatic sites by some transport system.

In vivo CdCl2-induced apoptotic DNA fragmentation in the testes of the male Wistar rat has been demonstrated on agarose gel. Characteristic DNA migration patterns (laddering) provide evidence of apoptosis (programmed cell death) in testicular tissue of rats administered CdCl2 at a level of 0.03 mmol/kg 48 h previously. Evidence that administration of an appropriate cadmium chelating agent within the first 24 h can suppress some or all of the apoptotic changes in testicular DNA has also been obtained for the first time. A greater reduction in apoptosis is observed as the interval between the administration of the cadmium and that of the chelating agent is shortened. Administration of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) to male Wistar rats given CdCl2 is effective in the modulation of the typically apoptotic DNA fragmentation and associated histopathologic injury when the antagonist is given within approximately 1 h after the CdCl2 exposure. When the antagonist is given at later times there is a progressively more pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern found with apoptosis. There is also a progressive increase in histopathological tissue changes as the antagonist is administered at progressively greater intervals after the cadmium.

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In order to estimate the potential advantages of new chelating agents which can enhance copper excretion in the chronic copper intoxication arising in Wilson's disease, the relative ability of none chelating agents to induce the urinary excretion of copper was compared with that of D-penicillamine (DPA) and triethylenetetramine.2HCl (TRIEN), all given ip at 1 mmol/kg to male Sprague-Dawley rats. The compounds examined were as follows: tris(2-aminoethyl)-amine.3HCl (TREN), tetraethylenepentamine.5HCl (TETREN), pentaethylenehexamine.6HCl (PENTEN), 1,4,7,11-tetraazaundecane.4HCl (TAUD), 1,5,8,12-tetraazadodecane.4HCl (TADD), 1-N-benzyltriethylenetetramine.4HCl (BzTT), 4,7,10,13-tetraazatridecanoic acid.2H2SO4 (TTPA), 1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane.4HCl (BPTETA), and N,N-bis(2-pyridylmethyl)-4-(aminomethyl)benzoic acid (4ABA). Of these, BzTT, TTPA, and 4ABA are new chelating agents not previously reported. The factors by which these chelating agents enhanced copper excretion over control (untreated) levels were as follows: DPA, 7.2; TREN, 1.6; TRIEN, 4.0; TETREN, 10.1; PENTEN, 7.8; TAUD, 7.8; TADD, 2.6; TTPA, 5.6; BzTT, 1.8; and 4ABA, 5.5. The results indicate that it may well be possible to develop additional chelating agents which are equal or superior to those now used in the treatment of Wilson's disease, as well as structural types whose immunological properties may be significantly different from DPA or TRIEN, the compounds currently used in the clinic for this disorder.

The efficacy of four newly synthesized monoesters of meso-2,3-dimercaptosuccinic acid (DMSA), mono-i-amyl- (Mi-ADMS), mono-n-amyl- (Mn-ADMS), mono-i-butyl- (Mi-BDMS), and mono-n-butyl-meso-2,3-dimercaptosuccinate (Mn-BDMS) in increasing survival and arsenic elimination in experimental arsenic poisoning was investigated. Male mice (strain NMRI) received arsenite sc (survival study: 130 mumol/kg, 7 mice/group; elimination study: 85 mumol/kg (LD5) together with a tracer dose of 73As(III), 6 mice/group). After 30 min mice were treated with 0.7 mmol/kg of DMSA or a monoester ip or via gastric tube (ig). Control animals received saline ip. In the survival study mice were observed for 30 days. In the elimination study, the 73-arsenic content of several organs (blood, liver, heart, lung, kidneys, spleen, testes, brain, small intestine, large intestine, muscle, and skin) was measured 0.5, 2, 4, 6, and 8 hr after the arsenic injection using a gamma counter. Survival increased correspondingly well with the increase of arsenic elimination. DMSA, Mi-ADMS, Mn-ADMS, Mi-BDMS, and Mn-BDMS markedly decreased arsenic content in most organs as soon as 1.5 hr after treatment. Only in small and large intestine were higher arsenic amounts found, indicating a shift in arsenic elimination from the renal to the fecal route, and thereby suggesting a protective effect for the kidneys. Given ip, the monoesters turned out to be similarly as effective as the parent drug DMSA. Following ig treatment, the DMSA monoesters Mi-ADMS and Mn-ADMS seemed to be superior to DMSA with regard to survival.(ABSTRACT TRUNCATED AT 250 WORDS)

The ability of a 13 amino-acid analog of atrial natriuretic peptide (ANP), A68828, to prevent development of cisplatin toxicity was evaluated in a rat model. ANP (1 microgram/kg/min), A68828 (10 micrograms/kg/min), A68828 (50 micrograms/kg/min), or peptide buffer was given as an intravenous infusion over 1 h beginning 15 min prior to an infusion of 5 mg/kg cisplatin. Animals receiving cisplatin plus peptide buffer vehicle developed predictable renal failure, with mean plasma creatinine and blood urea nitrogen concentrations of 1.09 +/- 0.09 mg/dL and 50.13 +/- 5.96 mg/dL, 72 h after treatment. ANP and A68828 (10 micrograms/kg/min) attenuated the increase in these indices of nephrotoxicity (mean plasma creatinine 0.86 +/- .06 mg/dL and 0.76 +/- 0.11 mg/dL, respectively). Surprisingly, the higher dose of A68828 (50 micrograms/kg/min) did not reduce cisplatin nephrotoxicity (72-h plasma creatinine 1.61 +/- 0.34 mg/dL). These results indicate that a short-term infusion of ANP or the analog A68828 can reduce the severity of cisplatin toxicity. At high doses of A68828 the beneficial effects of treatment may be lost.

Current attempts to remove iron from individuals suffering from iron overload have encountered difficulty due to the toxicity of the administered chelating agent. In a search for iron chelators of potentially reduced toxicity, nine monoanionic compounds have been examined. To determine the chemical features which govern their ability to induce the excretion of iron, the compounds were administered to female Sprague-Dawley rats. All carboxylate derivatives were tested for biliary excretion following iv injection, as well as for urinary excretion following iv or po injection. Sulfonate derivatives were tested for biliary and urinary excretion as well, but only one representative compound was tested po. The biological activity of the new pyridinones was compared to that of 1,2-dimethyl-3-hydroxypyrid-4-one, L1, which served as the standard. While none of the chelators was able to surpass L1 in both urinary and biliary iron excretion, all of the chelators at least equaled L1 in one of these two areas following iv administration. Two derivatives surpassed the standard in mobilizing iron into the bile, and all others were statistically equivalent. In terms of urinary excretion, two compounds were equivalent to L1 after iv administration, although none of the compounds equaled L1 when administered orally. The structure of (1,4-dihydro-3-hydroxy-2-methyl-4-oxo-1- pyridyl)methanecarboxylic acid was determined by X-ray diffraction, as this compound showed higher activity than previously reported by other investigators. We speculate that these chelators utilize organ-specific, monoanionic transport systems in the liver and kidneys to mobilize iron and that their toxicity may be substantially less than that of their neutral analogs.

This report describes the design, synthesis, characterization, and in vivo cadmium-mobilizing properties of a novel biscarbodithioate chelating agent, namely, disodium N,N'-diglucosyl-1,9-nonanediamine-N,N'-biscarbodithioate+ ++ (C9G2DTC), HOCH2(CHOH)4CH2(CS2Na)N(CH2)9N(CS2-Na)CH2( CHOH)4CH2OH, which can coordinate to a single cadmium ion with both of its carbodithioate groups (CS2Na) in its folded configuration. When evaluated for its cadmium efficacy at 1.0 mmol/kg x 5 ip in 109Cd-pretreated rats against sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as standard, the biscarbodithioate was found to reduce the whole-body levels of cadmium more rapidly in the rat than BGDTC which contains only one CS2Na group. The whole-body Cd depletions after the first ip injection of the new and the standard compound were 52% and 23%, respectively. The C9G2DTC was found to be more effective in removing cadmium from the liver (% Cd reductions compared to controls: C9G2DTC, 94, and BGDTC, 85), but slightly less effective in reducing renal cadmium levels (% Cd-reductions: C9G2DTC, 44, and BGDTC, 60). The ip LD50 of the bis-DTC was estimated to be slightly in excess of ca. 4.0 mmol/kg in the rat. A molecular model of this chelating agent indicates that, because of the flexibility of the nonane chain, both carbodithioate groups can approach closely enough to each other to permit complexation with the same cadmium ion to give a resulting structure without significant strain. A mechanism for the removal of Cd from CdMT by C9G2DTC is also proposed.

Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new dimercaptosuccinic acid (DMSA) analog with enhanced lipophilic properties, was evaluated for potential developmental toxicity. Intraperitoneal injections of Mi-ADMS were given to female Swiss mice (0, 47.5, 95, and 190 mg/kg) on gestational d 6-15. The maternal clinical status was monitored daily during treatment. At termination (gestational d 18), dams were evaluated for clinical status and gestational outcome. Each live fetus was weighed and examined for external, visceral, and skeletal abnormalities. Although no maternal mortality was observed, treatment with 95 and 190 mg/kg resulted in maternal toxicity, manifested as reduced body weight gain during treatment and increased relative liver weight. Embryo/fetal toxicity, consisting of a significant increase in the number of late resorptions as well as in the percentage of postimplantation loss, reduced (nonsignificant) fetal body weight, and an increase in the incidence of skeletal defects, was also observed at 190 mg/kg/d. However, no treatment-related external or soft-tissue malformations or developmental variations were found in any group. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 47.5 mg/kg/d, whereas the NOAEL for developmental toxicity was 95 mg/kg/d. These results indicate that Mi-ADMS did not produce developmental toxicity in mice in the absence of maternal toxicity.

Cadmium is a major industrial effluent and the cause of itai‐itai disease. As a biological detector for cadmium toxicity, an assay using the motile response of the protozoa species, Tetrahymena pyriformis, has been described. The assay relies on macroscopic bioconvective patterns to score the toxic response, giving a sensitivity better than 1 μM and a toxicity threshold to 5 ( μM for Cd+2. Using pattern formation as the toxicity monitor, the organic chelating agent D/‐PDMS is investigated individually for toxic effects at low dosages (without cadmium) and for poison protection directly (with cadmium). Dosages of 0.1–0.5 μM Di‐PDMS show protective chelation of cadmium and enhance pattern formation capabilities for 1 μM Cd+2.

A novel method for the synthesis of monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) is presented which utilizes the reaction of the vicinal sulfhydryl-protected anhydride with the corresponding alcohol in the presence of a base. The product is then treated successively with mercuric chloride to remove the protecting group and form the mercuric complex, and hydrogen sulfide to regenerate thiol groups by removal of mercury as HgS. This strategy was exploited to synthesize monobenzyl meso-2,3-dimercaptosuccinate (MBzDMS), C6H5CH2O(O)CCH(SH)CH(SH)C(O)OH, and demonstrates a feasible synthesis of monoesters difficult to obtain by direct esterification, via the use of the reactive anhydride. The resultant compound was found to be an effective cadminum-mobilizing agent when used with cadmium-exposed rats or mice and when administered by any one of several routes (ip, iv, po). This monobenzyl ester (MBzDMS) of DMSA was found to be somewhat less effective than the corresponding monoisoamyl ester (Mi-ADMS) in mobilizing cadmium from such cadmium deposits. The ability of MBzDMS to mobilize cadmium into the urine is significantly decreased by the coadministration of p-aminobenzoic acid, in support of the hypothesis that MBzDMS enters renal cells via an anion transport system. An analysis of the structural features of vicinal dithiols examined as antagonists for chronic cadmium intoxication allows a hypothesis to be formulated indicating essential features required for the design of effective new cadmium antagonists of this type.

Syntheses and relative cadmium mobilizing properties are described for three new monoaralkyl esters (HOOCCH(SH)CH(SH)COOR, where R = phenylethyl ((CH2)2C6H5), MPhEDMS; R = 3-phenylpropyl ((CH2)3C6H5), MPhPDMS; and R = 2-phenoxyethyl ((CH2)2OC6H5). MPhOEDMS) of meso-2,3-dimercaptusuccinic acid. These were prepared by the reaction of the corresponding alcohol with meso-2,3-dimercaptosuccinic acid (DMSA) in aqueous HCl. When administered intraperitoneally to cadmium-loaded mice at 0.50 mmol/kg/day for four consecutive days, all induced significant reductions in the whole body cadmium levels. MPhEDMS, 60%; MPhPDMS, 66%; and MPhOEDMS, 58% in comparison with control levels. At the same dosage monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate, sodium N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate++ + (BLDTC) induced reductions of 65% and 57%, respectively. Hepatic and renal cadmium were also depleted significantly, while brain cadmium levels were unchanged. These compounds induced a significant reduction in the cadmium levels of the spleen, and one, MPhOEDMS, produced a 10% decrease in pancreatic cadmium. The manner in which the later injections removed smaller fractions of the total body cadmium is consistent with a bodily distribution of these compounds by which they are concentrated primarily in the kidneys and the liver, with much smaller amounts reaching other organs. It is proposed that these compounds enter renal and hepatic cells through an anion transport system.

Cadmium(II) dithiocarbamates [Cd(dtc) 2 ] (d tc=4-carboxamidopiperidine-1-carbodithioate, morpholine-l-carbodithioate or 4-(2-hydroxyethyl)piperazine-1-carbodithioate) and [Cd(dtc) 2 ]·H 2 O (dtc=4-hydroxypiperidine-1-carbodithioate} have been prepared and characterized by thermal analysis and IR and NMR ( 13 C, 113 Cd) spectrometry. Two of these ligands have previously been shown capable of removing cadmium from its aged in vivo storage sites. The use of solid state 13 C NMR measurements to establish the coordination mode of the dithiocarbamate ligands is also examined and the difficulties which arise are discussed.

The effect of nine monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) on 203Hg retention after a single i.p. dose was evaluated in 6–7 week-old female albino rats. The monoesters were the monomethyl (MMDMS), monoethyl (MEDMS), mono-n-propyl (Mn-PDMS), monoisopropyl (Mi-PDMS), mono-n-butyl (Mn-BDMS), monoisobutyl (Mi-BDMS), mono-n-amyl (Mn-ADMS), monoisoamyl (Mi-ADMS) and mono-n-hexyl (Mn-HDMS). Dimercaptosuccinic acid or one of the monoesters were administered at a dose of 0.25 mmol kg−1 body wt. twice, i.e. 30 min and 24 h after 203Hg administration. The whole body (WB) radioactivity was determined on the 2nd, 4th and 6th days. The radioactivity in the carcass (C) whole body without the gastrointestinal tract), liver (L), both kidneys (K) and brain (B) was determined 6 days after 203Hg administration. All treated animals had a significantly lower body burden of mercury than the controls. The reduction of 203Hg retention in WB and other body compartments was higher in animals treated with monoesters than in rats treated with DMSA. The relative effectiveness of the monoesters was dependent on the nature of the alkyl groups, the efficiency being higher in higher analogues. Maximum activity was attained with the C5 (Mn-ADMS, Mi-ADMS) and C6 (Mn-HDMS) esters. These chelators reduced WB, C, L, K and B mercury retention by 90, 89, 76, 93 and 80%, respectively. Iso derivatives were more efficient than the normal isomers (Mi-PDMS > Mn-PDMS; Mi-BDMS > Mn-BDMS; Mi-ADMS > Mn-ADMS). The effect of all monoesters was higher in reducing kidney than liver mercury retention.

We report here an in vivo spin-trapping technique combined with electron paramagnetic resonance (EPR) spectroscopy to measure nitric oxide (.NO) production in the blood circulation of conscious mice. The method is based on the trapping of nitric oxide (.NO) by a metal-chelator complex consisting of N-methyl-D-glucamine dithiocarbamate (MGD) and reduced iron (Fe2+) to form a stable and water-soluble [(MGD)2-Fe(2+)-NO] complex, which gives rise to a characteristic three-line EPR spectrum of a mononitrosyl-Fe2+ complex (aN = 12.5 G and g(iso) = 2.04) at ambient temperatures. After simultaneous intravenous injection of sodium nitroprusside (an .NO donor) and the [(MGD)2-Fe2+] complex into the lateral vein of the mouse tail, the appearance of the three-line spectrum in the blood circulation of the mouse tail was monitored continuously by using an S-band EPR spectrometer, operating at 3.5 GHz. This represents the first spin trapping of .NO in living animals.

The therapeutic efficacy of six newly synthesized analogues of dimercaptosuccinic acid (DMSA) was investigated in acute arsenic trioxide poisoning in mice. Meso-2,3-di(acetylthio)succinic acid (DATSA) and meso-2,3- di(benzoylthio)succinic acid (DBTSA) are analogues of DMSA with protected thiol groups ("prodrugs"), and DMDMS, DEDMS, DnPDMS, and DiPDMS are various di-esters of DMSA with methyl, ethyl, n-propyl, and isopropyl alcohols, respectively. Thirty minutes after s.c. injection of an LD80 of arsenic trioxide (65 mumol/kg) male NMRI mice were treated with a single equimolar dose (0.7 mmol/kg) of DMSA i.p. or one of the analogues i.p. or via gastric tube (i.g.). Control animals received arsenic trioxide and saline 30 min later. The survival rate was recorded for 30 days. All of the animals treated with DMSA i.p. survived and all controls died within 2 days. Administered i.g., DATSA and DBTSA increased the survival rate to 29% and 43%, and injected i.p. to 86%. Treatment with DMDMS i.p. and i.g., and with DEDMS, DnPDMS, and DiPDMS i.g. did not reduce lethality. Given i.p., DnPDMS increased the survival rate to 72%, and DEDMS and DiPDMS to 86%, respectively. To investigate the efficacy of the DMSA analogues in reducing the tissue content of arsenic, male NMRI mice received an s.c. injection of an LD5 of arsenic trioxide containing a tracer dose of 73-As(III) (42.5 mumol/kg body wt). Thirty minutes later, saline (controls) or a single equimolar dose (0.7 mmol/kg) of DMSA i.p., or one of the analogues i.p. or i.g. was administered. The arsenic content of various organs (blood, liver, kidneys, heart, lungs, spleen, small intestine, large intestine, brain, testes, skeletal muscle, and skin) at 30 min, 2 h, 4 h, 6 h, and 8 h after the arsenic injection was measured using a gamma counter.(ABSTRACT TRUNCATED AT 250 WORDS)

Seven monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) were evaluated for relative activities in mobilizing and promoting excretion of mercury in mercury-laden mice. Compounds assessed were the ethyl (M-EDMS), n-propyl (Mn-PDMS), isopropyl (Mi-PDMS), n-butyl (Mn-BDMS), isobutyl (Mi-BDMS), n-amyl (Mn-ADMS), and isoamyl (Mi-ADMS) esters. 2,3-Dimercaptopropane-1-sulfonate (DMPS) and DMSA were used as positive controls. After the first oral dose of each compound at 0.5 mmol/kg, DMSA and DMPS reduced the corporal mercury burden 16% and 24%, respectively, compared to controls, while the monoesters effected reductions of 35% (M-EDMS) to 49% (Mi-ADMS). After the second treatment at the same dose, the respective reductions produced by DMSA and DMPS were 24% and 38%, and those conferred by the monoesters ranged from 52% (M-EDMS) to 61% (Mn-BDMS). Determination of the comparative dose-response relationships of DMSA and Mi-ADMS on corporal and renal mercury concentrations revealed the monoester to be more active than DMSA on both parameters at each dose used. The cumulative amount of mercury excreted in urine by control mice over a 3-day period was 7.08 micrograms; this was increased 22%, 85%, and 94% by daily i.p. injections of DMSA, DMPS, and Mi-ADMS, respectively, at a daily dose of 0.1 mmol/kg. The respective cumulative 3-day totals recovered in feces from control mice and from mice treated with DMSA, DMPS, and Mi-ADMS were 9.76, 8.21, 10.44, and 11.73 micrograms. Parallel daily measurements of retained whole body radioactivity from 203Hg in mice were in good agreement with the values calculated from the excretion data.

The efficiency of chelating agents to remove aged intracellular deposits of cadmium in young and older rats was studied. The administration of the chelating agent sodium N-(4-methoxybenzyl)-D-glucamine-N-carbodithioate monohydrate (MeOBDCG) 2 wk after a single intraperitoneal 115m Cd administration reduced the whole body, liver, and kidney retention in suckling rats to about 63, 42, and 71 percent and in older rats to 39, 17, and 76 percent of values obtained in respective controls. Chelation therapy was generally more effective in older than younger rats and the age-related effect was most pronounced in the liver. These results indicate that specific features of young organisms may significantly alter the effect of chelation treatment.

The relative effectiveness of 20 iron chelating agents in suppressing the growth and multiplication of Trypanosoma cruzi epimastigotes has been examined in vitro. 1,2-Dimethyl-3-hydroxypyrid-4-one (L1) and several of its newly synthesised N-substituted analogs containing hydrophobic substituents were significantly more effective than deferoxamine, even though they possess only two donor sites for iron(III) while deferoxamine has six. Analogs with hydrophilic substituents were uniformly less active than L1 itself. Variations in effectiveness as the polarity of the compound is varied indicate that the ability to cross the cellular membrane is of critical importance in the determination of the in vitro trypanocidal activity of iron(III) chelating agents. A group of four tris(2-aminoethyl)amine based tris-imines were also screened, all of which had poor activity (0-28% inhibition). Among the other iron(III) chelating agents which showed a relatively high level of activity at 50 and 100 micrograms/ml were salicylhydroxamic acid (70 and 73% inhibition) and hydroxyurea (42 and 52% inhibition). N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and acetohydroxamic acid exhibited only slight activity at 50 and 100 micrograms/ml. The best of these iron(III) chelating agents were as effective against the epimastigote form at both 50 and 100 micrograms/ml (74-82% inhibition) as benznidazole (81% inhibition), the drug currently used in the clinic.

Administration of N-benzyl-N-lactyl dithiocarbamate (BLDTC) to mice after chronic cadmium (Cd) administration evoked a prompt, dose-dependent reduction of the whole body burden; 75% of the retained Cd was mobilized and excreted after 20 i.p. injections of BLDTC at 1.0 mmol/kg/injection. This same dose regimen produced 71% and 98% reductions of the renal and hepatic Cd concentrations, respectively. There was no reduction by BLDTC of the endogenous level of any of seven other metals measured: iron, magnesium, selenium, copper, calcium, zinc, and manganese. Renal proximal tubular damage in mice which received Cd followed by BLDTC was much less than that observed in kidneys from mice which received Cd alone. Chronic Cd administration led to substantial epithelial vacuolar damage to renal distal tubules, and this process was not apparently reversed or antagonized by BLDTC treatment to the extent observed in proximal tubules.