Pharmacological profile of TAN-452, a novel peripherally acting opioid receptor antagonist for the treatment of opioid-induced bowel syndromes.

AIM: Opioid-induced bowel syndromes deteriorate patients' quality of life and may lead to nonadherence to opioid schedule and under-treatment of pain. The objective was to characterize the pharmacological profile of 17-cyclopropylmethyl-6,7-didehydro-4,5α-epoxy-6'-ethoxycarbonyl-3,14-dihydroxyindolo [2',3'-6,7]morphinan (TAN-452), a novel peripherally acting opioid receptor antagonist. MAIN METHODS: The in vitro binding affinity for the µ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR) and the inhibition of [35S]GTPγS binding were examined using membrane preparations from recombinant human (h) MOR, DOR, or KOR expressing cell. In vivo assays were performed to determine the inhibitory effect of TAN-452 on morphine-induced emesis (anti-emetic activity) in ferrets, morphine-induced inhibition of small intestinal transit (anti-constipation activity) in rats, and morphine-induced antinociception (anti-analgesic activity) in rats. A pharmacokinetic study was also performed. KEY FINDINGS: The binding affinities of TAN-452 (Ki) were 36.56 ±â€¯1.48 nM, 0.47 ±â€¯0.09 nM, and 5.31 ±â€¯1.80 nM for hMOR, hDOR, and hKOR, respectively. Its antagonistic activities (Kb) were 9.43 ±â€¯0.58 nM, 0.21 ±â€¯0.06 nM, and 7.18 ±â€¯0.75 nM, respectively. The ED50 values (95% Confidence interval) were <1.0 mg/kg p.o. and <0.3 mg/kg s.c. for anti-emetic activity, 9.45 (4.09, 47.79) mg/kg p.o. and 0.52 (0.10, 1.08) mg/kg s.c. for anti-constipation activity, and >300 mg/kg p.o. and >30 mg/kg s.c. for anti-analgesic activity. The pharmacokinetic study demonstrated low brain penetrability of TAN-452. SIGNIFICANCE: TAN-452 is a peripherally acting opioid receptor antagonist with selectivity for DOR that attenuates morphine-induced side effects, such as nausea, vomiting, and constipation, without affecting pain control.

Prevalence of Carbapenem-Resistant Gram-Negative Infections in the United States Predominated by Acinetobacter baumannii and Pseudomonas aeruginosa.

BACKGROUND: Carbapenem-resistant (CR) Gram-negative pathogens are recognized as a major health concern. This study examined the prevalence of infections due to 4 CR Gram-negative species (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli) in the United States and assessed their impact on hospital stays and mortality. METHODS: Hospitalized patients with laboratory-confirmed infection due to any of the 4 Gram-negative pathogens were identified from the Premier Healthcare Database. Proportions of CR were calculated by pathogen and infection site (blood, respiratory, urinary, or other) for the United States as whole and by census regions. Crude and adjusted odds ratios for in-hospital mortality were produced using logistic regression. RESULTS: From 2009 to 2013, 13 262 (4.5%) of 292 742 infections due to these 4 Gram-negative pathogens were CR. Of these CR infections, 82.3% were caused by A. baumannii (22%) or P. aeruginosa (60.3%), while 17.7% were caused by K. pneumoniae or E. coli. CR patients had longer hospital stays than carbapenem-susceptible (CS) patients in all pathogen-infection site cohorts, except in the A. baumannii-respiratory cohort. The crude all cause in-hospital mortality was greater for most pathogen-infection site cohorts of the CR group compared with the CS group, especially for A. baumannii infection in the blood (crude odds ratio [OR], 3.91; 95% confidence interval [CI], 2.69-5.70). This difference for the A. baumannii-blood cohort remained after adjusting for the relevant covariates (adjusted OR, 2.46; 95% CI, 1.43-4.22). CONCLUSION: The majority of CR infections and disease burden in the United States was caused by nonfermenters A. baumannii and P. aeruginosa. Patients with CR infections had longer hospital stays and higher crude in-hospital mortality.

A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors.

PURPOSE: Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers. EXPERIMENTAL DESIGN: The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival. RESULTS: Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase. CONCLUSION: S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.

Pharmacokinetics and safety assessments of high-dose and 4-week treatment with S-3304, a novel matrix metalloproteinase inhibitor, in healthy volunteers.

AIMS: To investigate the tolerability, safety and pharmacokinetics of S-3304 in healthy volunteers treated with high doses of S-3304 for 28 days. METHODS: Thirty-two healthy volunteers were recruited. Four male and four female subjects were allocated to one of four doses (800 mg, 1600 mg, 2400 mg and 3200 mg). At each dose six volunteers took active medication and two volunteers took placebo in a double-blind fashion. Volunteers took a single dose on days 1 and 28 for pharmacokinetic purposes, and took twice daily doses from day 3-27. The pharmacokinetics of S-3304 and its hydroxy metabolites were evaluated. Tolerance was based on subjective adverse events, clinical examination, vital signs, ECG and laboratory tests including haematology and biochemistry profiles using CTC grading. RESULTS: Doses up to 2400 mg twice daily were generally well tolerated. At 3200 mg twice daily, five volunteers including one randomized to placebo were withdrawn from treatment mainly due to alanine aminotransferase (ALT) elevation. C(max) of S-3304 on day 1, whose geometric mean and 95% confidence interval were 66.3 microg ml(-1) (48.8, 90.0) for 800 mg, 82.6 microg ml(-1) (69.3, 98.6) for 1600 mg, 89.5 microg ml(-1) (79.5, 100.7) for 2400 mg, and 110.5 microg ml(-1) (88.9, 137.7) for 3200 mg, respectively, was correlated with the log-transformed peak ALT (P < 0.0001 for male and P = 0.048 for female volunteers). CONCLUSIONS: In healthy volunteers the maximum tolerated dose of S-3304 was 2400 mg twice daily. ALT elevation was the most frequent dose-limiting factor and was correlated with C(max) on day 1.

Augmented anti-metastatic efficacy of a selective matrix metalloproteinase inhibitor, MMI-166, in combination with CPT-11.

The anti-metastatic efficacy of MMI-166, which is a selective matrix metalloproteinase (MMP) inhibitor, in combination with CPT-11 was examined using two metastasis models of human gastrointestinal cancer cells. In the liver metastasis model, C-IH human colon cancer cells were injected into the spleen of athymic BALB/c nude mice. Daily oral (p.o.) dosing of MMI-166 at 200 mg/kg starting 1 day after tumor inoculation led to a significantly prolonged survival effect by inhibiting liver metastasis of C-1H tumor cells. CPT-11 (5 or 20 mg/kg) was administered intraperitoneally (i.p.) three times on day 3, day 7 and day 11 and also improved the survival of tumor-inoculated mice compared with the vehicle control. When MMI-166 was combined with CPT-11, the anti-metastatic efficacy was significantly augmented. Moreover, long tumor-free survival was noted in two of eight mice that were given the combination therapy but not either MMI-166 or CPT-11 monotherapy. In the peritoneal dissemination model, TMK-1 human gastric cancer cells were injected i.p. into nude mice. While both MMI-166, administered daily p.o. from day 1 at 200 mg/kg, and CPT-11, administered intravenously (i.v.) three times, inhibited the tumor dissemination and growth, the combination therapy of MMI-166 plus CPT-11 showed a greater inhibitory effect than each monotherapy. A hematotoxicity study demonstrated that CPT-11 alone significantly decreased the number of white blood cells (WBC) and bone marrow cells (BMC) in the mice during treatment, while the daily administration of MMI-166 alone had no such effect. More importantly, the combination therapy of MMI-166 with CPT-11 did not augment the hematotoxicity caused by CPT-11. An in vitro cytotoxicity study showed that MMI-166 itself neither has direct cytotoxicity in C-1H and TMK-1 tumor cells, nor does it augment the cytotoxicity of SN-38, an active form of CPT-11. The findings indicate that the augmented anti-metastatic efficacy in combination treatment was not simply due to the augmentation of direct cytotoxic activity, but was rather an additive or synergistic effect of anti-metastatic activities with different mechanisms. In conclusion, we demonstrated that the anti-metastatic efficacy against C-1H colon cancer and TMK-1 gastric cancer were augmented by the combination therapy of MMI-166, an orally active MMP inhibitor, with CPT-11. However, the hematotoxicity caused by CPT-11 was not augmented in the combination with MMI-166. Thus, the combination therapy of MMI-166 and CPT-11 exhibited potent anti-metastatic efficacy without increased hematotoxicity. These results point to the clinical advantage of using MMI-166 in combination with CPT-11.

Augmented growth inhibition of B16-BL6 melanoma by combined treatment with a selective matrix metalloproteinase inhibitor, MMI-166, and cytotoxic agents.

BACKGROUND: MMI-166 is a selective matrix metalloproteinase (MMP) inhibitor. The purpose of this study was to evaluate the antitumor efficacy of the combined treatment of MMI-166 with paclitaxel or carboplatin. MATERIALS AND METHODS: Mice bearing B16-BL6 melanoma were treated p.o. with MMI-166 from 1 day after tumor inoculation. The mice were administered i.v. with either paclitaxel or carboplatin at the maximum tolerated dose (MTD). RESULTS: MMI-166 monotherapy inhibited in vivo growth of the B16-BL6 tumor to an extent similar to that of paclitaxel or carboplatin monotherapy. When MMI-166 was combined with paclitaxel or carboplatin, the antitumor efficacy was significantly (p < 0.01) augmented in comparison with either MMI-166 or each cytotoxic agent alone. The hematotoxicity study demonstrated that daily treatment with MMI-166 did not affect the blood cell number in the mice and more importantly the combination of MMI-166 with paclitaxel did not augment the hematotoxicity caused by paclitaxel. An in vitro cytotoxicity study showed that MMI-166 itself has neither direct cytotoxicity against B16-BL6 tumor cells nor does it augment the cytotoxicity of paclitaxel or carboplatin. CONCLUSION: These results indicate that augmented antitumor activity of the combination treatment was not simply due to the augmentation of direct cytotoxic activity, but was rather an additive effect of the antitumor activities of different mechanisms. They suggest the effectiveness of a combination therapy of MMI-166 with paclitaxel or carboplatin in clinical therapy.