Successful Treatment of a Hepatitis C-Positive Patient Who Received Kidney Transplant From a Hepatitis C-Positive Donor: A Case Report.

Kidney transplantation from hepatitis C virus (HCV)-positive donors to HCV-positive recipients has always been controversial regarding the safety and the outcomes. In the posttransplant period, treatment of hepatitis C with interferon-based regimens could lead to serious side effects. A patient with chronic hepatitis C and nephropathy, on dialysis, underwent renal transplantation from an HCV-positive donor and received direct-acting antiviral (DAA) drugs thereafter. His renal and liver functions, as well as the hepatitis C viral load, were evaluated at predetermined intervals throughout and after his treatment. Patient's viral load was undetectable 4, 12, and 24 weeks after initiation of his treatment. Renal and liver functions were maintained at baseline, with no evidence of transplant rejection. Our clinical case is one of the few examples in the medical literature that shows successful suppression of replication of HCV in an HCV-infected kidney transplant candidate who received within 2 months of listing a deceased donor kidney transplant from an HCV-infected donor. The recipient was treated with DAAs, and this case illustrates potential safety and efficacy of this approach.

Phospho-NSAIDs have enhanced efficacy in mice lacking plasma carboxylesterase: implications for their clinical pharmacology.

PURPOSE: The purpose of the study was to evaluate the metabolism, pharmacokinetics and efficacy of phospho-NSAIDs in Ces1c-knockout mice. METHODS: Hydrolysis of phospho-NSAIDs by Ces1c was investigated using Ces1c-overexpressing cells. The rate of phospho-NSAID hydrolysis was compared between wild-type, Ces1c+/- and Ces1c-/- mouse plasma in vitro, and the effect of plasma Ces1c on the cytotoxicity of phospho-NSAIDs was evaluated. Pharmacokinetics of phospho-sulindac was examined in wild-type and Ces1c-/- mice. The impact of Ces1c on the efficacy of phospho-sulindac was investigated using lung and pancreatic cancer models in vivo. RESULTS: Phospho-NSAIDs were extensively hydrolyzed in Ces1c-overexpressing cells. Phospho-NSAID hydrolysis in wild-type mouse plasma was 6-530-fold higher than that in the plasma of Ces1c-/- mice. Ces1c-expressing wild-type mouse serum attenuated the in vitro cytotoxicity of phospho-NSAIDs towards cancer cells. Pharmacokinetic studies of phospho-sulindac using wild-type and Ces1c-/- mice demonstrated 2-fold less inactivation of phospho-sulindac in the latter. Phospho-sulindac was 2-fold more efficacious in inhibiting the growth of lung and pancreatic carcinoma in Ces1c -/- mice, as compared to wild-type mice. CONCLUSIONS: Our results indicate that intact phospho-NSAIDs are the pharmacologically active entities and phospho-NSAIDs are expected to be more efficacious in humans than in rodents due to their differential expression of carboxylesterases.

The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies.

We have synthesized a novel derivative of indomethacin, phospho-tyrosol-indomethacin (PTI; MPI-621), and evaluated its anticancer efficacy in vitro and in vivo. PTI inhibited the growth of human colon, breast and lung cancer cell lines 6-30-fold more potently than indomethacin. In vivo, in contrast to indomethacin that was unable to inhibit colon cancer xenograft growth, PTI inhibited the growth of colon (69% at 10mg/kg/day, P < 0.01) and lung (91% at 15mg/kg/day, P < 0.01) subcutaneous cancer xenografts in immunodeficient mice, suppressing cell proliferation by 33% and inducing apoptosis by 75% (P < 0.05, for both). Regarding its pharmacokinetics in mice, after a single intraperitoneal injection of PTI, its plasma levels reached the maximum concentration (Cmax = 46 µM) at 2h (Tmax) and became undetectable at 4h. Indomethacin is the major metabolite of PTI, with plasma Cmax = 378 µM and Tmax = 2.5h; it became undetectable 24h postadministration. The cellular uptake of PTI (50-200 µM) at 6h was about 200-fold greater than that of indomethacin. Regarding its safety, PTI had no significant genotoxicity, showed less gastrointestinal toxicity than indomethacin and presented no cardiac toxicity. Mechanistically, PTI suppressed prostaglandin E2 production in A549 human lung cancer cells and strongly inhibited nuclear factor-κB activation in A549 xenografts. These findings indicate that PTI merits further evaluation as an anticancer agent.

Gastrointestinal (GI) Amyloidosis Presenting As Chronic Diarrhea: A Diagnostic Dilemma.

This case report describes a 63-year-old male patient with a four-year history of chronic diarrhea. Extensive diagnostic investigations failed to reveal a cause. Subsequent upper and lower gastrointestinal (GI) endoscopic procedures revealed the presence of amyloidosis in the GI tract. The patient was referred for further evaluation, but unfortunately, he presented with hypotension and shock, and ultimately succumbed to systemic amyloidosis involving multiple organs. GI amyloidosis, although rare, should be considered in patients presenting with chronic diarrhea, unexplained weight loss, or GI bleeding. Early recognition and appropriate management are crucial for optimizing patient outcomes. Healthcare providers should maintain a high index of suspicion for GI amyloidosis to ensure timely intervention and improve patient care.

Phospho-Aspirin (MDC-22) Prevents Pancreatic Carcinogenesis in Mice.

Pancreatic cancer is a deadly disease with a dismal 5-year survival rate of <6%. The currently limited treatment options for pancreatic cancer underscore the need for novel chemopreventive and therapeutic agents. Accumulating evidence indicates that aspirin use is associated with a decreased risk of pancreatic cancer. However, the anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we developed phospho-aspirin (MDC-22), a novel derivative of aspirin, and evaluated its chemopreventive efficacy in preclinical models of pancreatic cancer. Phospho-aspirin inhibited the growth of human pancreatic cancer cell lines 8- to 12-fold more potently than aspirin; based on the 24-hour IC50 values. In a Panc-1 xenograft model, phospho-aspirin, at a dose of 100 mg/kg/d 5 times per week for 30 days, reduced tumor growth by 78% (P < 0.01 vs. vehicle control). Furthermore, phospho-aspirin prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. In p48-Cre;Kras(G12D) mice, cerulein treatment (6 hourly injections two times per week for 3 weeks) led to a significant increase in ductal metaplasia, replacing the majority of the exocrine compartment. Administration of phospho-aspirin 100 mg/kg/day five times per week for 21 days (starting on the first day of cerulein injection) inhibited the acinar-to-ductal metaplasia, reducing it by 87% (P < 0.01, vs. cerulein-treated control). Phospho-aspirin appeared to be safe, with the animals showing no signs of toxicity during treatment. Mechanistically, phospho-aspirin inhibited EGFR activation in pancreatic cancer, an effect consistently observed in pancreatic cancer cells, primary acinar explants and in vivo In conclusion, our findings indicate that phospho-aspirin has strong anticancer efficacy in preclinical models of pancreatic cancer, warranting its further evaluation. Cancer Prev Res; 9(7); 624-34. ©2016 AACR.

A novel ibuprofen derivative with anti-lung cancer properties: synthesis, formulation, pharmacokinetic and efficacy studies.

Phospho-non-steroidal anti-inflammatory drugs (phospho-NSAIDs) are a novel class of NSAID derivatives with potent antitumor activity. However, phospho-NSAIDs have limited stability in vivo due to their rapid hydrolysis by carboxylesterases at their carboxylic ester link. Here, we synthesized phospho-ibuprofen amide (PIA), a metabolically stable analog of phospho-ibuprofen, formulated it in nanocarriers, and evaluated its pharmacokinetics and anticancer efficacy in pre-clinical models of human lung cancer. PIA was 10-fold more potent than ibuprofen in suppressing the growth of human non-small-cell lung cancer (NSCLC) cell lines, an effect mediated by favorably altering cytokinetics and inducing oxidative stress. Pharmacokinetic studies in rats revealed that liposome-encapsulated PIA exhibited remarkable resistance to hydrolysis by carboxylesterases, remaining largely intact in the systemic circulation, and demonstrated selective distribution to the lungs. The antitumor activity of liposomal PIA was evaluated in a metastatic model of human NSCLC in mice. Liposomal PIA strongly inhibited lung tumorigenesis (>95%) and was significantly (p<0.05) more efficacious than ibuprofen. We observed a significant induction of urinary 8-iso-prostaglandin F2αin vivo, which indicates that ROS stress probably plays an important role in mediating the antitumor efficacy of PIA. Our findings suggest that liposomal PIA is a potent agent in the treatment of lung cancer and merits further evaluation.

A novel Ras inhibitor (MDC-1016) reduces human pancreatic tumor growth in mice.

Pancreatic cancer has one of the poorest prognoses among all cancers partly because of its persistent resistance to chemotherapy. The currently limited treatment options for pancreatic cancer underscore the need for more efficient agents. Because activating Kras mutations initiate and maintain pancreatic cancer, inhibition of this pathway should have a major therapeutic impact. We synthesized phospho-farnesylthiosalicylic acid (PFTS; MDC-1016) and evaluated its efficacy, safety, and metabolism in preclinical models of pancreatic cancer. PFTS inhibited the growth of human pancreatic cancer cells in culture in a concentration- and time-dependent manner. In an MIA PaCa-2 xenograft mouse model, PFTS at a dose of 50 and 100 mg/kg significantly reduced tumor growth by 62% and 65% (P < .05 vs vehicle control). Furthermore, PFTS prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. PFTS appeared to be safe, with the animals showing no signs of toxicity during treatment. Following oral administration, PFTS was rapidly absorbed, metabolized to FTS and FTS glucuronide, and distributed through the blood to body organs. Mechanistically, PFTS inhibited Ras-GTP, the active form of Ras, both in vitro and in vivo, leading to the inhibition of downstream effector pathways c-RAF/mitogen-activated protein-extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK1/2 kinase and phosphatidylinositol 3-kinase/AKT. In addition, PFTS proved to be a strong combination partner with phospho-valproic acid, a novel signal transducer and activator of transcription 3 (STAT3) inhibitor, displaying synergy in the inhibition of pancreatic cancer growth. In conclusion, PFTS, a direct Ras inhibitor, is an efficacious agent for the treatment of pancreatic cancer in preclinical models, deserving further evaluation.