pH-Sensitive nanodiamond co-delivery of retinal and doxorubicin boosts breast cancer chemotherapy.

Herein for the first time we take the advantage of nanodiamonds (NDs) to covalently immobilize all-trans retinal (NPA) by an imine bond, allowing pH-mediated drug release. DOX is then physically adsorbed onto NPA to form an NPA@D co-loaded double drug in the sodium citrate medium, which is also susceptible to pH-triggered DOX dissociation. The cytotoxicity results showed that NPA@D could markedly inhibit the growth of DOX-sensitive MCF-7 cells in a synergetic way compared to the NP@D system of single-loaded DOX, while NPA basically showed no cytotoxicity and weak inhibition of migration. In addition, NPA@D can overcome the drug resistance of MCF-7/ADR cells, indicating that this nanodrug could evade the pumping of DOX by drug-resistant cells, but free DOX is nearly ineffective against these cells. More importantly, the fluorescence imaging of tumor-bearing mice in vivo and ex vivo demonstrated that the NPA@D was mainly accumulated in the tumor site rather than any other organ by intraperitoneal injection after 24 h, in which the fluorescence intensity of NPA@D was 19 times that of the free DOX, suggesting that a far reduced off-target effect and side effects would be expected. Therefore, this work presents a new paradigm for improving chemotherapy and reversing drug resistance using the ND platform for co-delivery of DOX and ATR.

OAT3 mediates methotrexate resistance in the treatment of rheumatoid arthritis.

OBJECTIVE: To study whether organic anion transporter 3 (OAT3) is involved in the development of methotrexate (MTX) resistance in the treatment of rheumatoid arthritis. METHODS: The experimental components of the animals were the normal group, collagen-induced arthritis (CIA) model group, and MTX treatment group. MTX-treated rats were divided into the MTX effective group (MTX-E) and the MTX ineffective group (MTX-N). MTX-N receives additional treatment with OAT3 lentivirus injected into the joint cavity. Transient transfection was used to alter the expression of OAT3 in rat fibroblast-like synovial (rat-FLS). RESULTS: The rate of effectiveness of MTX in treating CIA rats was 48.98%. Compared with CIA rats, MTX-E can greatly improve ankle joint synovial hyperplasia and joint damage, but MTX-N has no significant changes. The expression of OAT3 in the synovium of MTX-E was significantly higher than that of MTX-N. The MTX content in the MTX-E synovium was also higher than that in the MTX-N synovium. After injection of OAT3 overexpression lentivirus into the joint cavity of MTX-N, the effective rate of MTX reached 80%. The ankle synovial hyperplasia and joint damage were significantly improved in the overexpression group, and the MTX content was also significantly increased in the synovium. After rat FLS overexpressed OAT3, the inhibitory effect of MTX on rat FLS proliferation activity was significantly enhanced, and the absorption of MTX was also significantly increased, while silencing the expression of rat FLS OAT3 reversed the outcomes. CONCLUSION: OAT3 mediates the formation of MTX resistance and is a potential target for improving MTX resistance.

Incidence, Pathogenesis, and Management of Proton Pump Inhibitor-Induced Nephrotoxicity.

Proton pump inhibitors are widely used in the treatment of various acid-related diseases and are among the most commonly used drugs. Studies estimate that 25-70% of proton pump inhibitors are prescribed for inappropriate treatments, doses, and indications, where the benefits of proton pump inhibitor use may be less than the risk of adverse drug reactions for many patients. Acute interstitial nephritis is an immune-mediated atypical kidney injury in the long-term use of proton pump inhibitors that causes problems for clinicians and patients. In this review, we summarize the current knowledge of proton pump inhibitors inducing acute interstitial nephritis, chronic kidney disease, and even end-stage renal disease in terms of incidence, pathogenesis, factors, clinical features, and diagnosis. We discuss how these factors change under conditions of acute interstitial nephritis, chronic kidney disease, and end-stage renal disease. The purpose of this review is to assess the current evidence to help clinicians and patients interpret the potential causal relationship between proton pump inhibitor intake and nephrotoxicity. This prompts clinicians to consider the appropriate dose and duration of proton pump inhibitor therapy to avoid inappropriate use.

Effects of paeoniflorin-6'-O-benzene sulfonate on the pharmacokinetics, excretion and tissue distribution of leflunomide in rats.

Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a novel ester derivative of paeoniflorin, which has been shown to have synergistic pharmacodynamic effects with leflunomide (LEF). To determine the effects of CP-25 on the pharmacokinetics of LEF in rats, we developed a ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based method for the determination of levels of teriflunomide (TER, an active metabolite of LEF). This method was used to determine TER concentrations in the plasma, urine, faeces and bile; heart, liver, spleen, lung, kidney, intestinal, brain and synovial tissues; and peripheral blood mononuclear cells (PBMCs) of rats in the control (LEF [10 mg/kg]) and combined (CP-25 [50 mg/kg × 7d] plus LEF [10 mg/kg]) groups. TER area under the curve [AUC], Tmax , mean residence time (MRT), t1/2α and t1/2ß were significantly lower, and clearance (CL) was significantly higher in the combined group than in the control group. Oral CP-25 administration in combination with LEF was found to promote TER excretion in urine, faeces and bile and to reduce its contents in most tissues and organs, especially in the liver, which may reduce LEF-induced liver injury. CP-25 also increased TER exposure in the synovium and its absorption by PBMCs, and this could explain the synergistic effects of CP-25 and LEF.