Impaired insulin signaling in adipose tissue and skeletal muscle causes insulin resistance associated with the development of type 2 diabetes. However, the molecular mechanisms underlying insulin resistance remain to be elucidated. In this review, we describe the current understanding of the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and tumor necrosis factor (TNF)-α on insulin signal transduction in adipocytes. First, we determined that atorvastatin inhibits the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 through a decrease in the RhoA-Rho-kinase pathway, resulting in the inhibition of glucose uptake. Second, we found that TNF-α induces IRS-1 phosphorylation at serine residues 636/639 and inhibits the tyrosine phosphorylation of IRS-1 through the increase in both extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) phosphorylation. Interestingly, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, an AMP-activated protein kinase activator, suppresses TNF-α-induced IRS-1 serine phosphorylation at 636/639 and the phosphorylation of ERK by enhancing interactions between ERK and dual-specificity phosphatase-9. These results may be helpful in understanding the mechanisms underlying insulin resistance.
Marine natural products and biologically active compounds often contain cyclic ether units. Thus, regio- and stereoselective construction of these structures has long been a topic of interest in organic synthesis. This review summarizes new synthetic approaches to polycyclic ether natural products utilizing the features of chemical elements.
Hypoxia in tumor tissues plays a pivotal role in tumor progression and angiogenesis, and is associated with cancer therapeutic resistance. For the diagnosis of hypoxia, non-invasive imaging techniques, especially positron emission tomography (PET) with 2-nitroimidazole-based probes, are used, since 2-nitroimidazole-based probes are considered to undergo reductive metabolism on their 2-nitroimidazole moiety and become trapped in hypoxic cells. However, the detailed mechanism of their accumulation remains unclear because of the difficulty in estimating the metabolites by radioisotopic analysis. Imaging mass spectrometry (IMS) can distinguish the distribution patterns of the drug and its metabolites. To clarify the accumulation mechanism of 2-nitroimidazole-based probes in hypoxic cells, we evaluated [18F]fluoromisonidazole (FMISO), a 2-nitroimidazole-based PET probe, in combination with radioisotopic analysis and IMS. We found that the glutathione conjugate of reduced FMISO (amino-FMISO-GS) was the main FMISO metabolite, and was specifically distributed in the hypoxic regions of tumors. The same phenomenon was observed when we examined another 2-nitroimidazole-based probe, pimonidazole. The in vitro cellular uptake study revealed that FMISO accumulation in hypoxic cells depends on the cell type. In those cells exhibiting higher FMISO uptake, the reactive glutathione level and enzyme (glutathione S-transferase; GST) activity catalyzing the glutathione conjugation reaction was significantly higher, whereas the expression level of the efflux transporter (multidrug resistance-associated protein 1; MRP1) was significantly lower. Our study suggests that 2-nitroimidazole-based probes accumulate in hypoxic cells via glutathione conjugation following reductive metabolism, which depends not only on the glutathione conjugation capacity of the cells but also on hypoxic conditions.
Heterogeneous metal catalysts constitute a very important tool for the synthesis of functional materials and fine chemicals owing to their high efficiency, robustness, and facile recyclability. Biaryls are privileged structural motifs in many natural products, chiral ligands, and catalysts. The oxidative biaryl coupling reaction is one of the most promising methods for biaryl synthesis in terms of atom and step economies. However, although oxidative biaryl coupling of naphthols has been studied thoroughly, the coupling of aryl amines providing biaryl amines like 2,2′-diamino-1,1′-binaphthyl (BINAM) and 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN) derivatives remains elusive. Recently, we have found that aryl amines are efficiently dimerized with the use of a heterogeneous Rh/C catalyst under acidic conditions. This heterogeneously catalyzed method can be adapted to the highly selective cross-coupling reaction of aryl amines and the intramolecular biaryl coupling reaction. Furthermore, we developed an aerobic direct C-H oxidation of polycyclic aromatics catalyzed by a recyclable heterogeneous rhodium catalyst. These methodologies are advantageous compared with the existing reactions owing to the mild aerobic conditions employed and the facile recyclability of the heterogeneous catalysts used.
Cancer chemotherapy has a high frequency of side effects, and patients often experience adverse health effects. This review focuses on risk factors and supportive care for the prevention of chemotherapy side effects. 1) Drug-induced interstitial lung disease (DILD) is one of the serious adverse events associated with chemotherapy, and this retrospective study investigated the risk of DILD in Japanese patients with lung cancer. Among the 459 patients who received lung cancer chemotherapy from April 2007 to March 2013, 33 (7.2%) developed chemotherapy-associated DILD. Preexisting interstitial lung disease was a risk factor for DILD [odds ratio (OR)=5.38; 95% confidence interval (CI)=2.47-11.73]. Early death was observed in 10 of the 33 patients who developed DILD. Epidermal growth factor receptor-tyrosine kinase inhibitor use (OR=9.26; 95%CI=1.05-81.96) and two or more prior chemotherapy regimens (OR=6.95; 95%CI=1.14-42.35) were identified as poor prognostic factors. 2) The incidence of pemetrexed-induced rash is high. The aim of this retrospective study was to evaluate the efficacy of corticosteroids for pemetrexed-induced rash. Rash developed in 26.9% of patients who received pemetrexed between April 2009 and March 2014. Supplementation with dexamethasone (≥1.5 mg) on days 2 and 3 significantly reduced the incidence of rash compared with no supplementary corticosteroids (39.4% vs. 17.8%, p<0.05). Increasing the corticosteroid dose had no additional effect on pemetrexed-induced rash development. These results suggest that supplementary corticosteroids may prevent pemetrexed-induced rash, and low-dose corticosteroids are sufficient for such prevention.
Unnatural amino acids and the peptides bearing such units have gathered much attention due to their interesting biological activities and synthetic utility as chiral building blocks for the synthesis of complex molecules. This paper descibes an asymmetric synthesis of unnatural amino acid derivatives and their subsequent application to the preparation of unnatural amino acid-containing peptides. The α-imino carboxylic acid derivatives, which are common substrates for the synthesis of unnatural amino acids, could be readily prepared by MnO2-mediated oxidation of N-PMP-protected glycine derivatives. This reaction allowed us to synthesize novel derivatives such as α-imino perfluoroalkylesters, imides or thioesters. These compounds are useful for the synthesis of unnatural amino acid derivatives. MnO2-mediated oxidation was further applied to the synthesis of peptidyl imine. Moreover, a new methodology for the synthesis of unnatural amino acid-containing peptides was developed using the thus obtained imino peptides. This novel approach should be useful for the divergent synthesis of peptides possessing varieties of unnatural amino acid moieties.
Hemoglobin vesicles (HbVs) in which human hemoglobin is encapsulated in a phospholipid bilayer membrane (liposome) have been developed as artificial red blood cells. Although the effectiveness of HbVs, including their physicochemical characteristics and pharmacological effects, has been reported, data on the pharmacokinetic properties of HbVs are limited. Previously, we developed two kinds of radiolabeled HbV, 125I-HbV and 3H-HbV, in which the internal hemoglobin and lipid membranes were labeled with 125I and 3H, respectively. Using these isotope-labeled HbVs, we clarified the detailed pharmacokinetic properties of HbVs in healthy animals and experimental animal disease models of hemorrhagic shock, chronic cirrhosis, and hyperlipidemia. This review describes our previous results regarding the pharmacokinetic properties of HbVs, and we discuss the safety and usefulness of HbVs from the viewpoint of their pharmacokinetic characteristics. Furthermore, we have modified HbVs by employing them as a carbon monoxide (CO) carrier because the hemoglobin inside HbVs reversibly binds to CO, resulting in CO-bound HbVs (CO-HbVs). Here we report the potential of CO-HbVs for the treatment of intractable inflammatory disorders based on their therapeutic efficiency in experimental animal models.
The translocation of drugs across biological membranes not only occurs via passive diffusion but also by transporter-mediated processes. Knowledge of tissue-specific drug transporter expression, as well as characterization of substrate drugs of individual transporters, leads to a better understanding of the role of these transporters in the pharmacokinetics of drugs. The ATP-binding cassette transporter family member breast cancer resistance protein (BCRP) is one of the most important intestinal efflux transporters involved in the intestinal absorption or permeability of drugs. A genetic variant in the BCRP, 421C>A, is a useful biomarker for explaining large interindividual differences in the pharmacokinetics of sulfasalazine (SASP), a BCRP substrate. However, large intragenotypic differences remain in spite of the incorporation of this genotype into the pharmacokinetics of SASP. Epigenetic regulation alters gene expression without changing DNA sequences. In epigenetic regulation, microRNAs (miRNAs) appear to be the most extensively investigated due to their important roles in the posttranscriptional regulation of mRNAs. Our study showed that miR-328 negatively regulates BCRP expression in human tissues, and the intestine-derived exosomal miR-328 levels positively correlated with the SASP area under the blood concentration-time curve. These results suggest that circulating intestine-derived exosomal miR-328 in plasma has potential as a possible biomarker for estimating BCRP function in human intestines. A clearer understanding of epigenetic mechanisms regulating the expression of drug transporters will provide insights into novel approaches to individualized drug therapy.
Sunitinib has been shown to offer clinical benefits during the treatment of advanced renal cell carcinoma. However, molecular targeting drugs are expensive and can have a significant impact on medical expenses. The purpose of this study was to assess the cost-effectiveness of sunitinib as a first-line therapy compared with interferon-alpha (IFN-α) in metastatic renal cell carcinoma patients. A Markov model was used to show the clinical courses of patients with metastatic renal cell carcinoma who received sunitinib or IFN-α. The transition probabilities and utilities employed in this Markov model were derived from two sources. This study focused on the perspective of public healthcare payer, as only direct medical costs were estimated from the treatment schedule for metastatic renal cell cancer. In the cost-effectiveness analysis, outcomes were valued in terms of life years (LYs) and quality-adjusted life years (QALYs). We calculated the incremental cost-effectiveness ratio (ICER) during the cost-effectiveness analysis. The results were tested using Monte Carlo simulations. Sunitinib and IFN-α treatment resulted in LYs of 2.40 years and 2.03 years, QALYs of 1.58 and 1.25, and expected costs of 13,572,629 yen and 6,083,002 yen, respectively. As a result, the ICER associated with replacing IFN-α with sunitinib was 22,695,839 yen/QALYs. Our results suggest that compared with IFN-α, sunitinib prolongs LYs and QALYs, but the increases in quality achieved by sunitinib are more expensive than those produced by IFN-α.
It is important that pharmacists ensure safe chemotherapy implementation. In addition to inspecting chemotherapeutic prescriptions according to patient condition and drug-drug interactions, the management of chemotherapy-induced adverse effects and associated pharmaceutical intervention is one of the most important responsibilities of pharmacists in medical care teams. In May 2016, an oncology pharmacist was set responsible for the specialized, long-term, and successive pharmaceutical care, including instructions about appropriate use of medication at an outpatient chemotherapy center. We evaluated the effectiveness of the continuous pharmaceutical care. The number of medication counseling and associated pharmaceutical interventions increased with time. Specifically, the number of pharmaceutical interventions (prescription questions and pharmaceutical proposals) was 745 (459 and 286, respectively) in the surveillance period, which significantly increased compared to that observed within the same duration before posting an oncology pharmacist. The adoption rate was approximately 70% for prescription questions and 98% for pharmaceutical proposals. We also found that approximately 70% of the proposals attenuated the painful symptoms. Furthermore, approximately 60% of all pharmaceutical interventions were established after the third visit; in particular, approximately 20% of the pharmaceutical proposals were suggested after the sixth visit, indicating that continuous medication counseling results in an increase in pharmaceutical proposals. In conclusion, long-term and successive pharmaceutical care by oncology pharmacy specialists in outpatient chemotherapy contributes to a safe and less onerous chemotherapy implementation, as it has been highly adopted, is effective in many cases, and has been proven to be important for risk management in chemotherapy.
When selecting external medicines for the treatment of skin diseases, it is thought to be very important to consider differences in characteristics of their bases, because the bases may influence the clinical efficacy of the medicines. In this study, we investigated whether the differences in characteristics of three kinds of bases, white petrolatum, macrogol ointment, and aqueous gel affect wound healing. In vitro moisture permeability tests demonstrated that these bases have different characteristics in coatability and water retentivity, with the rank order of the intensity of coatability as white petrolatum>macrogol ointment>aqueous gel, and that of water retentivity as macrogol ointment>white petrolatum>aqueous gel. Similar rank order of these bases was observed for transepidermal water loss and stratum corneum water content in the dry skin on the abdomen of guinea pigs induced by topical application of acetone/ether mixture, followed by water. In addition, we found that treatment with macrogol ointment, but not white petrolatum or aqueous gel, significantly accelerated wound healing in rat skin, and that the contents of basic fibroblast growth factor and epidermal growth factor in the skin treated with macrogol ointment were significantly higher compared with non-treated skin. In conclusion, these results imply an important role of the bases of external medicines in the treatment of skin diseases.
Forty-four brands of transdermal patches for twelve kinds of active pharmaceutical ingredients (APIs) are available in Japan as of April 30, 2018. Although approximately one-third of the corresponding pharmaceutical interview forms lack information on how to evaluate the adhesive properties of the patches, the peel test, probe tack test, or inclined ball tack test have generally been adopted. This means that it might be difficult to simply compare the adhesive properties among the patches because the testing methods are not unified in some cases. In this study, measurements of the adhesive properties of 38 transdermal patches of ten different APIs were performed using several unified testing methods (180° peel test, 90° peel test, self-adhesion test, and probe tack test) under unified experimental conditions. The adhesive properties were found to be quite different among the patches, even for the same API, dose, and size. For example, the ratios of the maximum to minimum measured values of tack and 180° peel strength for tulobuterol patches were 5 and 29, respectively. In the case of generic products for which the bioequivalence to a brand-name product is assured, the variation in adhesive properties can extend the range of choices for patients, which is advantageous. Providing information to medical experts on adhesive properties through, for example, pharmaceutical interview forms and package inserts, is considered to be useful for helping patients to make better choices.
Adhesive properties of 38 transdermal patches of ten different active pharmaceutical ingredients (APIs) were measured using unified methods. The adhesive properties were quite different among the patches, even for the same API, dose, and size. In the case of generic products for which the bioequivalence to a brand-name product is assured, the variation in the adhesive properties can extend the range of choices for patients. This study will help medical experts to notice the differences in adhesive properties of transdermal patches.
The intestinal motor function declines in the elderly. Many patients have constipation and ingest magnesium oxide for a prolonged period. One-dose packaging of drugs is adopted for many elderly patients to help them to avoid forgetting to take an increase in the number of oral drugs to be taken and improve convenience. Several studies on differences in stability among magnesium oxide preparations including generic drugs have been reported, but no study on the influence of the storage conditions after one-dose packaging on the properties of magnesium oxide tablets has been reported. Three types of magnesium oxide tablet were one-dose-packaged and stored for 12 weeks with and without a desiccant. The difference in hardness and weight significantly increased in all tablets stored without a desiccant. The disintegration time significantly extended in the tablets stored without a desiccant from 2 weeks after the initiation of storage and that of the B tablet markedly extended. However, all tablets passed the disintegration criteria of the disintegration test. The pH-area under the concentration-time curve significantly decreased in the tablets stored without a desiccant. It was suggested that when the one-dose-packaged magnesium oxide preparation is stored, it should be placed in a bag containing a desiccant.