Although oral drugs account for 80% of the world drug market, many difficulties arise in their development. The drug absorption profile after oral administration may be influenced by multiple factors, including dosing conditions and physiological state of the gastrointestinal (GI) tract. Variability in GI fluid volume may influence the absorption characteristics. Indeed, the contributions of passive diffusion, transporters, and metabolic enzymes depend on GI drug concentration, which is influenced by changes in GI fluid volume. However, this important variable has been neglected in many prediction methods for oral drug absorption and drug interactions, and for convenience it is often assumed that the GI water volume is fixed at a constant value. Major global regulatory agencies such as the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) recommend using a constant fluid volume of 250 mL (the fluid volume of a glass of water) to estimate the theoretical GI concentration of drugs after oral administration. However, the actual volume of water in the GI tract is both time- and site-dependent as a result of water intake, absorption, secretion, and GI transit. This review article summarizes our data showing that luminal water volume is influenced by the osmolality of the applied solution, and illustrates how this effect may contribute to changes in GI drug concentration, resulting in altered drug absorption.
Delivery of nucleic acid therapeutics to target body organs requires injection of nanocarriers into the bloodstream. However, as such nanocarriers would also be delivered to non-target organs, low delivery efficiency to target organs and risk of unexpected effects are clear limitations of this technology. We recently applied iontophoresis (IP) for direct delivery of nucleic acid therapeutics to various organs. IP relies on a weak electric current for noninvasive transdermal drug delivery. We found that IP can deliver hydrophilic macromolecules and nanoparticles into the skin. We previously succeeded in transdermal delivery of siRNA, and subsequent knockdown (70%) of target mRNA levels in the skin via IP of siRNA (Int. J. Pharm., 383, 2010, Kigasawa et al.). Moreover, we found that cell signal activation and cleavage of intercellular junctions are induced by IP (J. Biol. Chem., 289, 2014, Hama et al.). We hypothesized that this phenomenon should be observed in not only skin but also other organs, and subsequently carried out IP of nucleic acid therapeutics to various body organs including liver, pancreas and kidney. This technique resulted in delivery of nucleic acid therapeutics into the various target body organs, and subsequent knockdown of target genes. These results suggest that direct delivery to target body organs via non-blood circulatory pathway is possible. This technology may offer a solution to the various limitations associated with current drug delivery systems (DDS).
Pancreatic cancer is the fourth-leading cause of death from cancer in Japan, after lung, colorectal, and stomach cancers and has the lowest survival among these tumors, because of not only no symptoms, no screening tool and no biomarkers but also high rates of recurrence and metastasis. In addition, pancreatic cancer has excessive stroma which serves as a severe biological barrier for anticancer drug delivery and successful treatment. Therefore, there are many challenges for drug delivery systems for the treatment of pancreatic cancer. Recently, we developed self-assembly PEGylation retaining activity (SPRA) technology, which comprises a reversible pegylated protein complex without loss of bioactivity. SPRA technology is based on a host-guest interaction between PEGylated β-cyclodextrin and adamantane-appended protein. In this review, first pancreatic cancer is introduced, second, principle drug delivery systems for the treatment of pancreatic cancer are described, and third the concept of SPRA technology as well as examples of SPRA proteins, especially focusing on the potential of SPRA-bromelain for treatment of pancreatic cancer, are introduced.
Recently, mRNAs and microRNAs (miRNAs) have been identified in exosomes, which can be taken up by neighboring or distant cells. These exosomal-miRNAs may regulate gene expression in recipient cells. miRNAs are a type of non-coding RNA that induce post-transcriptional gene silencing of their target genes and regulate a wide range of biological processes, including apoptosis, differentiation, metabolism, and cell proliferation. According to recent reports, aberrant expression of miRNAs is associated with most pathological disease processes, including carcinogenesis. Therefore circulating onco-miRs are considered as significant therapeutic targets for cancer therapy. However, there is no report to regulate the function of miRNAs in exosomes. In this study, we developed novel drug delivery system using anti-exosome antibody-oligonucleotide conjugates (ExomiR-Tracker) for functional inhibition of circulating miRNAs. The “ExomiR-Tracker” is the world's first innovative molecule that has targeting property for exosome-recipient cells and specifically delivers nucleic acid medicines to the target cells. We found that ExomiR-Tracker can bind to the surface of exosomes and that the complexes are introduced into exosome-recipient cells then inhibit the activity of miRNA. We showed that ExomiR-Tracker can accumulate in cancerous tumors after intravenous administration. Existing technologies have difficulties for introducing anti-miR into exosomes and extremely low possibility to deliver anti-miR to exosome-recipient cells after intravenous administration. However, we successfully developed useful inhibition technology against exosomal-miRNA.
Because active-targeted liposomes are very complex formulations, quality characteristics of functional lipids have not been defined yet, and this is a major obstacle in clinical application of active targeted liposomes. We have developed high functionality and quality (HFQ) lipids, which define quality characteristics of functional lipids for clinical drug delivery system (DDS) applications. Because HFQ lipids are designed to enable facile and rapid functionalization of DDS carrier by simple and one-step mixing, we are expanding applications for not only liposomes but also exosomes and cells. Recently, we developed multi-color deep imaging by tissue clearing for analysis of spatial distribution of DDS in various tissues. Nanocarriers are usually non-uniformly distributed in solid tumors because of their heterogeneity. Especially, in refractory cancer such as pancreatic cancer, the presence of collagen and blood vessels greatly affects intra-tumor distribution of DDS carrier. Therefore information on spatial relations between the tissue structure and DDS carrier is important to regulate precisely intra-tumor distribution of DDS carrier. Recently, our group has established multi-color deep imaging to analyze spatial distribution of stromal collagen, liposomes, and blood vessels in pancreatic tumor tissue. In this review, we present recent research in developing HFQ lipids. Moreover, current status of research on DDS for pancreatic cancer treatment is reviewed.
Traditionally, anticancer drug discovery research has been conducted based on immortalized cancer cell lines, either cultured in vitro or grown in vivo. In the USA and Europe, patient derived xenograft (PDX) model is rapidly expelling traditional in vitro and in vivo models due to the good predictability of clinical outcome and its nature of retaining characteristics and heterogeneity in the original tumor. Furthermore, a significant association was also reported between drug responses in patient and corresponding PDX as high as 87%. We are preparing a PDX model for Japanese cancer patients including drug resistance examples and rare cancers. Using the established PDX model, we confirmed the possibility that the tumor microenvironment might affect the efficacy and distribution of drugs even if the target receptor is expressed in tumor sites as compared to the cell line (CDX) model, which has been widely used in drug discovery. Interestingly, although expressing a target receptor in viable tumor cells, we also have found a PDX model with a lower distribution of molecular target drug. Therefore we will evaluate the usefulness of the PDX model in drug development by exploring new biomarkers and elucidating the mechanisms of drug resistance in target tumors. Moreover, pharmaco-imaging system will allow us to visualize the exposure and distribution of drugs in tumors at macro and micro levels. Finally, we evaluate relations between distribution of drugs in the tumor microenvironment including target tumor cells, neovessels, stromal cells, immune cells, and fibroblasts.
Advances in genomic medicine have enabled the development of precise cancer therapies (precision cancer medicine) through multigene testing. Toward this end, we have developed a novel clinical sequencing system called PleSSision (Pathologist edited, Mitsubishi Space Software supervised clinical sequence system for personalized medicine) that performs amplicon exome sequencing targeting 160 cancer genes. Using this system, we have examined more than 600 cases over 3 years, and have identified druggable gene alteration in approximately 60% of the cases. Performing such clinical sequencing requires management of the sample quality and sequencing by pathologists and laboratory technicians; bioinformatics analysis by biomedical scientists; and patient care by nurses and pharmacists, all based on specific skills and knowledge of genomics. In addition, patients diagnosed with a hereditary cancer syndrome based on clinical sequencing results must receive care from a genetic counselor and a medical doctor with expertise in genetics. Recently, poly(ADP-ribose)polymerase (PARP) inhibitors and immune checkpoint inhibitors have been used in the treatment of patients with hereditary cancer syndromes, so collaboration involving other medical staff, especially genomic pharmacists, is also required. In this session, we provide an overview of cancer genomic medicine and emphasize the role that genomic pharmacists play in cancer precision medicine.
The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.
The development of cancer genomic medicine has been embraced as an important new policy issue in “The 3rd Basic Plan to Promote Cancer Control Programs” formulated by the Japanese government. Cancer-associated gene panel testing has been recognized by the public health insurance system since July 2019, and is a critical component of the clinical implementation of genomic science. Because of this dynamic change in cancer medicine, pharmacists are now expected to acquire knowledge about genomic science, and to apply it to individualized and appropriate pharmacotherapies. This review outlines the roles of pharmacists in cancer genomic medicine.
We established an outpatient service in November 2017 to provide cancer gene profiling test services to cancer patients. To date, we have seen approximately 100 patients. Our staff includes genetic counselors and nurses specialized in genetic medicine. Our experience highlights the importance of healthcare professionals having in-depth knowledge of cancer therapeutic drugs and/or investigational drugs based on cancer genome medicine. Recently, poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for treating breast cancer patients with germline BRCA mutation; thus, in-depth knowledge of genetics and skills for genetic counseling are often considered indispensable in working with cancer patients. However, because the prompt treatment of clear and present cancer is the top priority in clinical settings, providing genetic information at that time, including that of unaffected family members, is of low priority for most patients who are dealing with the severe side effects of anti-cancer therapies. Pharmacists have an essential role to play in cancer therapeutics, talking with patients in order to assess their condition and to clarify the status of their treatment with anticancer agents. Genetic pharmacists should therefore work closely with genetics nurses and genetic counselors in the clinical practice of cancer genomic medicine. In this symposium, I would like to describe our experience caring for patients through our outpatient service, and to discuss the ideal framework for multidisciplinary cooperation to promote cancer genomic medicine.
Among breast cancer cases, 5-10% are thought to have germline mutations in genes associated with onset. Among these, hereditary breast cancer-ovarian cancer syndrome, which develops from breast cancer susceptibility (BRCA) gene mutation, has become widely known. Since 2018, olaparib has been clinically available for patients with inoperable or recurrent breast cancer. However, to use this medicine, BRCA gene mutation must be confirmed. Our hospital has prepared a BRCA genetic testing procedure, counseling system, and environment for the safe use of olaparib for BRCA genetic mutation positive patients. Until patients get the results of the BRCA gene examination, the attending physician and certified in breast cancer nurse care for the patient. If a positive result is obtained, we have established cooperation with a neighboring hospital, since our hospital cannot provide the genetic counseling. The main role of pharmacists is to develop a description system, as with other therapeutic agents, and to develop measures to help with supportive care for side effects. Also important is the development of a system to provide information to community pharmacies. At this symposium, we will report on how we developed our treatment strategy for patients with hereditary breast cancer syndrome, and the integrated role of pharmacists at Hamamatsu Medical Center.
Since September of 2017, the Department of Pharmacy at Keio University Hospital has participated in activities of the A-3 Group in the “Program for Promoting a Platform of Genomics-based Drug Discovery” conducted by the Japan Agency for Medical Research and Development (AMED). The A-3 Group works to develop programs for fostering human resources in genomic medicine in order to solve various problems, and the Keio Department of Pharmacy plans and holds twice-yearly seminars for pharmacists interested in genomic medicine. In this review, we give an overview of efforts toward the development of pharmacists involved in genomic medicine, and we present the results of questionnaires about previous seminars.
The environment surrounding clinical pharmacy practices has changed greatly in the past thirty-some years, basically since the end of the 1980s. During this period, the separation ratio between pharmacists' dispensing and prescribing functions has increased, from 12% to 74%. The three big events in this timeline include the beginning of pharmaceutical care for inpatients by hospital pharmacists in 1988; the transition of pharmacy schools to a six-year educational program in 2006; and the revision of Pharmaceutical Affairs Law, as well as its name change, in 2014. In concert with these events, the central role of the pharmacist has changed from being dispensing-centric to an active participation in patient treatment via medication as a member of the medical care team. As a key participant in these changes, the author helped to improve the operations of hospital pharmacists, strengthened their role with advanced information and communication technology (ICT) support, and established a baseline for clinical pharmacy research and education. Accordingly, in this paper, the history of this development will be reviewed, and the future of a global standard for pharmaceutical education will be discussed.
Recent advances in high-throughput technologies have revealed that 75% of the human genome is transcribed to RNA, whereas only 3% of transcripts are translated into proteins. Consequently, many long non-coding RNAs (lncRNAs) have been identified, which has improved our understanding of the complexity of biological processes. LncRNAs comprise multiple classes of RNA transcripts that regulate the transcription, stability and translation of protein-coding genes in a genome. Natural antisense transcripts (NATs) form one such class, and the GENCODE v30 catalog contains 16193 lncRNA loci, of which 5611 are antisense loci. This review outlines our emerging understanding of lncRNAs, with a particular focus on how lncRNAs regulate gene expression using interferon-α1 (IFN-α1) mRNA and its antisense partner IFN-α1 antisense (as)RNA as an example. We have identified and characterized the asRNA that determines post-transcriptional IFN-α1 mRNA levels. IFN-α1 asRNA stabilizes IFN-α1 mRNA by cytoplasmic sense-antisense duplex formation, which may enhance the accessibility of an RNA stabilizer protein or decrease the affinity of an RNA decay factor for the RNA. IFN-α1 asRNA can also act as competing molecules in the competing endogenous (ce)RNA network with other members of the IFNA multigene family mRNAs/asRNAs, and other cellular mRNA transcripts. Furthermore, antisense oligoribonucleotides representing functional domains of IFN-α1 asRNA inhibit influenza virus proliferation in the respiratory tract of virus-infected animals. Thus, these findings support, at least in part, the rationale that dissecting the activity of NAT on gene expression regulation promises to reveal previously unanticipated biology, with potential to provide new therapeutic approaches to diseases.
We previously reported that anticholinergic (AC) drug use increases with age in the elderly Japanese population. In this analysis, we investigated attribution for each AC drug type to total AC burden using different elderly age groups. Prescription records (from 09/23/2015 to 12/31/2016) for outpatients using any AC were extracted from pharmacy claims (primary source) and hospital-based databases. AC burden (number of AC drugs and AC score) and AC type were assessed using the Anticholinergic Cognitive Burden (ACB) scale, Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Beers criteria. Age was categorized using three subgroups (65-74, 75-84, and ≥85 years). Overall, 125426, 140634, 35628, and 23149 of the pharmacy outpatients received ≥1 AC drug from the ACB scale, ADS, ARS, or Beers criteria, respectively. The number of AC drugs increased with age for the ACB scale and ADS groups; but decreased for the ARS and Beers criteria. Antihypertensives provided the biggest contribution to AC score using the ACB scale and ADS, and antihistamines for the ARS. Proportional attribution to AC score typically increased with age for antihypertensives (ADS highest proportion: 34.6% for ≥85 years) and cardiac agents, but decreased for antihistamines (ARS lowest proportion: 15.3% for ≥85 years), corticosteroids, and antiepileptics. Similar findings were typically observed for the hospital database. In conclusion, antihypertensives were the principal type of AC drugs using the ACB scale and ADS and their attribution to AC score increased with age. Antihistamines were the principal drug type for the ARS.
This study investigated attribution of each anticholinergic (AC) drug type to total AC burden in large elderly data in 2015-2016 using Anticholinergic Cognitive Burden (ACB) scale, Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Beers criteria. AC use and burden increased with age with ACB and ADS but decreased with ARS and Beers criteria. Antihypertensives were the most attributable AC in ACB and ADS while antihistamines attributed the most in ARS.
Suspended injectable formulations such as sustained-release luteinizing hormone-releasing hormone (LH-RH) analogue loaded in polylactic acid-glycolic acid copolymer (PLGA) particles have been developed on market. Such formulations have potential issue of suspended particles blocking the injection needle. In this research, two types of injectability tests (gliding force, particles discharge) were developed to evaluate the needle passageability of suspended particles. The model suspension was newly designed using mono-dispersed polyethylene (PE) spheres and qualified dispersing fluid to enhance universality and validity of the test. The suspension-filled syringe, in which three sizes of spheres (L, M, S) were dispersed, was vertically fixed and pushed by auto-compression/tensile tester. The gliding force was continuously detected during testing time and all discharged PE spheres were collected and weighed. The combination of sphere (L, M, S) and injection needle were varied to evaluate the effect of the diameter ratio of sphere against needle hole (D/W) on passageability through needle. These injectability tests revealed that the blockage of a needle hole was occasionally observed when the D/W value increased up to 0.35-0.5, which was detected by jump-up of gliding force and drastic decrease of discharged sphere. In addition, the effect of the formulation properties (concentration of suspended spheres, viscosity of dispersing fluid) and operational factor (injection speed) on injectability was also investigated. The results from this study would be valuable in developing suspended injections and predicting injection trouble at the medical scene.
The widespread use of health foods, including supplements, is now common among patients. This is because many health foods are being claimed to be beneficial. If patients use medicines and health foods concurrently, the interaction between the two might lead to adverse events. Additionally, it is reported that pharmacists do not generally care about health food use in their patients, because they also lack sufficient knowledge about health foods. On the contrary, there are some licenses to be a health food advisor in Japan, and the generic name of these licenses is “advisory staff”. Pharmacists who have this license are specialists in both medicines and health foods, and thus, they might pay more attention to the concurrent use of medicines and health foods compared to those who do not have the advisory staff license. To address this issue, we conducted a study with an online questionnaire about health food consultation, and 87 pharmacists with advisory staff license participated. Only 36.8% of participants were found to always ask their patients about health food use. However, 92.0% of them had experience of consultation about the simultaneous use of medicines and health foods, and 17.2% of them recognized adverse events by knowing about the concurrent use. Patients who experienced adverse events have used either eicosapentaenoic acid/docosahexaenoic acid supplement with epadel or Ginkgo biloba extract with warfarin. Therefore, an active interview with pharmacists is important to avoid such adverse events in patients.
In this study, we evaluated the efficiency of fly ash (FA) recycling technology, produced from a coal-fired power plant, with the capability to adsorb cesium ion[Cs(I)] and strontium ion [Sr(II)] from aqueous phase. Zeolite was produced from FA by hydrothermal treatment in an alkaline solution. Zeolite 12, 24, and 48 have a Garronite structure. Moreover, the specific surface area of Zeolite was greater than that of FA. Zeolite 12 demonstrated the adsorption capability of Cs(I) and Sr(II) from aqueous phase. Adsorption isotherms data fitted both the Langmuir equation (correlation coefficient: >0.895) and the Freundlich equation (correlation coefficient: >0.881). In addition, the kinetic data fitted the pseudo-second-order model when compared to the pseudo-first-order model. Cs(I) and Sr(II) were selectively adsorbed by Zeolite 12 in complex solution system. Our findings indicate that Zeolite can be produced from FA by hydrothermal treatment in an alkaline solution and shows the capability to adsorb Cs(I) and Sr(II) from aqueous phase. Therefore, Zeolite can be useful adsorbent for purification in water environments.
To prevent the abuse of new psychoactive substances (NPS), a total of 2372 substances and two plants are controlled as “Designated Substances” in Japan as of September 2019. Although the distribution of these substances has decreased for the past three years, newly-emerged NPS are still being found. In this study, we detected four lysergic acid diethylamide (LSD) derivatives as designer drugs from four paper sheet products, which were obtained from 2014 to 2017 in Japan. The compounds were identified as 4-Acetyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (ALD-52), N,N,7-triethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (ETH-LAD), 7-Allyl-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (AL-LAD), N,N-diethyl-7-methyl-4-propionyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1P-LSD), by GC-MS, LC-MS, LC-Q-TOF-MS and NMR analyses. Further, we studied the extraction methods of LSD derivatives from paper sheet, and the analytical conditions of GC-MS, LC-MS and LC-FL(fluorescence). Among LSD derivatives, 1P-LSD have been controlled as designated substances (Shitei Yakubutsu) under the Pharmaceutical and Medical Device Act in Japan since April 2016. For the legislation of the other derivatives identified in this study, the evaluation of their pharmacological properties are now in progress.
In the hospital, antibiotics are widely used to treat infections. We report a case of acute kidney injury (AKI) caused by an antibiotic drug combination. A 30-year-old Japanese male presented with lung metastases, pneumothorax, empyema, and methicillin-resistant Staphylococcus aureus (MRSA) infection. The patient received a combination of vancomycin and piperacillin/tazobactam, which resulted in elevated vancomycin trough concentration and subsequently in AKI. Renal function was restored upon vancomycin and piperacillin/tazobactam cessation. Though this patient had AKI most likely due to the combined use of two agents as has been reported in many cases, vancomycin trough concentration showed an unexpected abnormal increase when halting vancomycin treatment. This is the first report indicating a drug-drug interaction between vancomycin and piperacillin/tazobactam with unexpected abnormal vancomycin trough concentration, leading to AKI, additionally we think that there was a situation that he stressed against the kidney by a history of medications caused renal dysfunction and co-administration. We suggest that when using vancomycin in combination with piperacillin/tazobactam, the trough concentration of vancomycin must be confirmed simultaneously with renal function and evaluation, and that the combination of these two drugs should be minimized.