The term “theranostics” is a compound word combining “therapeutics” and “diagnostics”. Discovery of the X-ray made an extraordinary contribution to the field of medical science. Development of computer science after World War II has been absolutely imperative for the development of medical imaging technology to date. The invention of X-ray computed tomography (CT) has revolutionized medical image diagnostic systems. Several functional imaging modalities emerged not only in the radiological field but also in magnetic resonance and ultrasonic fields. The fusion of three digital imaging techniques, MR Redox imaging, electron paramagnetic resonance (EPR) oxygen mapping, and hyperpolarized 13C MRI techniques in the magnetic resonance field, contribute to the newly-termed theranostics. Future development of a suitable contrast agent for each imaging modality will be a key for the success of theranositics.
Oxidative stress contributes to the development of diabetic complications. Increasing epidemiologic evidence suggests that diabetes mellitus is associated with dementia and cognitive decline. However, the underlying mechanisms are not fully understood. We have evaluated brain redox status and its association of cognitive dysfunction in diabetic animal models by dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) and other oxidative stress markers. In this review, we discuss the role of oxidative stress in the development of diabetes-related dementia and clinical regulation of the redox state in new approaches to augmenting diabetes-related dementia.
The advent of functional contrast agents and nanoparticle drug delivery systems (nano-DDS) is opening new pathways to understanding pathophysiology using magnetic resonance imaging (MRI). Nitroxyl radical compounds are promising functional contrast agents for redox evaluation. We have developed a novel nitroxyl radical theranostic compound for noninvasive real-time imaging of blood-brain barrier-permeable antitumor drugs. Divalent manganese ions (Mn2+) can also be used as an intracellular functional MRI contrast agent. Manganese-enhanced MRI (MEMRI) provides a unique opportunity to study neuronal activation and architecture. Extracellular Mn2+ can enter cells through NMDA receptors for glutamate and/or voltage-gated calcium channels. Thus, Mn2+ can behave as a functional contrast agent depending on the cellular activity/viability. This paper summarizes the recent progress in MEMRI for neuroimaging and cancer research. Nanocarriers for DDS can contain multiple functional elements, such as therapeutic drugs, MRI contrast agents, fluorescent dyes, and radioisotopes, without significant changes in the particle kinetics/dynamics. Various materials have also been reported as nano-DDS carriers, including micelles, liposomes, dendrimers, quantum dots, and carbon materials such as fullerenes, with each material providing a different set of characteristics as a nano-DDS carrier. Our recent research into nano-DDS-based contrast agents and the theranostic applications is also outlined.
Lipid derived radicals and their metabolic products are closely involved in the pathogenesis of oxidative stress diseases, such as inflammation and angiogenesis, through the formation of a protein or DNA complex. The starting point of lipid peroxide generation is lipid-derived radicals, which increase explosively via radical chain reaction. Therefore, the trapping of lipid-derived radicals is useful in understanding the mechanism of the formation of oxidative stress diseases, and in suppressing the following chain reaction. On the other hand, nitroxides with a stable unpaired electron allow for spin trapping with carbon-centered radicals. Hence, we focused on the following points to develop lipid radical detection methods. 1) Fluorescence will be quenched through interaction with nitroxide's unpaired electron. 2) Nitroxide can react with lipid-derived radicals via radical-radical reaction. 3) Fluorescence will recover from the loss of an unpaired electron in nitroxide, after reaction with the lipid-derived radicals, by using a profluorescent nitroxide. In this paper, I will discuss the development of a lipid-derived detection method using profluorescent nitroxide switching methods, and discuss its application to cell imaging.
Tumors develop a characteristic microenvironment depending on their specific genetic mutations. The direct products of mutant genes and the resulting microenvironmental changes provoke metabolic changes in the tumor. If noninvasive imaging techniques including magnetic resonance imaging (MRI) could be used to detect such microenvironmental and metabolic changes in tumors, we might be able to provide more effective treatment strategies for individual tumors in patients. In addition to conventional imaging techniques, this review article introduces quantitative 3D oxygen imaging using electron paramagnetic resonance imaging (EPRI) and hyperpolarized 13C metabolic MRI and shows how these imaging techniques can help to monitor and predict tumor response to various treatments including radiation therapy and antiangiogenic agents. Hyperpolarization is a method for enhancing the MRI signal of 13C in a molecule by 10000-fold, which makes it possible to trace the metabolic reaction of externally administered molecules in the body noninvasively. For example, a precise cancer diagnosis can be made in a 3-min scan with a [1-13C] pyruvate as a metabolic tracer. The first clinical trial on the use of hyperpolarized 13C MRI in patients with prostate cancer was conducted at the University of California San Francisco (UCSF), and we plan to start the second clinical trial on this technique in the near future.
Redox metabolism plays a central role in maintaining homeostasis in living organisms. The electron transfer system in mitochondria produces ATP via endogenous redox molecules such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), and coenzyme Q10 (CoQ10), which have flavin or quinone moieties. One-electron transfer reactions convert FMN, FAD, and CoQ10 to the free radical intermediates FMNH and FADH, and CoQ10H, respectively. Dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) allows us to visualize free radicals in vitro and in vivo. We present a spectroscopic imaging technology with DNP-MRI, which enables the imaging of multiple free radical intermediates such as FADH and CoQH. DNP-MRI can also identify various endogenous free radical intermediates derived from redox transformations.
The mortality associated with end stage heart failure (HF) is high, despite the development of new and increasingly effective drugs and non-pharmacological therapies. Repetitive hospitalizations predict fatal outcomes, and each hospitalization should prompt individual conversations with the patient, the family and the caregivers. A multidisciplinary disease management program promotes the education of patients and their families, and modifies their behaviour, with a view to ultimately improving the prognosis and quality of life. Beginning with the earliest stages of HF, on through the late stages, a multidisciplinary disease management program should be implemented.
Inpatients with heart failure take a number of high-risk drugs such as anti-thrombotic and anti-arrhythmic drugs, in addition to other drug types, including diuretics and cardioprotective agents. Pharmacists should support the pharmacological management of these patients by evaluating their clinical condition and laboratory data, due to the frequency of renal failure. Furthermore, it is known that poor adherence to a drug regimen is one of the aggravating factors for heart failure. It is necessary to conduct regular patient education to facilitate early hospital discharge and to prevent the recurrence of heart failure. In Chiba University Hospital, a single pharmacist is in charge of both the cardiac care unit (CCU) and the cardiovascular ward. In the course of a patient's hospital stay, from admission to discharge, the pharmacist performs various duties such as evaluating and proposing a medication plan after checking the patient's regular medications, conducting patient education, promoting appropriate prescriptions, overseeing the preparation of injection drugs, and providing drug information to medical staff. There are many cases in which avoidance of drug interactions or overdose, in order to prevent renal failure, is needed. Thus, pharmacists play important roles in the management of patients with heart failure by ensuring the efficacy and safety of each patient's drug therapy.
Hyogo Prefectural Amagasaki General Medical Center has formed a heart failure team. Here, I report on the role of the pharmacist in this heart failure team at this hospital. Patient education is one of the roles of the pharmacist. It is the pharmacist's responsibility to improve medication adherence among patients. For this purpose, the pharmacist uses a brochure created by the heart failure team. The brochure outlines drug information in an easy-to-understand manner. The roles of a pharmacist were addressed in a lecture presented to the heart failure team. These lectures helped improve the pharmaceutical knowledge of the team, allowing the team to prescribe medicines more safely and appropriately. Maintaining co-operation between hospital and community pharmacies is another important role of a hospital pharmacist. This allows patients to be properly educated by pharmacists even after discharge from the hospital.
Some patients of advanced age with heart failure (HF) require repeated hospital care. In an aging society, the importance of medical and social care support systems for patients with HF further increases. In Onomichi-city, a comprehensive community care system has been in place since its introduction in 1997. The system is called “Onomichi Type”. This is an interprofessional care system in which a variety of healthcare professionals, with common basic knowledge of disease prevention, treatment and welfare, collaborate with other care professionals. These professionals gain shared knowledge in regard to care management, and fulfill their respective roles at Care Conferences held during a patient's hospital stay. Elderly patients also often have multiple comorbidities and take a lot of medicines. Some patients might forget to take their medicine, whereas others might take an overdose. Thus, sharing a patient's complete medical information with pharmacists is also necessary. We began to collaborate with pharmacists in hospitals and at pharmacies in 2014. The pharmacist plays a great role in providing comprehensive community medical care.
As heart failure progresses to the end stage, it becomes more difficult to maintain the same level of quality of life using the established therapy for the heart failure patients. We believe that an innovative home medical care for heart failure therapy that focuses on the individual's quality of daily living and early intervention is necessary. The roles of home medical care include: early discharge to home as opposed to long hospitalization; the prevention of re-hospitalization; the provision of good care; treatment of any exacerbations; and options available at the end of the patient's life at home. Being able to provide all of the above will allow heart failure patients to live at their home. Home medical care for heart failure requires collaborative teamwork among multiple institutions and medical professionals. Among this collaborative group, the role of pharmacists is critical. Since many of the elderly with heart failure are taking multiple medications, it is important to evaluate the compliance and to intervene for improvement. Pharmacists visiting the patient's home will be able to check the patient's living environment, to evaluate medication compliance, to reconsider the necessary medications for the specific patient, and to consult physicians. Pharmacists can also explain clearly to patients and their family members any changes in medical therapy, as the conditions for an end-stage heart failure patient may change drastically in a short time. By achieving all of the above, it may be possible to prevent re-hospitalization and to help maintain the quality of life for heart failure patients.
The pharmacist's role in home care is increasingly important. We are required to collaborate with multiple other professions. As home care pharmaceutical managers, pharmacists verify the timeline of side effects and the onset of expected effects. It is also important to verify all prescriptions from the pharmaceutical viewpoint, and to point out potential negative interactions or consequences of each prescribed medication, suggesting changes or dosage reduction in drugs as appropriate. Additionally, we verify the cause of unused drugs (i.e. patient non-compliance) and take action. As an effort to provide quality home care, pharmacists share information with other professions for collaborative management of a patient's needs. We act as a bridge between related government, agencies and citizens, assisting in creating a healthy lifestyle for the residents of our community. The days when pharmacists just sit in their pharmacies and dispense drugs are gone. Therefore, we need to collaborate more with medical, nursing care, and governmental professionals in our communities.
Vitamin K is a cofactor for γ-glutamyl carboxylase, which catalyzes the posttranslational conversion of specific glutamyl residues to γ-carboxyglutamyl residues in a variety of vitamin K-dependent proteins (VKDPs) involved in blood coagulation, bone and cartilage metabolism, signal transduction, and cell proliferation. Despite the great advances in the genetic, structural, and functional studies of VKDPs as well as the enzymes identified as part of the vitamin K cycle which enable it to be repeatedly recycled within the cells, little is known of the identity and roles of key regulators of vitamin K metabolism in mammals and humans. This review focuses on new insights into the molecular mechanisms underlying the intestinal absorption and in vivo tissue conversion of vitamin K1 to menaquinone-4 (MK-4) with special emphasis on two major advances in the studies of intestinal vitamin K transporters in enterocytes and a tissue MK-4 biosynthetic enzyme UbiA prenyltransferase domain-containing protein 1 (UBIAD1), which participates in the in vivo conversion of a fraction of dietary vitamin K1 to MK-4 in mammals and humans, although it remains uncertain whether UBIAD1 functions as a key regulator of intracellular cholesterol metabolism, bladder and prostate tumor cell progression, vascular integrity, and protection from oxidative stress.
Oleaginous white petrolatum ointment (WP ointment) is one of the most commonly used dosage forms in the preparation of topical products. In general, WP ointments containing medium chain fatty acid triglycerides (MCT) are manufactured through a process of melting, mixing, agitating, and cooling. To investigate the pharmaceutical properties of WP ointments in greater detail, we examined manufacturing factors which could potentially influence the pharmaceutical properties of the finished product. WP ointment samples containing 10% MCT were stirred with a homogenizer and a paddle mixer at 65°C, then the homogenizer was stopped. Next, the paddle-mixer was stopped at several planned temperature points at which different samples were taken. Each sample was then cooled under the following planned conditions: rapid-cooling [−50°C/h] and slow-cooling [−7.5°C/h]. The pharmaceutical properties of each WP ointment sample, along with the appearance (Optical/digital microscope), hardness (Rheometer), and bleeding ability (100 Mesh wire-net cone) were measured. Then, release profiles were performed with a WP ointment using the model active ingredient Vitamin D. As a result, high hardness, low bleeding ability and low release profile were observed in the WP ointment samples that were manufactured under the condition of stopping the paddle-mixer at 40°C. However, the influence of cooling speed was observed to affect only hardness. Through optical microscopic observation, it was found that the appearance of WP ointment samples differed depending on the conditions under which they were manufactured. In this study, it was clear that the pharmaceutical properties of WP ointment samples were particularly influenced by the paddle-mixer stopping temperature.
The aim of this study was to examine the effects of food thickeners on the pharmacodynamics of voglibose, an α-glucosidase inhibitor. The pharmacodynamics of voglibose were examined in an open-label study in 9 healthy participants after the ingestion of a single oral dose of a voglibose oral-disintegrating tablet, with and without food thickener immersion. The area under the incremental blood sugar concentration-time curve was larger and the rate of increments in the blood sugar concentration was higher with the voglibose oral-disintegrating tablets immersed in the food thickener than with the tablets that were not immersed. Immersing the voglibose oral-disintegrating tablets in the food thickener possibly delayed their disintegration rate. This suggests that commercially available food thickeners may be associated with changes in the disintegration of voglibose oral-disintegrating tablets and should therefore be used carefully in certain clinical situations.
When the kidney is seriously impaired, various uremic toxins (UTs) accumulate in the body, often exerting unfavorable effects on physiological functions and drug pharmacokinetics. To prevent this, it is important to determine plasma UT levels accurately in chronic kidney disease patients. Although attempts to predict plasma UT levels using biomarkers have been made, the correlation between UT levels and the markers is not yet fully understood. In this study, we assessed the correlations among plasma levels of indoxyl sulfate (IS), indoleacetic acid (IA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) in 20 hemodialysis patients and evaluated the relationship between the plasma levels of UTs and clinical parameters, such as serum creatinine (Scr), blood urea nitrogen, and estimated glomerular filtration rate (eGFR), with special focus on IS. There were no correlations among the plasma levels of the three UTs before and immediately after hemodialysis. However, a significant correlation was observed between plasma IS levels and Scr before hemodialysis (r=0.643, p=0.002), with the correlation becoming much stronger when using the data obtained immediately after hemodialysis (r=0.744, p<0.001). Further, plasma IS levels showed a significant negative correlation with eGFR (r=−0.558, p=0.011). However, no correlations were observed for IA or CMPF. The results obtained from this study suggest that plasma IS levels can be predicted from Scr values, although the precise mechanism behind the correlation remains to be clarified.
It has been 6 years since the establishment of the position of “sports pharmacist” as one type of pharmacist. In the sporting world of Japan, sports pharmacists are expected to promote athletes' awareness of antidoping regulations and provide them with relevant education. However, currently, these pharmacists' main duty is to provide athletes and their coaches with guidance on medication. Using a model for the prediction of athletes' actions, we have worked to promote athletes' awareness of antidoping regulations and encourage sports pharmacists to perform relevant activities, such as antidoping education. As a result, we clarified that athletes' awareness regarding antidoping rules influences their actions when experiencing minor illnesses. In addition, we have proposed approaches to encourage athletes to undertake antidoping activities. The present study aimed to clarify competitive sports coaches' awareness of antidoping regulations, the instructions that those coaches give athletes when they experience minor illnesses, and coaches' awareness of athletes' usage of drugs and supplements. Analysis using a model for the prediction of actions revealed that to promote coaches' awareness of antidoping regulations, education aimed at raising their level of knowledge of doping is warranted. Furthermore, coaches were aware of the necessity of continuously providing athletes with antidoping instructions, but they did not keep sufficient track of athletes' usage of drugs and supplements. To encourage sports coaches to perform antidoping activities, it is effective to provide them with opportunities to develop their knowledge of doping prevention in their areas.