Management of chemotherapy-induced adverse effects and the associated pharmaceutical interventions as well as supportive care evidence creation are the most important responsibilities of oncology pharmacists. We have evaluated the (1) efficacy of long-term and successive pharmaceutical care in outpatient chemotherapy and (2) nephroprotective effects of magnesium (Mg) against cisplatin-induced nephrotoxicity (CIN). The results revealed that the adoption rate of pharmaceutical proposals was 98%, and that approximately 70% of the proposals attenuated painful symptoms. Moreover, approximately 60% of pharmaceutical interventions were established after the third visit; in particular, approximately 20% were suggested after the tenth visit. These results have shown that long-term and successive pharmaceutical care by oncology pharmacists in outpatient chemotherapy contributes to a safe and less onerous chemotherapy implementation. CIN frequency and serum creatinine elevation were significantly attenuated by Mg premedication during the cisplatin, docetaxel, and fluorouracil regimen, without changes in adverse effects and response rate. Mg premedication has been suggested to exert a protective effect against CIN without influencing on adverse effects and anti-tumor efficacy. The nephroprotective effect of Mg against CIN was evaluated using Wistar rats. Cisplatin (2.5 mg/kg) was administered once or three times weekly with or without 40 mg/kg MgSO4. The results revealed that Mg regulates the expression of organic cation transporter 2, multidrug and toxin extrusion protein 1, and copper transporter 1, leading to reduced renal platinum accumulation, which results in CIN attenuation. In conclusion, evaluation of pharmaceutical care and supportive care by oncology pharmacists is necessary for advanced care of cancer patients.
Immune cells such as T cells, macrophages and dendritic cells express various cholinergic system components, including muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs, respectively) and choline acetyltransferase (ChAT), depending on the status of the immune system. The cholinergic system which these components comprise has important effects on the regulation of immune and inflammatory responses. α7 nAChR is a neuronal-type nAChR composed of a homopentamer of the α7 subunit and is characterized by high permeability to Ca2+. It is also expressed in immune cells. For example, α7 nAChRs expressed in B cells suppress IgG production by suppressing B cell maturation into plasma cells. In addition, α7 nAChRs expressed in macrophages suppress production and release of tumor necrosis factor (TNF)-α in a mouse lipopolysaccharide (LPS)-induced sepsis model, thereby protecting the mice from lethal shock. In this review, we summarize the functions of α7 nAChRs expressed in CD4+ helper T (Th) cells and antigen-presenting cells (APCs), such as dendritic cells and macrophages. We focus in particular on their role in Th cell differentiation. α7 nAChRs on APCs interfere with antigen presentation, which leads to suppression of Th cell differentiation. By contrast, α7 nAChRs on naïve Th cells enhance their differentiation. These distinct roles of α7 nAChRs expressed in APCs and Th cells could be useful for development of drugs and therapeutic strategies for the treatment of immune- and inflammation-related diseases and cancers.
M1 macrophages, also known as inflammatory macrophages, play an important role in the innate and adaptative immune responses against pathogens. However, the overactivation of these macrophages leads to the development and progression of various inflammatory diseases. Thus, the regulation of these macrophages is necessary to prevent such diseases. Necroptosis, a programmed form of necrosis, induces several damage-associated molecular patterns, such as high-mobility group box 1, adenosine triphosphate, and mitochondrial DNA, which activate various immune cells, thus leading to inflammation. Recent studies have shown that necroptosis in M1 macrophages is associated with inflammation in many pathological conditions. However, the molecular mechanisms underlying necroptosis in M1 macrophages are not completely understood. Thus, we examined the effects of a broad-spectrum caspase inhibitor, zVAD-fmk, on cell death in lipopolysaccharide (LPS)-induced M1 macrophages. Necrostatin-1, an inhibitor of necroptosis, partially inhibited zVAD-fmk-induced cell death and phosphorylation of mixed lineage kinase domain-like protein (MLKL) in M1 macrophages. Moreover, the inhibition of generation of reactive oxygen species (ROS) and activation of p38 mitogen-activated protein kinase (MAPK) reduced zVAD-fmk-induced necroptosis in M1 macrophages. Furthermore, the inhibition of ROS generation suppressed the activation of MLKL and p38 MAPK in zVAD-fmk-treated M1 macrophages. These results indicate that zVAD-fmk-induced cell death occurs via necroptosis through ROS-mediated activation of MLKL and p38 MAPK in M1 macrophages. Unraveling the molecular mechanisms of necroptosis in M1 macrophages might help understand their significance in inflammatory diseases.
DNA preserves and inherits genetic information. 7,8-dihydro-8-oxoguanine (GO) and abasic sites are some of the most common DNA lesions generated endogenously in living organisms and they induce mutations. The resultant mutations in our DNA cause diseases such as cancers. GO and abasic sites are known to induce mutations at the positions of the lesions. We revealed GO induced mutations at points distant from a lesion besides mutations at the lesion site in human cells when WRN helicase or DNA polymerase λ was knocked down. In addition, an abasic site analog, tetrahydrofuran, also induced the same type of mutations and large deletions. Thus, these endogenous DNA damages could induce more diverse mutations than previously thought. Recently, much research toward the development of gene therapy approaches has been carried out to apply gene therapy in a clinical setting. In this study, we found that the usual plasmid DNA with suitable transcription regulatory sequences achieved durably expressed transgenes in mouse liver. In addition, we successfully improved gene-correction efficiency with tailed duplex DNA fragments by introducing a second mismatch. These results give us important information to apply a transgene expression approach and tailed duplexes in a clinical setting.
A requirement, which students must satisfy, for a diploma at the Showa University School of Pharmacy is the ability to “plan, practice, and assess pharmacotherapy”. To continuously assess the ability of students to meet this requirement and to provide patients with proper pharmacotherapy during student clinical rotations, we formulated the “Rubric assessment for pharmacotherapy” and evaluated its usefulness in tutorial learning classes. Clinical pharmacy faculty members created the rubric based on the Subjective, Objective, Assessment, and Plan (SOAP) note guidelines of the university. Third- (2016) and fourth-year students (2017) were required to self-assess their SOAP notes to analyze six clinical cases using the rubric. The rubric consists of three domains: (1) Evaluation of patient condition, (2) Proposal of pharmacotherapy, and (3) Plan for an assessment of pharmacotherapy. The rubric comprises 31 subdomains and is evaluated according to four levels of performance. In this study, 978 rubric sheets that were used by students to evaluate their own SOAP notes were analyzed. We found that the students were able to continuously self-assess their performance using the rubric while continuously improving their achievement level (p<0.05). The results of this study suggest that rubric assessments may be used as a tool for supporting students to plan, practice, and assess pharmacotherapy.
The authors formulated a “Rubric assessment for pharmacotherapy” to continuously assess students’ ability to perform pharmacotherapy and provide patients with proper pharmacotherapy during student clinical rotations, and evaluated its usefulness. The rubric consists of three domains with 31 subdomains. Students were able to continuously self-assess their performance using the rubric, while continuously improving their achievement level. The rubric assessments may be useful for students to assess and improve their ability to practice pharmacotherapy.
We investigated the success rates of eyedrop instillation and the distance between the cornea and the dropper tip in 100 volunteers using high-speed digital video recording. Past eyedrop adherence studies assumed that instillation occurred without failure. The ideal distance between the cornea and dropper tip remained unclear, although the general estimate was approximately 2.54 cm (1 inch). This study was approved by the Institutional Review Boards of all participating medical institutions, and all volunteers provided written, informed consent. Successful instillation was defined as when 1 drop fell accurately into the eye on the first attempt. The instillation of ≥2 drops or drops delivered outside the eye was considered a failure. The distance between the eye and dropper tip was measured using still images from a paused digital video camera and a digital ruler. Forty percent of the volunteers instilled eyedrops without instructions from ophthalmologists, pharmacists, or other healthcare workers. When the images were analyzed, the success rate of the first instillation was 70.1%. When the eye was arbitrarily divided into 9 sections, most of the drop sites were the iris or the center of the eye. The distance between the dropper tip and cornea was 2.62±1.75 (median 2.20) cm. These results indicate that the generally recommended distance is usually followed. The successful instillation rate based on the distance from the dropper tip to the cornea was 77% at 1.6±0.88 cm and 54.9% at 4.8±1.25 cm.
To decrease the amount of waste biomass and develop a useful application. Coconut fiber (CF) was used to prepare a novel adsorbent to remove methylene blue (MB), which is a recalcitrant organic compound in the water environment. We were able to produce novel adsorbents such as CCF500 and CCF1000 by the calcination treatment of CF. The specific surface area and pore volume of CCF1000 were higher than those of CF or CCF500. Quantity of MB adsorbed was in the order; CCF500<CF<CCF1000 under our experimental condition. Additionally, the specific surface area and pore volume were strongly related to the adsorption of MB (Correlation coefficient: >0.986). The adsorption mechanism of MB using CCF1000 was demonstrated in this study. The intensities of carbon (C), nitrogen (N), and sulfur (S) onto CCF1000 surface increased after adsorption of MB. In addition, the binding energies of nitrogen (1s) at approximately 400 eV and sulfur (2s and 2p) at approximately 165 and 230 eV which were generated after adsorption. Therefore, the adsorption of MB from aquatic solution was strongly involved with the physicochemical properties of CCF1000 surface. Our findings showed that CCF500 and CCF1000 could be produced from CF by calcination treatment, which demonstrates that the amount of waste biomass decreased. In particular, CCF1000 displays the capability to adsorb MB from aquatic solution. These results showed that CCF1000 could be a useful adsorbent for aquatic environment purification.
Benzoyl peroxide (BPO) has been widely used to treat acne vulgaris. Skin flaking, erythema and skin irritation have been observed as side effects of BPO in the treatment of this disorder. In a clinical study, cherry bark-containing jumihaidokuto significantly reduced the erythema induced by BPO application. However, its mechanism of action has not been clarified. In the present study, an application of 10% BPO caused erythema and an increase in interleukin (IL)-1α in the skin of hairless mice, and these changes were significantly suppressed by cherry bark-containing jumihaidokuto at 600 mg/kg. In addition, using a three-dimensional cultured human epidermis model (LabCyte EPI-MODEL), cherry bark-containing jumihaidokuto extract at 250 or 500 μg/mL significantly suppressed IL-1α mRNA expression induced by the application of 0.2 mM BPO. Therefore, cherry bark-containing jumihaidokuto may have suppressed BPO-induced erythema by inhibiting the increase in the IL-1α level in the skin.
Asthma and chronic obstructive pulmonary disease (COPD) are characterised by chronic inflammation in the lung that is associated with airway obstruction. Inhaled therapy with a combination of corticosteroid and a long-acting β2-agonist is an effective anti-inflammatory medicine for asthma, but in patients with severe asthma and COPD fails to completely control these symptoms with current therapies. The inflammatory process in these diseases, which involves activation of the coagulation and fibrinolytic system in the lung, offers the opportunity for alternative anti-inflammatory therapies. In this study, we investigated the effects of anti-coagulants on lipopolysaccharide (LPS)-induced airway inflammation in mice. A/J mice were exposed to LPS, a bacterial endotoxin, intranasally and accumulation of inflammatory cells, TNF-α, C-X-C motif chemokine (CXCL) 1, and osteopontin in bronchoalveolar lavage fluid (BALF) was monitored by flow cytometry and an enzyme-linked immunosorbent assay. LPS exposure induced airway neutrophilia and accumulation of TNF-α, CXCL1, and osteopontin in BALF. This LPS-induced airway inflammation was not relieved using a corticosteroid, fluticasone propionate (FP), or a direct inhibitor of Factor Xa, rivaroxaban. In contrast, a direct thrombin inhibitor, dabigatran, inhibited LPS-induced airway neutrophilia and decreased inflammatory cytokine production in a dose dependent manner. Furthermore, combination of dabigatran and FP elicited stronger inhibition of LPS-induced airway inflammation. Therefore, these results suggest that dabigatran could be an effective new therapy for severe respiratory diseases.
In Japan, the use of methanol, trichloroethylene, and tetrachloroethylene in aerosol household products is banned under the Act on the Control of Household Products Containing Harmful Substances. As the official analytical methods for testing for these substances have not been revised for over 35 years, several issues have been pointed out. Thus, we developed a new method to revise the official method in our previous study. In this study, validation of the proposed method for detecting the target substances was conducted using two aerosol-product samples (A and B), which contained methanol, trichloroethylene, and tetrachloroethylene. Sample A comprised regulated values of these compounds, while sample B comprised one-tenth of the regulated amounts. They also contained several volatile compounds that served as interfering substances. Subsequently, the samples were analyzed using head space/gas chromatography-mass spectrometry, and it was confirmed that the three target substances were separated from the other chemicals on chromatograms. Validation tests were conducted at seven laboratories to evaluate the proposed method using the prepared samples. In one laboratory, the recovery of trichloroethylene and tetrachloroethylene in sample B was slightly higher at 120%, while the recoveries obtained from the other tests were between 70% and 120%. Relative standard deviation at each laboratory was less than 10%. Furthermore, the relative standard deviations between the validation tests with respect to each chemical were less than 15%. Therefore, the method validated in this study was considered to be effective as a revised method for testing for methanol, trichloroethylene, and trichloroethylene in household aerosol products.
Achieving appropriate inhalation in patients with coronavirus disease 2019 (COVID-19) is a common challenge in the use of repurposed metered-dose inhaler (MDI) formulations. The purpose of this study was to evaluate the effect of five valved holding chambers (VHCs) on the inhalation of ciclesonide from Alvesco MDI. The aerodynamic particle size distribution of ciclesonide discharged from Alvesco MDI was evaluated using a Next Generation Impactor in the presence and absence of VHCs. The use of VHCs retained or slightly increased the amount of ciclesonide in the fine particle diameter range (aerodynamic particle size below 3 μm) (FPD) and reduced the amount at the induction port after coordinated inhalation. However, the use of VHC reduced the FPD of the formulation by increasing the time between the MDI discharge and the pump suction by various degrees among the five VHCs. These results indicated that use of the VHCs and minimizing the inhalation delay time should ensure sufficient inhalation of ciclesonide particles.
In Japan, mitragynine, 7-hydroxymitragynine and Mitragyna speciosa Korth. (M. speciosa, “Kratom”) were controlled as Designated Substances under the Pharmaceutical and Medical Device Act from March 2016. In this study, the origins of 16 Kratom products obtained from the illegal drug market in Japan were investigated by DNA analyses and LC-MS analyses. When the PCR-restriction fragment length polymorphism (RFLP) was performed using the restriction enzyme XmaI (as reported by Sukrong et al. to be able to distinguish M. speciosa), the same DNA fragment patterns were obtained from all 16 products. On the other hand, as a result of the identification of the plant species of each product by nucleotide sequence analyses, the sequences of M. speciosa were detected in only 14 products. Despite the facts that mitragynine and 7-hydroxymitragynine were detected also in the other two products by the LC-MS analyses, M. speciosa DNAs were not amplified from these products by the PCR. Moreover, the DNA amplicons of the other psychotropic plant (Mesembryanthemum sp., e.g. “Kanna”) were detected. This plant PCR amplicon has the restriction site for the XmaI at the same position of the M. speciosa PCR amplicon and it is difficult to distinguish “Kratom” and “Kanna” by the conventional PCR-RFLP. When the restriction enzyme XhoI was used simultaneously with the Xmal, the specific DNA fragment was only observed from the M. speciosa amplicon and it was possible to distinguish both species using this improved PCR-RFLP method. This method is useful to identify the origin of Kratom products distributed in the illegal drug market.