In the present study, the effects of cooling (to 28°C) on the vasodilatation induced by diazoxide (10−9−3×10−4 M), isoproterenol (10−9−3×10−4 M) and magnesium sulphate (0.1-30 mM) on serotonin-pre-contracted human umbilical artery and the role of nitric oxide in these effects were analyzed. Diazoxide, isoproterenol and magnesium produced concentration-dependent relaxation of human umbilical artery precontracted with serotonin (10−6 M). During cooling, the pIC50 values and maximal responses to these agents were significantly lower than at 37°C. Cooling to 28°C in the presence of NG-nitro-L-arginine methyl ester (L-NAME, 10−4 M) did not modify the effects of temperature on diazoxide, isoproterenol and magnesium-induced relaxations. These results suggest that cooling-induced changes of diazoxide, isoproterenol, and magnesium sulphate in human umbilical artery are independent of nitric oxide.
Many factors contribute to the onset of insomnia. However, few studies have identified the factors related to the onset of insomnia in hypertensive patients. We conducted a pharmacoepidemiologic study to examine the incidence of insomnia in hypertensive patients by using a post-marketing surveillance database. The insomnia onset was defined as the time of first prescription of hypnotics. The insomnia incidence rate in hypertensive patients under antihypertensive therapy was 0.77/100 person-years. The median insomnia onset date was 5 weeks. The insomnia type in 50.2% of the patients was difficulty in initiating sleep. We assessed the factors contributing to insomnia by using a nested case-control design. We selected 10 time-matched controls for every case. The hypotensive effect induced by antihypertensive therapy on the case group was lesser than that on the control group (p<0.01). The odds ratios (ORs) were estimated using multivariate conditional logistic regression. The factors contributing to insomnia onset were α blockers (OR, 2.38; 95% confidence interval [CI], 1.14-4.98), β blockers (OR, 1.54; 95% CI, 0.99-2.39), and calcium channel blockers (OR, 0.62; 95% CI, 0.43-0.90) compared with angiotensin-converting enzyme inhibitors; female sex (OR, 1.76; 95% CI, 1.27-2.44); complication of gastric/duodenal disorders (OR, 2.35; 95% CI, 1.14-4.86) or musculoskeletal system/connective tissue disorders (OR, 2.43; 95% CI, 1.23-4.79); and concomitant antihypertensive therapy (OR, 0.44; 95% CI, 0.31-0.63). This study identified the potential factors that may help to predict insomnia onset in hypertensive patients under antihypertensive therapy.
Furanocoumarins (FCs) such as bergamottin (BG) and 6′,7′-dihydroxybergamottin (DHBG) contained in grapefruits are known to be cytochrome P450 3A4 (CYP3A4) inhibitors. These are contained in larger quantity in peel than in pulp, and therefore, processed peel products possibly have strong CYP3A4 inhibitory activity. The CYP3A4 inhibitory potency of these processed peel products, however, remains to be elucidated. The FC content and CYP3A inhibitory activities of various processed fruit peel products were investigated. CYP3A inhibitory activities of crystallized grapefruit peel, grapefruit marmalade, lemon peel and bitter orange slice were close to that of 100% grapefruit juice, while the activities of yuzu slice, pomelo (buntan) marmalade and crystallized iyokan peel were very weak, 1/8-1/20 of 100% grapefruit juice. The maximum BG content was 5.6 μg/g in lemon peel. The maximum DHBG content was 7.2 μg/g in crystallized grapefruit peel, about 1/30 that of raw peel. Grapefruit marmalade and crystallized grapefruit peel contained similar amounts of FCs to 100% grapefruit juice, but FCs were not detected in pomelo (buntan) marmalade or crystallized iyokan peel. Good correlation (r=0.78) was observed between the FC contents of these peel products and those CYP3A inhibitory activities. Preparation of homemade grapefruit marmalade and crystallized peel revealed that considerably lower DHBG content in these products and lower CYP3A inhibitory activity than anticipated were attributable to outflow of DHBG to broth during boiling of the raw peel.
In this study, we investigated the status of researching drug information online, and the type of Internet user who uses anonymous Web communities and websites. A Web-based cross-sectional survey of 10875 male and female Internet users aged 16 and over was conducted in March 2010. Of 10282 analyzed respondents, excluding medical professionals, about 47% reported that they had previously searched the Internet for drug information and had used online resources ranging from drug information search engines and pharmaceutical industry websites to social networking sites and Twitter. Respondents who had researched drug information online (n=4861) were analyzed by two multivariable logistic regressions. In Model 1, the use of anonymous websites associated with age (OR, 0.778; 95% CI, 0.742-0.816), referring to the reputation and the narrative of other Internet users on shopping (OR, 1.640; 95% CI, 1.450-1.855), taking a prescription drug (OR, 0.806; 95% CI, 0.705-0.922), and frequent consulting with non-professionals about medical care and health (OR, 1.613; 95% CI, 1.396-1.865). In Model 2, use of only anonymous websites was associated with age (OR, 0.753; 95% CI, 0.705-0.805), using the Internet daily (OR, 0.611; 95% CI, 0.462-0.808), taking a prescription drug (OR, 0.614; 95% CI, 0.505-0.747), and experience a side effect (OR, 0.526; 95% CI, 0.421-0.658). The analysis revealed the profiles of Internet users who researched drug information on social media sites where the information providers are anonymous and do not necessarily have adequate knowledge of medicine and online information literacy.
Enteric microspheres formulations of papain were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP), Eudragit L 100 and Eudragit S 100, to avoid gastric inactivation of papain. Smaller internal and external aqueous phase volume provided maximum encapsulation efficiency (74.49-79.76%), least particle size (52.4-60.2 μm) and 21-26% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastro-resistance of formulations. The anionic microspheres, zeta potential between −18.21 and −20.06 mV, aggregated in 0.1 N HCl (i.e., gastric pH 1.2), due to protonation of carboxylic groups of enteric polymer and loss of surface charge with subsequent change in zeta potential. The aggregates being <500 μm size would not impede gastric emptying. However, at pH>5.0 (duodenal pH) the microspheres showed de-aggregation due to restoration of surface charge. HPMCP and Eudragit L 100 microspheres facilitated almost complete release of papain within an hour at pH 6.0 and 6.8, respectively while Eudragit S 100 microspheres released 84.56% papain at pH 7.4, following Higuchi kinetics. FTIR spectroscopy revealed entrapment of enzyme; PXRD & DSC indicated amorphous character and SEM showed spherical shape of microspheres. In simulated gastro-intestinal pH condition, HPMCP, Eudragit L 100 and Eudragit S 100 microspheres showed good digestion of paneer and milk protein. Thus, enteric microspheres formulations could serve as potential carrier for oral enzyme delivery. Stability studies indicated the formulations with around 5% overage would ensure 2 years shelf life at room temperature.
A spray freeze drying (SFD) method, using a spray nozzle, liquid N2 and a lyophilizer, was developed to prepare composite particles of a poorly water-soluble drug. The resultant particles were found to have a porous structure. The purpose of the present research was to prepare a sustained release formulation using the SFD technique. Tolbutamide (TBM)and Eudragit S were used as model drugs and pH-dependent carrier, respectively. Eudragit S is a polymer that is soluble at or above pH 7.0. Morphological evaluation of the composite particles revealed that they had a porous structure with a significantly larger specific surface area than bulk TBM. The physicochemical properties of the particles were found to be dependent on the drug to carrier ratio, with the crystallinity of the TBM decreasing as the proportion of Eudragit S increased. Dissolution tests in solutions of pH 1.2 and pH 6.8 showed that the release profiles of TBM from the SFD composite particles were improved compared to bulk TBM, through the use of the pH-dependent carrier. On the other hand, following compression of the composite particles, sustained release was observed in a solution of pH 6.8, whereas almost no dissolution occurred in a solution of pH 1.2.
A simple and low-cost HPLC method with UV absorbance detection was developed and validated to simultaneously determine strychnine and brucine, the most abundant alkaloids in the processed Semen Strychni, in rat tissues (kidney, liver, spleen, lung, heart, stomach, small intestine, brain and plasma). The tissue samples were treated with a simple liquid-liquid extraction prior to HPLC. The LOQs were in the range of 0.039∼0.050 μg/ml for different tissue or plasma samples. The extraction recoveries varied from 71.63 to 98.79%. The linear range was 0.05-2 μg/ml with correlation coefficient of over 0.991. The intra- and inter-day precision was less than 15%. Then the method was used to measure the tissue distribution of strychnine and brucine after intravenous administration of 1 mg/kg crude alkaloids fraction (CAF) extracted from the processed Semen Strychni. The results revealed that strychnine and brucine possessed similar tissue distribution characterization. The highest level was observed in kidney, while the lowest level was found in brain. It was indicated that kidney might be the primary excretion organ of prototype strychnine and brucine. It was also deduced that strychnine and brucine had difficulty in crossing the blood-brain barrier. Furthermore, no long-term accumulation of strychnine and brucine was found in rat tissues.
Long-term treatment with minocycline is known to induce pigmentation or discoloration in tissues but how remains unclear. We investigated the mechanism of pigmentation using B16 melanoma cells. First, we confirmed that intracellular melanin levels increased on minocycline treatment. Then, using the reverse transcriptase-polymerase chain reaction (RT-PCR), we found the expression of mRNA of tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2, to also be significantly increased by treatment with minocycline at 5 μg/ml for 72 h. These results suggest that the minocycline-induced stimulation of melanogenesis occurs at the transcriptional level. Western-blotting revealed slight phosphorylation of extracellular signal-regulated kinase (ERK) 30-60 min after the minocycline treatment. The mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor U0126 and the p38 inhibitor SB203580 were used to examine the signaling pathway associated with the mRNA expression of tyrosinase, TRP-1, or TRP-2 when B16 melanoma cells were treated with minocycline. The SB203580 inhibited the mRNA expression of tyrosinase and TRP-1, suggesting the minocycline-induced melanogensis occurred via a p38 signaling pathway.
The aim of this study was to ascertain the effects of α-lipoic acid (ALA) treatment on relaxant responses of acetylcholine (ACh) and isoprenaline (ISO) in aortic rings precontracted with serotonin (5-HT, 10−6 M) obtained from streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in the rats by 50 mg/kg streptozotocin (STZ) via an intraperitoneal injection. Rat body and aorta weights were measured. The isometric tension to ACh (10−9-3×10−6 M) and ISO (10−9-10−4 M) of 5-HT-precontracted diabetic and non-diabetic rat (control), diabetic-ALA-treated, and ALA-treated aortas, in organ baths were recorded. Six weeks after STZ treatment blood glucose was elevated compared to control rats. In aortic rings from diabetic rats ACh and ISO-induced relaxations were impaired whereas endothelium-independent relaxation to sodium nitroprusside (SNP) was unaffected. ALA (100 mg/kg/day) treatment for 5 weeks enhanced ACh and ISO-induced relaxation in diabetic aortas. This recovering effect was via NO because prevented by incubating the vessels with NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). It may be assumed that ALA treatment in vivo, can protect against impaired vascular responsiveness in STZ-induced diabetic rats.
Reports have indicated a relationship between adverse drug reaction (ADR) and Human Leukocyte Antigen (HLA) polymorphism and a relationship between Body Constitution (BC) and HLA polymorphism. Thus, a relationship between ADR and BC is suggested. We therefore created a questionnaire (hereinafter “Questionnaire”) to survey the typical BC of Stevens-Johnson Syndrome (SJS) patients to determine how they differ from healthy persons, and studied the relationship between the development of SJS and BC. The Questionnaire had 30 typical items selected from those relevant to the BC necessary for the diagnosis and therapy of Sho-syndrome in Kampo Medicine. In the comparison of the prevalence of BCs between SJS patients and control persons, the prevalence of three BCs in the SJS group was significantly higher than that in the control group: 1) Does your throat ever feel closed up? Answer: Yes, 2) Do you easily feel hot flashes or burning cheeks even though your hands and feet feel cold? Answer: Yes, and 3) Do your lips or gums look dull red? Answer: Yes. In the analysis using the decision tree, the concentrated group of SJS patients (eightyfold) was extracted using two decision trees consisting of 3 index variables. Persons with BCs from any of 1) to 3) are suggested to be at high risk of developing SJS.
To realize regenerative medicine, it is very important to eliminate the transformed stem cells selectively included in iPS cells, ES cells and adult stem cells derived from organs, because the transformed stem cells have a risk of tumorigenesis after the cell transplantation. Ueoka et al., have developed hybrid liposomes (HL) which selectively accumulated to membranes of tumor cells and have high inhibitory effects on the growth of tumor cells along with the induction of apoptosis. Therefore, we have investigated the application of HL23 (DMPC/10 mol%C12(EO)23) to the selective elimination of transformed stem cells using hepatoblast, which we could induce from human fetal hepatocytes by the treatment of 1 mM sodium butyrate for 8 days. During the induction process, the transformed cells appeared and produced abnormal prothrombin (PIVKA-II), which is a clinical marker for hepatoma, and also formed colonies in soft agar plate, which is a criteria for neoplastic cell transformation. On the other hand, by the treatment with 0.33 mM HL23 for 96 h during the induction process, PIVKA-II production rate of the cells and colonies formed in the soft agar plate also remarkably decreased less than those of the normal cells. Furthermore, the population of hepatoblasts in the remaining cells increased about four times. These results suggest that the transformed hepatic stem cells could be selectively eliminated by the treatment of HL23, and HL treatment of the stem cells would be a useful culture method for quality control of the stem cells to reduce a risk of tumorigenesis after the cell transplantation.
We reported previously that spline interpolation is effective as a pretreatment before analyzing clinical data by time series. However, further improvement is required to understand the detailed tendency of clinical data. In this study, the tendency of interpolated hematological data was investigated in the period between the most tolerated dose (MTD) and low-dose chemotherapy (LDC) for colorectal cancer. All patients were received both MTD and LDC. Hematological data, white blood cell count (WBC), red blood cell count (RBC) and mean corpuscular volume (MCV), were interpolated. The accuracy of interpolation was verified using leave-one-out cross-validation. The difference, Δi, was calculated from interpolated data and exhibited as a function of time. The predictions of RBC and MCV were accurate with high correlation coefficients, although the interpolation of WBC data was inaccurate. A marked difference was observed in the trend of Δi between LDC and MTD periods. SD-RBC showed significant differences between LDC and MTD periods. The SD-MCV average in the LDC period was larger than in the MTD period. SD-MCV showed no significant difference. An attractor plot of Δi in RBC clarified the tendency of the interpolated RBC data. There is a possibility that Δi of RBC and/or SD-RBC may contribute to monitoring adverse reactions and decision of medication. Moreover, it is also useful to check on attractor plot of Δi in RBC together with SD-RBC in order to find out untoward reactions and decision of medication.
Accumulation of β amyloid (Aβ) peptides to nerve cells should be associated with the onset of Alzheimer's disease (AD). We prepared hybrid liposomes (HL) composed of 90 mol% phospholipids having various charged head groups (cationic L-α-dimyristoyltrimethyl ammonium propane (DMTAP), anionic L-α-dimyristoylphosphatidylserine (DMPS) or zwitterionic L-α-dimyristoylphosphatidylcholine (DMPC)) and 10 mol% polyoxyethylene(23) dodecyl ether (C12(EO)23)), and investigated the inhibitory effects of HL on the accumulation of Aβ1-40 peptides into human neuroblastoma (SH-SY5Y) cells in vitro. It is noteworthy that remarkable inhibitory effects on the accumulation of Aβ1-40 peptides were observed for SH-SY5Y cells treated with anionic HL-DMPS, though the accumulation was not inhibited by cationic HL-DMTAP. On the other hand, the immediate fusion of HL-DMTAP into SH-SY5Y cells was confirmed using a confocal laser microscope. Interestingly, the specific interactions between anionic HL-DMPS and Aβ1-40 peptides were observed using the thioflavin T (ThT) assay. In addition, the cytotoxicity of Aβ1-42 peptides on the SH-SY5Y cells decreased after the treatment with HL-DMPS. These results suggest that anionic HL-DMPS could be used as a novel medicine for AD in the future.
The revised Pharmaceutical Affairs Act that came into force in June 2009 prohibits the sales of nonprescription drugs by mail. However, as a provisional measure, regular users and inhabitants of remote islands that do not have pharmacies or drug stores would be able to purchase nonprescription drugs by mail for two years. However, this regulation is now being discussed from the perspectives of safety and convenience. The purpose of this study was to conduct a survey on the purchasing of nonprescription drugs over the Internet by inhabitants of remote islands belonging to Goto City in Nagasaki prefecture. The results showed that approximately 78.0% of the Internet-literate respondents living on large islands (with pharmacies, drug stores, and pharmacists, e.g., Fukue-shima), 65.4% of the Internet-literate respond- ents living on small islands scattered around large islands (where pharmacies, drug stores, and pharmacists are not located, e.g., Mae-shima) had purchased necessities except nonprescription drugs, but the rate of purchasing nonprescription drugs over the Internet was approximately less than 10%. The results of this survey suggest that it is not necessary to purchase nonprescription drugs over the Internet. However, owing to a small but significant minority of inhabitants who need to purchase nonprescription drugs over the Internet, there is an urgent need for establishing an optimum system for supplying medicinal products to remote islands.
Alendronate, an oral bisphosphonate (e.g., Fosamax®), is effective in the treatment of osteoporosis, and the Fosamax® package insert advises that the bioavailability is reduced when taken with mineral water containing high levels of metal cations (Ca2+, Mg2+, etc.). However, standards regarding the water used when taking alendronate are unclear. In this study, the influence of mineral water on the absorption of oral alendronate was investigated based on urinary excretion of its unchanged form in rats. Alendronate was diluted in each water sample and administered orally (0.7 mg/kg) to male Wistar rats after 24-hour fast. Urine samples were collected until 24 h after dosing. Urine samples were alkalinized, and alendronate in urine was precipitated as a calcium salt, followed by loading on an anion exchange cartridge. Eluted alendronate was derivatized with 9-fluorenylmethoxycarbonyl (Fmoc) chloride and determined by HPLC with fluorescent detection. Cumulative urinary excretion recoveries of alendronate were calculated from the amounts of urinary excretion. Alendronate was rapidly excreted in the first 6 h, and similar elimination rate constants were seen (from 0.28 to 0.45 h−1/2) among the water samples. Cumulative urinary excretion recoveries with tap water, evian® and 100% deep ocean water were 0.98±0.17%, 0.80±0.18% and 1.01±0.16% (mean±S.E., n=4). Those with Contrex® (0.33±0.07%) were significantly lower when compared with ultrapure water (1.56±0.35%, p<0.01). These findings suggest that the absorption of alendronate decreases based on the calcium concentration of mineral water. In conclusion, mineral water containing high levels of calcium is not recommended when alendronate is taken.
Genetic polymorphism of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) is widely known to contribute to interindividual differences in the pharmacokinetics of some antiepileptic drugs. We developed a rapid detection assay of polymorphisms of CYP2C9 and CYP2C19, using the Light Cycler® polymerase chain reaction (PCR) system. Using this assay, we examined polymorphisms in 20 Japanese pediatric patients prescribed phenytoin for the treatment of epilepsy, and classified their polymorphisms into four groups: group I, CYP2C9*1/*1 and CYP2C19*1/*1; group II, CYP2C9*1/*1 and CYP2C19*1/*2 or *1/*3; group III, CYP2C9*1/*1 and CYP2C19*2/*2; and group IV, CYP2C9*1/*3 and CYP2C19*1/*2 or *1/*3. The mean maximal elimination rates (Vmax) in groups I, II, III and IV were 13.1, 11.2, 10.2 and 8.0 mg/day/kg, respectively, with statistically significant differences among groups (p=0.012, Kruskal-Wallis analysis). The intrinsic metabolic activity (Vmax/Km) of groups I, II, III and IV were 2.9, 2.2, 1.5 and 1.1 l/day/kg, respectively (p=0.009), again with significant differences among groups. These findings indicate that polymorphism of CYP2C9 and CYP2C19 plays an important role in phenytoin metabolism in children. With a total processing time for this assay of less than 3 hours, prediction of the optimal phenytoin dosage based on the CYP2C9 and CYP2C19 genotypes will be possible before commencement of therapy, resulting in the prevention of phenytoin overdoses in pediatric patients with epilepsy.
Keeping track of patients' medication histories is an important component of pharmacy practice. In this study, we conducted a questionnaire survey on medication histories among pharmacists and performed covariance structure analysis to investigate pharmacists' attitudes toward medication histories. The survey was conducted among pharmacists who work at pharmacies. With regard to the questions on medication histories, factor analysis and covariance structure analysis were performed to create a path diagram. The response rate to the questionnaire was 97.0%. The factor analysis revealed six factors, including: “patient assessment”, “learning attitude”, “practicing the recording of medication histories”, “conscious effort to improve medication histories”, “uniformity in medication histories” and “issues regarding medication histories”. Meanwhile, covariance structure analysis revealed that the five-factor model excluding “issues regarding medication histories” was the best-fitted model. According to this model, it was clear that the pharmacists were extremely conscious about introducing improvements to the content of medication histories. In this study, covariance structure analysis enabled the effective analysis of the attitudes of pharmacists toward medication histories. We believe that creating and conducting a training program to clarify and resolve issues related to medication histories and then reviewing the outcome of such a training program will lead to quality improvement and standardization of the future management of medication histories.
An ionization technique, direct analysis in real time (DART) has recently been developed for the ambient ionization of a variety samples. The DART coupled with time-of-flight mass spectrometry (TOFMS) would be useful as a simple and rapid screening for the targeted compounds in various samples, because it provides the molecular information of these compounds without time-consuming extraction. In this study, we investigated rapid screening methods of illicit drugs and their metabolites, such as methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA), amphetamine (AP) and 3,4-methylenedioxyamphetamine (MDA) in human urine using DART-TOFMS. As serious matrix effects caused by urea in urine samples and ionizations of the targeted compounds were greatly suppressed in the DART-TOFMS analyses, simple pretreatment methods to remove the urea from the samples were investigated. When a pipette tip-type solid-phase extraction with a dichloromethane and isopropanol mixed solution as an eluent was used for the pretreatment, the limits of detection (LODs) of 4 compounds added to control urine samples were 0.25 μg/ml. On the other hand, the LODs of these compounds were 0.5 μg/ml by a liquid-liquid extraction using a dichloromethane and hexane mixed solution. In both extractions, the recoveries of 4 compounds from urine samples were over 70% and these extraction methods showed good linearity in the range of 0.5-5 μg/ml by GC-MS analyses. In conclusion, our proposed method using DART-TOFMS could simultaneously detect MA, MDMA and their metabolites in urine at 0.5 μg/ml without time-consuming pretreatment steps. Therefore it would be useful for screening drugs in urine with the molecular information.
In recent years, it is necessary to acquire knowledge not only about medicine but also over-the-counter (OTC) drugs and health food for children, because lowering trend in the age of the health hazard by improper use of health food is reported. Therefore, in order to estimate the extent of use of OTC drugs and health food, the school pharmacists administered a questionnaire to students in grade-school (n=123), junior high school (n=303), and high school (n=115) in Fukuyama city. As a result of the questionnaire survey, surprisingly, the usage ratio of OTC drugs and health food showed the most increase in grade-schooler. The trigger of use of health food is “parents' recommendations” in the lower grades, otherwise the ratio of “use by themselves” was increased in the higher grades. Moreover, a remarkable difference was observed by the kinds of use in students with or without exercise. Interestingly, exercise group expected “physical strength” effects than no exercise group. In addition, the ratio of consultation to the pharmacist at the time of purchase of OTC drugs and health food was low in all grade students. In particular, the ratio of consultation to the pharmacist at the time of purchase of health food was very low in high school students. Therefore, to provide accurate information of medicine and health food for students, the school pharmacist should engage not only in routine work but also in positive guidance about OTC drugs and health food in the future.
Care Managers (CMs) were surveyed to clarify the issues involving the promotion of cooperation between care managers and pharmacists in long-term-care and explore solutions. The length of work experience, occupational background, experience of pharmaceutical service; pharmacist visit patients' home for providing medicine and pharmaceutical care into a care plan, degree of understanding on pharmaceutical service, and awareness of work involved in pharmaceutical service were studied to see whether there made differences in the requests from CMs for information on pharmacists and for information gathering methods. The χ2 test was used to this end. The opinions and requests described by the CMs were validated through text mining. More CMs tended to obtain information and knowledge through training sessions and professional magazines than those who did so through cooperation with pharmacists on a practical level. However, the survey strongly indicated that CMs with high level of understanding and awareness of pharmaceutical service wished to obtain information on pharmacists through cooperation with them on a practical level, and CMs with low level of understanding and awareness of pharmaceutical service wished to obtain such information through training sessions and professional magazines. Results of text mining showed that CMs wished pharmacists to strengthen the cooperation with physicians and provide information on pharmaceutical service. These findings have led to the conclusion that the issues surrounding the promotion of cooperation between CMs and pharmacists centered around “work cooperation on a practical level” and “provision of information to CMs about the roles of pharmacies and pharmacists and their work.”
It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) affect the pharmacokinetics of methotrexate, but there are several reports showing negative consequences. In this study, we evaluated drug interactions by performing a meta-analysis on published data examining the effect of NSAIDs on pharmacokinetic parameters of methotrexate. The combined standardized mean difference of the maximum blood concentration after oral administration of methotrexate was calculated to be −0.00 (95% confidence interval, −0.30 to 0.30) based on 6 clinical trials, and there was no significant effect of NSAIDs (p=0.9967). However, it is also represented that the NSAIDs significantly increased the area under the blood concentration-time curve of methotrexate (combined standardized mean difference, 0.73; 95% confidence interval, 0.32 to 1.14; p=0.0004; 11 trials). Furthermore, the combined standardized mean differences in total and renal clearance of methotrexate were estimated to be −0.80 (95% confidence interval, −1.41 to −0.18; p=0.0109; 6 trials) and −0.76 (95% confidence interval, −1.40 to −0.11; p=0.0220; 11 trials), respectively, implying that NSAIDs interfere with urinary excretion of methotrexate. In conclusion, the integration of the published reports by these meta-analyses shows that NSAIDs increase blood levels of methotrexate by influencing renal excretion of the antifolate.