Impact of holding position during inhalation on drug release from a reservoir-, blister- and capsule-type dry powder inhaler.

OBJECTIVE: To determine whether drug release may be impaired by tilting some dry powder inhalers (DPIs). METHODS: Using an inhalation simulator, we measured drug release from Turbuhaler® (TBH), Diskus® (DKS) and Breezhaler® (BZH) at several peak inhaled flow rates (PIFs) while the DPIs were held at level and tilted (80°). Drug release was then measured from all three DPIs at 0, 30, 60 and 90° of tilt, and capsule rotation was also recorded. RESULTS: Drug release from TBH was flow-dependent while that from DKS and BZH was flow-independent. With TBH, the plot of drug release vs. PIF either at level or at tilted position scattered along approximately the same regression lines. With DKS and BZH, drug release at tilted position was significantly lower than that while at level. With DKS the decrease was almost 20%, while with BZH, drug release frequently failed. With BZH, significant reductions in drug release were observed while the device was tilted by 30-90°. CONCLUSION: The position in which the DPI is held may affect drug delivery, especially when using BZH.

Investigation of Appropriate Inhalation Technique for Mometasone Furoate Dry Powder Inhaler.

The aim of this study was to establish an appropriate inhalation method with a mometasone furoate dry powder inhaler (MF-DPI). Utilizing a tone-based inhalation training device, we investigated the maximum peak inspiratory flow rate time (Tmax PIFR) and peak inspiratory flow rate (PIFR) to determine whether either had an influence on lung deposition with use of an MF-DPI. A low tone indicated a PIFR of 28 L/min and a high tone that of 40 L/min, while 60 L/min was considered to be the standard. We established an inhalation profile in consideration of a human inhalation pattern, in which Tmax PIFR was set at 0.5 s (Tmax PIFR 0.5 s) and 2.5 s (Tmax PIFR 2.5 s). The reference cut-off value derived with a cascade impactor test was used for evaluation of the rate of delivered dose in the lung, which was the amount of drug from stage 3 to 7 at all PIFRs. We then investigated the relationship of the fine particle fraction (FPF) with the claimed dose at Tmax PIFR of 0.5 s and PIFR. There were no differences among the Tmax PIFR values for the doses emitted from the device or for the rate of delivered doses in stages 3-7. However, FPF for the claimed dose at 40 L/min was significantly lower than that at 60 L/min, which was dependent on PIFR. Our results showed that PIFR but not Tmax PIFR has an effect on lung deposition after inhalation with an MF-DPI.

Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin.

5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5-HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin.

The evaluation method for antiplatelet effect of acetylsalicylic acid.

Reduced platelet aggregation by acetylsalicylic acid administration has been associated with adverse outcomes in patients with thrombotic diseases, thus it is important to determine aspirin resistance in those cases. The antiplatelet effect of acetylsalicylic acid is rarely measured, but it has many problems. The aim of this study was to find the evaluation method for antiplatelet effect after administration of acetylsalicylic acid. We developed a particle counting method based upon laser light scattering, and utilized the platelet aggregation agonists, collagen, at 0.25, 0.5 and 1.0 µg/mL, and adenosine diphosphate (ADP), at 0.5, 1.0 and 2.0 µM, to determine their effective concentrations. Seventeen healthy volunteers were administered acetylsalicylic acid at 162 mg/day, with platelet aggregation determined before and 20 min after administration. In all subjects, the rate of platelet aggregation induced by 1.0 µg/mL of collagen before taking acetylsalicylic acid was the highest value obtained, while 20 min after acetylsalicylic acid administration, aggregation induced by collagen at 1.0 µg/mL was significantly decreased as compared to before administration. As for the other concentrations of collagen and all those of ADP tested, platelet aggregation was either not significantly induced before taking acetylsalicylic acid or the rate of aggregation was not significantly decreased after taking acetylsalicylic acid. Our results indicate that collagen at 1.0 µg/mL is appropriate as a platelet aggregation agonist for evaluating the antiplatelet effect of acetylsalicylic acid. Thus, it is useful that the measurement is performed only once.

Method for individualized evaluation of antiemetic effect induced by 5-HT3 receptor antagonist.

5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 ± 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.

Theoretical analysis of efficacy of biological agent for rheumatoid arthritis based on target molecular binding occupancy.

Recently, biological agents have been used for treatment of rheumatoid arthritis (RA), though the standard therapeutic doses vary among the agents utilized. To investigate the mechanisms related to those differences, we theoretically analyzed the target molecular binding occupancies of 4 biological agents: tocilizumab, infliximab, adalimumab, and etanercept. The average binding occupancy to the target molecule (Φss) was estimated to be 99.50 ± 0.44 % in a steady state after administration of the standard therapeutic dose of each agent. Furthermore, achieved American College of Rheumatology (ACR) 20, used as an index of clinical efficacy, increased in correlation with the value for Φss. These results suggest that clinical effects are achieved with a high value of target molecular binding occupancy. Thus, we considered that all of the agents examined in this study are antagonists and elicit clinical efficacy by inhibiting the signaling of biologically active substances that are not necessary for life maintenance and are secreted or released specifically in pathological conditions. In addition, target molecular binding occupancy can be used as an appropriate index for evaluating the standard therapeutic dose of biological agent for RA.

Interactions between new quinolone antibacterials and diagnostic drug containing manganese.

A diagnostic drug containing manganese chloride tetrahydrate as a major ingredient is available since 2006. It is used in magnetic resonance imaging as a negative contrast medium for magnetic resonance cholangiopancreatography of the gastrointestinal tract. However, there is no report regarding interaction between manganese and new quinolone antibacterials. We investigated the interactions between new quinolone antibacterials and a diagnostic drug containing manganese in vitro. We evaluated the rate of formation of chelate complex by reacting new quinolone antibacterials (levofloxacin, ofloxacin, ciprofloxacin) with a diagnostic drug containing manganese. The EC50 values of the formation of chelate complex for levofloxacin, ofloxacin, and ciprofloxacin were 5.14 ± 0.14, 5.29 ± 0.14, and 0.96 ± 0.04 mM, respectively. The rates of formation of chelate complex by levofloxacin, ofloxacin, and ciprofloxacin in a reaction with the diagnostic drug were 17.0, 18.9, and 55.5 % in clinical condition, respectively. Our results suggest that a complex of each antibacterial and manganese was formed, with ciprofloxacin causing the strongest interaction. In addition, our findings indicate that the degree of interaction may be an important problem in clinical settings with concomitant administration of a new quinolone antibacterial and diagnostic drug containing manganese.

Theoretical investigation of aspirin dosage regimen to exhibit optimal antiplatelet effects and decrease risk of upper gastrointestinal lesions.

We investigated dosage regimens for aspirin therapy in regard to antiplatelet effects in patients without gastrointestinal lesions. Findings for inhibition of biosynthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)) were simulated based on pharmacokinetic and pharmacodynamic models using an irreversible process of inhibition of cyclooxygenase-1 (COX-1) by aspirin. We found that the inhibition of biosynthesis of TXB(2) at a steady state was greater than 90% when the dose of aspirin administered exceeded 81 mg, which was considered to exhibit a sufficient antiplatelet effect. Furthermore, it was confirmed that a dose of 162 mg or more is needed to exert an immediate antiplatelet effect on the initial day of administration. On the other hand, the inhibition of biosynthesis of PGE(2) ranged from 40-90% when aspirin was administered at a dose of 10.125-324 mg. Thus, the risk of gastrointestinal lesions differed in a dosage-dependent manner. The biosynthesis inhibition of PGE(2) was calculated to be 37.9%, with that value set as the target level for prevention of gastrointestinal disorders. We also noted a difference between platelets and gastric mucosa cells in regard to the turnover rate of COX-1, and attempted to simulate the inhibition of biosynthesis of TXB(2) and PGE(2) following administration of aspirin. However, it was not possible, as the inhibition of biosynthesis of TXB(2) was greater than 90% and that of PGE(2) was less than 37.9%, even with various dosage regimens. Our findings suggest that it is difficult to determine a rational dosage regimen of aspirin to exert an antiplatelet effect without inducing gastrointestinal lesions.

Prediction of distribution volume of vancomycin in critically ill patients using extravascular lung water and pulmonary vascular permeability indices.

OBJECTIVE: Alterations in distribution volume affect the concentrations of hydrophilic drugs in plasma and tissues at the time of initial therapy. When the distribution volume of hydrophilic antimicrobials is increased in critically ill patients with a serious infection, antimicrobial concentrations are reduced, which may adversely affect the efficacy of antimicrobial therapy. A transpulmonary thermodilution technique system (PiCCO) enables measurements of pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI), which are related to pulmonary edema and pulmonary vascular permeability, respectively. In addition, those indices may also be related to the distribution volume of hydrophilic antimicrobials. The aim of this study was to investigate the relationships of PVPI and EVLWI with the distribution volume of vancomycin (Vss), as well as to establish a method for estimating Vss for planning an appropriate initial dose for individual patients. METHODS: Seven patients were administered vancomycin intravenously and underwent extended hemodynamic monitoring with the PiCCO system in the intensive care unit (ICU) from April 2009 to March 2011. Vss was calculated using the Bayesian method, and the relationships of PVPI and EVLWI with Vss were investigated. RESULTS: The relationship between Vss/actual body weight (ABW) and median EVLWI on days when blood levels were measured was significant (r = 0.900, p = 0.0057), whereas the relationship between Vss/ABW and PVPI was not significant (r = 0.649, p = 0.1112). CONCLUSION: EVLWI determined by the PiCCO system is useful to predict Vss and should lead to more effective vancomycin therapy for critically ill patients at the initial stage.

Theory-based analysis of anti-inflammatory effect of infliximab on Crohn's disease and rheumatoid arthritis.

In Japan, the recommended dosage regimens of infliximab (IFX) for treatment of rheumatoid arthritis (RA) and Crohn's disease (CD) are different. However, the differences have not been analyzed theoretically. In a previous study, we constructed a pharmacokinetic-pharmacodynamic model to investigate the effects of IFX for CD and found it useful to establish a rational dosage regimen of IFX for individual patients with CD. In the present study, we investigated whether the theory-based model could be used for cases of RA and also used it to evaluate the validity of the dosage regimen. The results obtained with our model were in good agreement with observed tender joint count (TJC) ratio data, which was considered to show the validity of our analysis. Thus, we concluded that the model could be used for patients with RA. Furthermore, a second administration of IFX given 2 weeks after the first infusion was important to achieve remission in the early stage of RA. We also compared the estimated pharmacodynamic parameters of RA with those of CD. The elimination rate constant of inflammation in RA was greater than that in CD, suggesting that the recovery from inflammation in RA is faster than that in CD, and indicating a reason for the difference in dosage between RA and CD. In conclusion, use of our model in light of the individual quantitative factor of tumor necrosis factor (TNF)-α allows establishment of IFX dosage regimens for individual patients.

[Development and evaluation of effective learning system for patient interview training as a part of pre-education clinical pharmacy practice].

The aim of this study was to develop an effective learning system for patient interview training as a part of a pre-education clinical pharmacy. We devised a learning system for performing pharmaceutical care training and then investigated its usefulness. The learning content was a first interview with a simulated patient (SP). All students were divided into 8 groups of 5. Each student practiced interviewing an SP while 2 other students checked the performance of the interviewer, with roles rotated within each group. Additionally, the teachers also rotated among the groups to check the students. We evaluated the results contained in 55 check sheets used by teachers to evaluate the learning system, 223 check sheets used by students, and 110 check sheets used by the SPs. We found that there was a significantly greater number of students rated as unable to perform by the teachers as compared to those rated by the other students. In addition, the ratings for the items, "other symptom is confirmed" and "the severity and properties of the symptom are confirmed" were similar to the above result. Furthermore, there was a significantly greater number of students rated as unable to perform by the teachers as compared to those rated by the SPs in regard to the item "interviewed using open-ended questions." After the students had performed their first attempt at a first interview, 28.6% were rated as unable to perform by the teachers, which was significantly reduced to 15.8% after the fourth attempt and 10.4% after the fifth attempt. Our results indicate that students must practice the first interview at least 4 times before reaching a level of competency. In addition, our findings suggest that both teachers and SPs should undertake pre-education training in clinical pharmacy practice, as the evaluations were significantly different among the teachers, students, and SPs in the present study.

[Investigation into the effect of gastric secretion inhibitor for the prevention of upper gastrointestinal lesions associated with low-dose aspirin].

In this study, we investigated the effect of histamin H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) for the prevention of upper gastrointestinal lesions associated with low-dose aspirin. We carried out a retrospective study of 2811 patients who had been prescribed low-dose aspirin (Bayaspirin® 100 mg) for more than 30 days at Tokai University Hachioji Hospital from 2006 to 2008. We classified them into three groups: aspirin alone group (n=1103), aspirin with H2RA group (n=844) and aspirin with PPI group (n=864). Patients who developed upper gastrointestinal lesions were diagnosed with gastric ulcer, duodenal ulcer, gastritis or duodenitis by gastroscopy. We then compared the incidence of upper gastrointestinal lesions among the groups. The incidence in aspirin alone group, aspirin with H2RA group and aspirin with PPI group was 2.54%, 1.54% and 1.04%, respectively; that of aspirin with PPI group being significantly lower (p<0.05). Additively, the odds ratio (OR) of aspirin with H2RA group and aspirin with PPI group was 0.60 (95% confidence interval [95%CI]: 0.31-1.17) and 0.40 (95% CI: 0.19-0.86) as compared with aspirin alone group, respectively. The upper gastrointestinal lesions were developed within two years in all groups. Our results suggest that the combined administration of low-dose aspirin and PPI is effective for the prevention of upper gastrointestinal lesions associated with low-dose aspirin. Also, the pharmacists should be especially careful for upper gastrointestinal lesions development within two years after administration of low-dose aspirin, regardless of combined whether H2RA or PPI.

Structural features of the NAD-dependent in situ retinoic acid supply system in esophageal mucosa.

BACKGROUND: We previously reported that an NAD-dependent in situ retinoic acid supply system, which comprises some isoforms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and provides retinoic acid from retinol via a 2-step oxidation process, exists in the rat esophagus. Herein, their isoforms responsible for the pathway and its localization in the rat esophagus was examined. METHODS: The expressions of mRNAs of various isoforms of ADH and ALDH were examined in the fraction mainly comprising mucosal layer of the rat esophagus by RT-PCR. Expression levels of Class IV ADH and ALDH 1A1 were compared between the fractions and that mainly comprising muscle layer of the rat esophagus by quantitative PCR. The catalytic activities producing retinoic acid from retinal were compared between the 2 fractions and its optimum pH was also determined. RESULTS: Classes I, III, and IV ADHs and ALDHs 1A1 and 3A1 were predominant isoforms in the rat esophageal mucosa. The expression levels of mRNA of Class IV ADH and ALDH 3A1 were significantly higher in the mucosal than in the muscle layer. Consistently, the catalytic activities producing retinoic acid from retinal were significantly higher in the former than the latter. The optimum pH of the process was 9.0. CONCLUSIONS: Considering the affinities for retinol and retinal of ADHs and ALDHs expressed in the rat esophagus, the NAD-dependent in situ retinoic acid supply system in the rat esophagus is thought to comprise Class IV ADH and ALDH 1A1. In the rat esophagus, the system exists predominantly in the mucosal layer.

Clinical predictors of culprit plaque rupture assessed on intravascular ultrasound in acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) commonly results from vulnerable plaque rupture, and occasionally results from thrombus formation in lesions without plaque rupture. The aim of the present study was to clarify the clinical features of different etiology of ACS and clinical predictors of culprit plaque rupture assessed on intravascular ultrasound (IVUS). METHODS AND RESULTS: One hundred and ten ACS patients with emergent coronary angiography were classified into 2 groups based on the presence or absence of culprit plaque rupture assessed on IVUS. Clinical characteristics were compared between the 2 groups. Culprit coronary plaque rupture was observed in 60 patients (55%). Patients with plaque rupture were younger and were more likely to be male (P<0.03 and P<0.02, respectively). In the rupture group, the prevalence of metabolic syndrome was higher (P<0.002), and among the components of metabolic syndrome, waist circumference was greater and serum high-density lipoprotein cholesterol level was lower (P<0.0001 and P=0.0004, respectively). IVUS-assessed lesion remodeling index was greater in the rupture group (P<0.0001). On multivariate analysis metabolic syndrome was an independent predictor of culprit plaque rupture (odds ratio =5.26, 95% confidence interval =1.49-21.40, P<0.02). CONCLUSIONS: Abdominal obesity and low high-density lipoprotein-cholesterol level are the characteristics of metabolic syndrome that seem to be the key factors for vulnerable plaque rupture with coronary compensatory enlargement.

[Clinical evaluation of drug information provided by the pharmacists in the intensive care unit].

Pharmacists working in the intensive care unit (ICU) in Saiseikai Yokohamashi Tobu Hospital are mainly responsible for managing the stock of drugs, providing drug information to other medical staff, educating them for rational drug therapy, and providing pharmaceutical care to the patients. In order to evaluate the contribution to the rational drug therapy, we investigated the acceptance rate of the drug information that the pharmacists in the ICU provided to the physicians from February to May in 2009. The number of cases in which drug information was provided by the pharmacists to the physicians during the period was 288. It was suggested that more than half of the information could optimize the drug dosage regimens and correct the inadequate prescriptions. Furthermore, 98.9% of the information provided by pharmacists was accepted by physicians. We questioned 5 intensivists to evaluate the information with a 5 point scale (maximum score was 4, minimum score was 0) and then the average of score was 3.3. In addition, their evaluation of the information about optimizing the drug dosage regimens marked the highest point (over 3.5). Meanwhile, providing drug information which led the physicians to correct the inadequate prescriptions contributed to reduce the cost of the drug therapy by 900000 yen during the period. As a result, it was suggested that the intensivists highly appreciated the information offered by the pharmacists and the information contributed to enhance high-quality drug therapy. Additionally, the economic impact was identified through the cost reduction in drug therapy.

Receptor occupancy theory-based analysis of interindividual differences in antiemetic effects of 5-HT3 receptor antagonists.

BACKGROUND: The aim of this study was to estimate interindividual differences in the antiemetic effects of 5-HT(3) receptor antagonists by evaluating the influence of pharmacokinetics on 5-HT(3) receptor occupancies, based on receptor occupancy theory. METHODS: We analyzed interindividual differences of 5-HT(3) receptor occupancies and antiemetic effects after the oral and/or intravenous administration of standard doses of the following 5-HT(3) receptor antagonists: azasetron, granisetron, indisetron, ondansetron, ramosetron, and tropisetron. RESULTS: The interindividual difference between maximum and minimum 5-HT(3) receptor occupancies after oral administration ranged from 0.6% to 64.0%, and that difference after intravenous administration ranged from 0.6% to 29.6%. Following oral administration, the interindividual difference between maximum and minimum complete vomiting inhibition rates ranged from 0.2% to 16.1%. After intravenous administration, that difference ranged from 0.8% to 52.5%. CONCLUSION: Interindividual differences in the clinical effects of 5-HT(3) receptor antagonists could be evaluated based on receptor occupancy theory, and the differences varied among drugs. Drug selection considering these individual variations might be useful for the patients who experienced vomiting associated with chemotherapy.

Adiponectin is increased and correlated with the degree of proteinuria, but plasma leptin is not changed in patients with chronic glomerulonephritis.

AIM: Altered regulation of adiponectin and leptin may be relevant to endothelial dysfunction and cardiovascular complications in patients with chronic glomerulonephritis. METHODS: The relationship between the levels of plasma adiponectin, leptin and proteinuria, glomerular filtration rate and metabolic risk factors was investigated in 38 patients with chronic glomerulonephritis. RESULTS: Plasma adiponectin was much higher in patients with heavy proteinuria (38.8 +/- 27.8 microg/mL) than in patients with mild proteinuria (13.3 +/- 5.1 microg/mL, P < 0.001) and with moderate proteinuria (18.1 +/- 8.0 microg/mL, P < 0.01). The levels of serum leptin were not changed among these groups. Proteinuria and lipoprotein(a) were a strong and direct correlate of plasma adiponectin (r = 0.75, P < 0.0001), while serum albumin and the glomerular filtration rate correlated inversely with this protein (r = -0.56, P = 0.0002; r = 0.38, P = 0.02). Body mass index and triglyceride were direct correlates (r = 0.37, P = 0.02 and r = 0.37, P = 0.02, respectively) of plasma leptin in patients with glomerulonephritis. CONCLUSIONS: Plasma adiponectin but not plasma leptin levels correlate with proteinuria in patients with chronic glomerulonephritis.

Single nucleotide polymorphisms of 17beta-hydroxysteroid dehydrogenase type 7 gene: mechanism of estramustine-related adverse reactions?

OBJECTIVES: To investigate the influence of single nucleotide polymorphisms (SNP) on transcription of the 17beta-hydroxysteroid dehydrogenase (HSD17B7) gene. METHODS: Luciferase reporter genes containing a 5'-flanking of the HSD17B7 gene, as well as the sequence around the SNP, were transfected into LNCaP and DU145 cells. Then, luciferase assays were carried out. RESULTS: The presence of the G allele resulted in an increase of transcriptional activity derived from the 5'-flanking region of the HSD17B7 gene by 270% and 370% in LNCaP and DU145 cells, respectively. Transcriptional activity of the HSD17B7 gene containing the G allele was higher than that of the C allele. CONCLUSIONS: The transcriptional activity of the HSD17B7 gene containing the G allele is higher than that of the C allele. This difference in HSD17B7 expression may regulate the risk of peripheral edema as an adverse reaction induced by estramustine phosphate sodium.

Theory based analysis of anti-inflammatory effect of infliximab on Crohn's disease.

Tumor necrosis factor (TNF)-alpha, a primary mediator of inflammatory responses, is increased in patients with active Crohn's disease (CD) and considered to play an important role in the regulation of inflammation in CD. Infliximab (IFX) is a chimeric murine-human monoclonal IgG1 antibody that targets TNF-alpha and is used as a therapeutic agent for CD. Although that dosage regimen has been established through clinical trial experience, it has not been analyzed theoretically. We analyzed of sequential changes of the Crohn's disease activity index (CDAI) using a pharmacokinetic-pharmacodynamic model integrating the pharmacokinetics of IFX and turnover rate of TNF-alpha. The time course effects of IFX derived from the present model were matched to reported data regarding CDAI ratios, and we found that the clinical effect of IFX reached a maximum value 2 to 4 weeks after administration and was maintained for the next several weeks. Our results suggested that the standard dosage regimen of IFX is theoretically appropriate. Further, based on the results of various dosage regimens, a second administration of IFX 2 weeks after the first dose was shown to achieve remission in the early stage of active CD, when IFX was given as a repeated treatment.

Effects of mouth washing procedures on removal of budesonide inhaled by using Turbuhaler.

Mouth washing after inhalation of corticosteroids is effective for prevention of local adverse effects. We determined the amounts of drug residues remaining on the oropharyngeal mucosa following inhalation of budesonide (BUD) via a Turbuhaler (BUD-TH) (100 microg). Further, we studied the effects of mouth washing on the removal of drug residues by quantification of BUD in expectorated wash solution using an HPLC method. The amount of BUD recovered after gargling and rinsing for 5 s each was 19.4+/-9.4 microg, as compared to 23.8+/-13.6 microg after rinsing alone for 10 s and 18.3+/-8.9 microg after gargling alone for 10 s, though the differences were not significant. Our results indicated that about 20% of the dose was remaining on the oropharyngeal mucosa after inhalation. In a comparison of washing times, the amounts of BUD recovered were 26.3+/-3.2 microg after gargling and rinsing for 3 s each, and 19.4+/-9.3 microg after those for 5 s each. As for the effect of lag time before beginning mouth washing, the ratio of BUD recovered following mouth washing with a lag time of 1 min was 73.2%, while it was reduced to 27.8% after 10 min, as compared to immediate mouth washing following administration. Our results suggest that the amount of BUD removed by mouth washing is associated with the lag time between inhalation and mouth washing, however, not with the duration of mouth washing. We concluded that immediate mouth washing after inhalation is most useful for the removal of drugs following BUD-TH administration.