Assessment of Drug-Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy.

Aprepitant is a known inducer of CYP2C9, the main warfarin-metabolizing enzyme. Consequently, co-administration of these two drugs may result in reduction of the anticoagulation activity of warfarin. However, the nature and degree of time-dependent changes in prothrombin time international normalized ratio (PT-INR) after aprepitant and warfarin co-treatment in patients receiving anticancer chemotherapy has not been elucidated. We retrospectively examined the changes in warfarin dose, PT-INR, and warfarin sensitivity index (WSI; average of PT-INR value/average of daily warfarin dose) during four weeks, i.e., one week before and three weeks after aprepitant administration. The mean and standard deviation values of WSI for one week before and one, two, and three weeks after the beginning of aprepitant administration were 0.51±0.22 (1.00, n=34), 0.74±0.30 (1.53±0.59, n=30), 0.38±0.15 (0.82±0.22, n=28), and 0.46±0.29 (0.87±0.23, n=24), respectively. Values in parentheses represent relative changes versus WSI of one week before and number of subjects. Although the mean value of WSI significantly increased one week after aprepitant administration compared to that at one week before the administration, it in turn significantly decreased two weeks after compared to one week before (paired t-test, p<0.05 after Bonferoni correction). In patients taking warfarin, PT-INR should be carefully monitored for at least two weeks after the beginning of aprepitant administration because it may fluctuate with both aprepitant and chemotherapy during this period.

High-speed classification of coherent X-ray diffraction patterns on the K computer for high-resolution single biomolecule imaging.

Single-particle coherent X-ray diffraction imaging using an X-ray free-electron laser has the potential to reveal the three-dimensional structure of a biological supra-molecule at sub-nanometer resolution. In order to realise this method, it is necessary to analyze as many as 1 × 10(6) noisy X-ray diffraction patterns, each for an unknown random target orientation. To cope with the severe quantum noise, patterns need to be classified according to their similarities and average similar patterns to improve the signal-to-noise ratio. A high-speed scalable scheme has been developed to carry out classification on the K computer, a 10PFLOPS supercomputer at RIKEN Advanced Institute for Computational Science. It is designed to work on the real-time basis with the experimental diffraction pattern collection at the X-ray free-electron laser facility SACLA so that the result of classification can be feedback for optimizing experimental parameters during the experiment. The present status of our effort developing the system and also a result of application to a set of simulated diffraction patterns is reported. About 1 × 10(6) diffraction patterns were successfully classificatied by running 255 separate 1 h jobs in 385-node mode.

The Incidence of Heterotopic Ossification in Surgically and Non-surgically Treated Elbow Fractures at a Municipal Hospital in Japan.

Background: Heterotopic ossification (HO) is a well-recognised complication of after elbow trauma. The prevalence and risk factors of HO have been previously reported. However, these reports were based on elbow trauma that had undergone surgical treatment and most of them were from Western countries. This study aimed to assess the incidence of HO in patients with elbow fractures who were treated surgically and non-surgically in Japan. Methods: We retrospectively identified consecutive patients who were treated of elbow fractures and fracture-dislocations at our institution in recent consecutive 3-year periods. We extracted patient demographics, injury mechanisms and treatment details from the medical records. Furthermore, we reviewed radiographs to classify the fracture pattern and identify the presence or absence of HO. Results: HO was identified in 6/97 (6%) patients. Fracture-dislocation was noted in 4/6 patients. The fracture types with HO included terrible triad injury (n = 2), isolated coronoid process fractures (n = 2), distal humerus A-type fractures (n = 1) and radial head fracture (n = 1). According to the Hastings and Graham classification, HO was classified as Class I in five patients and Class II B in one patient who underwent additional surgery for HO resection. Conclusions: The incidence of HO was relatively low in our patients. However, of the 20 conservatively treated elbows, one patient developed clinically relevant HO and required excision of HO. Even patients with elbow fractures treated conservatively should be informed of the potential risk of developing severe HO requiring surgical excision. In addition, surgeons in this region could use these data to inform patients about the risk of HO development after an elbow injury. Level of Evidence: Level IV (Therapeutic).

Induction of CYP3A activity by dexamethasone may not be strong, even at high doses: insights from a case of tacrolimus co-administration.

BACKGROUND: Dexamethasone (DEX) induces CYP3A activity in a concentration-dependent manner. However, no study has examined changes in the blood concentration of CYP3A substrate drugs when DEX is administered at high doses. Herein, we present a case in which tacrolimus (TAC), a typical CYP3A substrate drug, was co-administered with a chemotherapy regimen that included high-dose DEX. CASE PRESENTATION: A 71-year-old woman underwent liver transplantation for hepatocellular carcinoma 18 years prior to her inclusion in this case study. She was receiving TAC orally at 2 mg/day and had a stable trough blood concentration of approximately 4 ng/mL and a trough blood concentration/dose (C/D) ratio of approximately 2. The patient was diagnosed with post-transplant lymphoproliferative disease (histological type: Burkitt's lymphoma) after admission. Thereafter, the patient received cyclophosphamide-prednisolone (CP), followed by two courses of R-HyperCVAD (rituximab, cyclophosphamide, doxorubicin, vincristine, and DEX) and R-MA (rituximab, methotrexate, and cytarabine) replacement therapy. DEX (33 mg/day) was administered intravenously on days 1-4 and days 11-14 of R-HyperCVAD treatment, and aprepitant (APR) was administered on days 1-5 in both courses. The TAC C/D ratio decreased to approximately 1 on day 11 during both courses, and then increased. Furthermore, a decreasing trend in the TAC C/D ratio was observed after R-MA therapy. The decrease in the TAC C/D ratio was attributed to APR administration rather than to DEX. CONCLUSION: The induction of CYP3A activity by a high dose of DEX may not be strong. The pharmacokinetic information on DEX and in vitro enzyme activity induction studies also suggested that CYP3A activity induction is not prominent under high-dose DEX treatment.

Classification of drugs for evaluating drug interaction in drug development and clinical management.

During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment. In this review, we aim to highlight the viewpoints of the Japanese guideline and enumerate drugs that were involved or are anticipated to be involved in evident pharmacokinetic drug interactions and classify them by their clearance pathway and potential intensity based on systematic reviews of the literature. The classification would be informative for designing clinical studies during the development stage, and the appropriate management of drug interactions in clinical practice.

Dual EGFR and ABL Tyrosine Kinase Inhibitor Treatment in a Patient with Concomitant EGFR-Mutated Lung Adenocarcinoma and BCR-ABL1-Positive CML.

Tyrosine kinase inhibitor (TKI) combination is expected to increase in the era of precision medicine. TKI combination may be required to treat double primary cancers, each having a targetable gene, or to treat a single malignancy with multiple targetable genes. Here, we demonstrate the first report of dual EGFR and ABL TKI treatment in a patient with concomitant EGFR-mutated lung adenocarcinoma and BCR-ABL1-positive chronic myeloid leukemia (CML). A 60-year-old man with an 8-year history of CML was diagnosed as advanced EGFR-mutated lung adenocarcinoma. Complete molecular response of CML had been achieved by imatinib, and ABL-TKI had been switched to nilotinib four years previously due to muscle cramps. We discontinued nilotinib and started afatinib. Although partial response of lung adenocarcinoma was achieved, cytogenetic relapse of CML was observed following nilotinib discontinuation. We applied the previously described framework of cytochrome P450 3A4-mediated oral drug-drug interactions and selected gefitinib and nilotinib to treat both malignancies. We effectively and safely administered this combination for seven months. The present report is the first to demonstrate the safety and efficacy of dual EGFR and ABL TKI treatment in a patient with concomitant EGFR-mutated lung adenocarcinoma and CML.

Rationale, design, and profiles of the New Integrated Suburban Seniority Investigation (NISSIN) Project: a study of an age-specific, community-based cohort of Japanese elderly.

BACKGROUND: Although there have been many studies on aging in a number of developed countries, data on the effects of aging during early senescence are scarce. We designed a study to investigate an age-specific cohort in a suburban Japanese city to determine the factors that contribute to living long and well. METHODS: In every year from 1996 through 2005, residents of Nissin City, Japan who were about to reach the age of 65 years participated in health check-ups and completed a baseline self-administered questionnaire that included items on demographic and lifestyle characteristics, physical function, and quality of life. When the participants reached 70 years of age, they underwent secondary health check-ups at the same site, or received home visits from public health nurses, and their health-related outcomes were noted. RESULTS: A total of 3073 64-year-olds were enrolled in the study (response rate, 43.9%). There was considerable intersexual variation in demographic and lifestyle factors. Among men and women, 24.3% and 3.0% were current smokers, respectively, and 68.7% and 19.5% were current alcohol drinkers. Cohort members were in slightly better physical condition than the Japanese general population: they were less likely to be obese and hypertensive and more likely to have 20 teeth or more. Follow-up of the cohort is ongoing. CONCLUSIONS: We have established a unique age-specific cohort with a consecutive entry-exit system. This project should provide data on early changes in health and related factors in this new era of longevity.

Prevalence of cytochrome P450-mediated potential drug-drug interactions in residents of intermediate care facilities for older adults in Japan.

AIM: Limited information is available on the prevalence of drug-drug interactions (DDI) in residents of long-term care facilities who often receive multiple drugs. This study aimed to evaluate the prevalence of clinically relevant cytochrome P450-mediated potential DDI in residents of intermediate care facilities for older adults (called Roken) in Japan. METHODS: A nationwide drug utilization study was carried out for Roken residents in 2015 (up to five residents per facility). Potential DDI were identified with an explicit list of drugs that can be involved in clinically relevant cytochrome P450-mediated DDI in Japan. Logistic regression was used to evaluate the association of the number of drugs prescribed with the presence of potential DDI, adjusted for age, sex and long-term care needs level. RESULTS: The study included 1222 residents of 348 Roken who were prescribed two or more active drug substances. The participants who received ≥6 and ≥10 drugs represented 49% and 10% of total participants, respectively. In total, 42 two-drug combinations involving potential DDI were identified in 33 participants (2.7%) - benzodiazepines, proton pump inhibitors, calcium channel blockers and anti-epileptic drugs were frequently involved. The adjusted odds ratios for potential DDI were 2.84 (95% confidence interval 1.15-7.02) or 7.82 (95% confidence interval 2.96-20.70) in residents receiving six to nine drugs or ≥10 drugs, compared with those receiving two to five drugs. CONCLUSIONS: Approximately 3% of Roken residents were at risk for clinically relevant DDI. Reducing the number of drugs prescribed through medication reviews would mitigate the potential risk. Geriatr Gerontol Int 2019; 19: 513-517.

General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information.

BACKGROUND: Induction of cytochrome P450 (CYP) 3A4 potentially reduces the blood concentrations of substrate drugs to less than one-tenth, which results in ineffective pharmacotherapy. Although the prediction of drug-drug interactions (DDIs) that are mediated by induction of CYP3A4 has been performed mainly on the basis of in vitro information, such methods have met with limited success in terms of their accuracy and applicability. Therefore, a realistic method for the prediction of CYP3A4-mediated inductive DDIs is of major clinical importance. OBJECTIVE: The objective of the present study was to construct a robust and accurate method for the prediction of CYP3A4-mediated inductive DDIs. Such a method was developed on the basis of the principle applied for prediction of inhibitory DDIs in a previous report. A unique character of this principle is that the extent of alterations in the area under the plasma concentration-time curve (AUC) is predicted on the basis of in vivo information from minimal clinical studies without using in vitro data. METHODS: The analysis is based on 42 DDI studies in humans reported in 37 published articles over the period 1983-2007. Kinetic analysis revealed that the reduction in the AUC of a substrate of CYP3A4 produced by consecutive administration of an inducer of CYP3A4 could be approximated by the equation 1/(1 + CRCYP3A4 * ICCYP3A4), where CRCYP3A4 is the ratio of the apparent contribution of CYP3A4 to the oral clearance of a substrate and ICCYP3A4 is the apparent increase in clearance of a substrate produced by induction of CYP3A4. Using this equation, the ICCYP3A4 was calculated for seven inducers (bosentan, carbamazepine, efavirenz, phenytoin, pioglitazone, rifampicin [rifampin], and St John's wort [hypericum]) on the basis of the reduction in the AUC of a coadministered standard substrate of CYP3A4, such as simvastatin, in ten DDI studies. The CRCYP3A4 was calculated for 22 substrates on the basis of the previously reported method from inhibitory DDI studies using a potent CYP3A4 inhibitor such as itraconazole or ketoconazole. RESULTS: The proposed method enabled the prediction of AUC reduction by CYP3A4 induction with any combination of these substrates and inducers (total 154 matches). To assess the accuracy of the prediction, the AUC reductions in 32 studies were analysed. We found that the magnitude of the deviation between the mean values of the observed and predicted AUCs of all substrate drugs was <20% of the AUCs of the respective substrate drugs before administration of the inducers. In addition, rifampicin was found to be the most potent inducer among the compounds analysed in the present study, with an ICCYP3A4 value of 7.7, followed by phenytoin and carbamazepine, with values of 4.7 and 3.0, respectively. The ICCYP3A4 values of the other CYP3A4 inducers analysed in the present study were approximately 1 or less, which suggests that the AUCs of coadministered drugs may not be reduced to less than approximately half, even if the drug is metabolized solely by CYP3A4. CONCLUSION: By using the method reported in the present study, the susceptibilities of a substrate drug of CYP3A4 to inductive DDIs can be predicted quantitatively. It was indicated that coadministration of rifampicin, phenytoin and carbamazepine may reduce plasma AUCs to less than half for a broad range of CYP3A4 substrate drugs, with CRCYP3A4 values greater than 0.13, 0.21 and 0.33, respectively.

Lifestyle risk factors for intrahepatic stone: findings from a case-control study in an endemic area, Taiwan.

BACKGROUND AND AIM: To examine associations between lifestyle risk factors and intrahepatic stone (IHS), we conducted a case-control study in Taiwan, which has the highest incidence of IHS in the world. METHODS: Study subjects were 151 patients newly diagnosed with IHS at Chang Gung Memorial Hospital between January 1999 and December 2001. Two control subjects per case were selected randomly from patients who underwent minor surgery at the same hospital and from family members or neighbors of the hospital staff. Controls were matched to each case by age and gender. Information on lifestyle factors was collected using a self-administered questionnaire. Strength of associations was assessed using odds ratios derived from conditional logistic models. RESULTS: Female patients were significantly shorter than female controls. Compared to subjects with two or fewer children, odds ratios for those with six or more children were 20.4 in men (95% confidence interval, 1.89-221) and 2.82 (0.97-8.22) in women. Increasing level of education lowered the risk of intrahepatic stone (trend P = 0.004 for men and < 0.0001 for women). Women who had consumed ground-surface water for a long period had a somewhat increased risk (trend P = 0.05). CONCLUSION: Lower socioeconomic status and poor hygiene may be involved in the development of intrahepatic stones.

[Quantitative Prediction of Drug-Drug Interaction Caused by CYP Inhibition and Induction from In Vivo Data and Its Application in Daily Clinical Practices-Proposal for the Pharmacokinetic Interaction Significance Classification System (PISCS)].

　Drug-drug interactions (DDIs) can affect the clearance of various drugs from the body; however, these effects are difficult to sufficiently evaluate in clinical studies. This article outlines our approach to improving methods for evaluating and providing drug information relative to the effects of DDIs. In a previous study, total exposure changes to many substrate drugs of CYP caused by the co-administration of inhibitor or inducer drugs were successfully predicted using in vivo data. There are two parameters for the prediction: the contribution ratio of the enzyme to oral clearance for substrates (CR), and either the inhibition ratio for inhibitors (IR) or the increase in clearance of substrates produced by induction (IC). To apply these predictions in daily pharmacotherapy, the clinical significance of any pharmacokinetic changes must be carefully evaluated. We constructed a pharmacokinetic interaction significance classification system (PISCS) in which the clinical significance of DDIs was considered in a systematic manner, according to pharmacokinetic changes. The PISCS suggests that many current 'alert' classifications are potentially inappropriate, especially for drug combinations in which pharmacokinetics have not yet been evaluated. It is expected that PISCS would contribute to constructing a reliable system to alert pharmacists, physicians and consumers of a broad range of pharmacokinetic DDIs in order to more safely manage daily clinical practices.

General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs.

BACKGROUND: Cytochrome P450 (CYP) 3A4 is the most prevalent metabolising enzyme in the human liver and is also a target for various drug interactions of significant clinical concern. Even though there are numerous reports regarding drug interactions involving CYP3A4, it is far from easy to estimate all potential interactions, since too many drugs are metabolised by CYP3A4. For this reason, a comprehensive framework for the prediction of CYP3A4-mediated drug interactions would be of considerable clinical importance. OBJECTIVE: The objective of this study was to provide a robust and practical method for the prediction of drug interactions mediated by CYP3A4 using minimal in vivo information from drug-interaction studies, which are often carried out early in the course of drug development. DATA SOURCES: The analysis was based on 113 drug-interaction studies reported in 78 published articles over the period 1983-2006. The articles were used if they contained sufficient information about drug interactions. Information on drug names, doses and the magnitude of the increase in the area under the concentration-time curve (AUC) were collected. METHODS: The ratio of the contribution of CYP3A4 to oral clearance (CR(CYP)(3A4)) was calculated for 14 substrates (midazolam, alprazolam, buspirone, cerivastatin, atorvastatin, ciclosporin, felodipine, lovastatin, nifedipine, nisoldipine, simvastatin, triazolam, zolpidem and telithromycin) based on AUC increases observed in interaction studies with itraconazole or ketoconazole. Similarly, the time-averaged apparent inhibition ratio of CYP3A4 (IR(CYP)(3A4)) was calculated for 18 inhibitors (ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin, saquinavir, nefazodone, erythromycin, diltiazem, fluconazole, verapamil, cimetidine, ranitidine, roxithromycin, fluvoxamine, azithromycin, gatifloxacin and fluoxetine) primarily based on AUC increases observed in drug-interaction studies with midazolam. The increases in the AUC of a substrate associated with coadministration of an inhibitor were estimated using the equation 1/(1 - CR(CYP)(3A4) x IR(CYP)(3A4)), based on pharmacokinetic considerations. RESULTS: The proposed method enabled predictions of the AUC increase by interactions with any combination of these substrates and inhibitors (total 251 matches). In order to validate the reliability of the method, the AUC increases in 60 additional studies were analysed. The method successfully predicted AUC increases within 67-150% of the observed increase for 50 studies (83%) and within 50-200% for 57 studies (95%). Midazolam is the most reliable standard substrate for evaluation of the in vivo inhibition of CYP3A4. The present analysis suggests that simvastatin, lovastatin and buspirone can be used as alternatives. To evaluate the in vivo contribution of CYP3A4, ketoconazole or itraconazole is the selective inhibitor of choice. CONCLUSION: This method is applicable to (i) prioritize clinical trials for investigating drug interactions during the course of drug development and (ii) predict the clinical significance of unknown drug interactions. If a drug-interaction study is carefully designed using appropriate standard drugs, significant interactions involving CYP3A4 will not be missed. In addition, the extent of CYP3A4-mediated interactions between many other drugs can be predicted using the current method.

Analysis of pharmacokinetic data provided in Japanese package inserts and interview forms focusing on urinary excretion of pharmacologically active species.

In optimizing oral pharmacotherapy for patients with renal failure, information on actual urinary excretion ratio of the unchanged drug, which is obtained by dividing a urinary excretion ratio by a bioavailability after oral dose, is quite helpful. In addition, urinary excretion ratio of the active species is sometimes equally important where metabolites have a pharmacological potency. In the present study, we conducted a survey of Japanese package inserts and interview forms of drugs, which is being prescribed at the University of Tokyo Hospital, on pharmacokinetic data that enables an estimation of actual urinary excretion ratio. The total urinary excretion of a drug was documented in 70.1% of package inserts and 84.5% of interview forms, respectively. The total urinary excretion is often measured by radioactivity and thus includes its metabolites and degradation products. However, inclusion of degradation products/metabolites was described explicitly for 43.7% and 66.2%, and the absolute fraction of the unchanged drug or degradation product/metabolite was given only for 29.0% and 48.9% in package inserts and interview forms, respectively. The pharmacological activity of metabolite(s) was documented for 19.8% and 54.3%, and the oral bioavailability was described only for 5.7% and 30.6% in respective documents. For some drugs, the time period for the urine collection was too short to evaluate the urinary excretion ratio. With regard to 65 drugs (38.7%), more detailed information on urinary excretion was found in published books, but not provided in the package inserts or interview forms. It is hoped that more distinct and sufficient descriptions on the urinary excretion and bioavailability will be associated to the package inserts and the interview forms in future, for safe and efficient use of prescription drugs.

Metastatic Prostate Cancer of Hand.

Soft tissue metastases of prostate cancer to other sites are extremely rare, and, to our best knowledge, there have been no reports of metastasis to soft tissue of the hand. A 63-year-old man was diagnosed with prostatic cancer. During treatment, bone and soft tissue metastases to the right hand, appearing in the first web space, were observed. The tumor was resected, along with both the first and second metacarpal bones. The thumb was reconstructed by pollicization of the remaining index finger, enabling the patient to use the pollicized thumb for activities of daily living. This is the first case report of prostate cancer metastasizing to the soft tissue in hand. After wide resection, pollicization was able to reconstruct a functional hand and thumb.

Perceived mental stress and mortality from cardiovascular disease among Japanese men and women: the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study).

BACKGROUND: Perceived mental stress has been associated with risk of coronary heart disease (CHD) in white men, but no prospective data are available for other ethnic groups. METHODS AND RESULTS: From 1988 to 1990, a total of 73 424 Japanese (30 180 men and 43 244 women), aged 40 to 79 years, without a history of stroke, CHD, or cancer completed a lifestyle questionnaire including perception of mental stress under the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study). Systematic surveillance was completed until the end of 1997, with a 580 378 person-year follow-up, and the underlying causes of death were determined according to the International Classification of Diseases, 10th revision. For women, there were 316 with total stroke, 113 with CHD, and 643 with total cardiovascular disease (CVD); for men, there were 341, 168, and 778, respectively. Women who reported high stress had a 2-fold higher age-adjusted risk of mortality from total stroke and CHD and 1.5-fold higher risk of total CVD compared with those who reported low stress. Further adjustment for known cardiovascular risk factors and selected psychological variables did not alter the associations materially. The multivariate relative risk for women who perceived high stress versus low stress was 2.24 (95% CI 1.52 to 3.31, P<0.001) for total stroke, 2.28 (95% CI 1.17 to 4.43, P=0.02) for CHD, and 1.64 (95% CI 1.25 to 2.16, P<0.001) for total CVD. For men, these relations were generally weaker but suggestive of myocardial infarction. CONCLUSIONS: Perceived mental stress was associated with increased mortality from stroke for women and with CHD for men and women.

The relationships of gender, cigarette smoking, and hypertension with the risk of aneurysmal subarachnoid hemorrhage: a case-control study in Nagoya, Japan.

PURPOSE: To examine the relationship of gender, cigarette smoking, and a history of hypertension to the risk of aneurysmal subarachnoid hemorrhage (SAH), using a case-control study. METHODS: Case subjects consisted of a consecutive series of 201 patients with spontaneous SAH with aneurysm(s) confirmed by angiography and/or CT scan. One hospital and one community control subject was matched to each case by gender and age (+/- 2 years). Multiple conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) adjusted for potential confounders. RESULTS: Current smoking and a history of hypertension were each significantly associated with an increased risk of subarachnoid hemorrhage for men and women combined. There was also a non-significant trend towards synergism between these two factors with respect to an increased risk of subarachnoid hemorrhage for each gender separately and both combined. A significantly increased risk was observed for a history of hypertension (adjusted OR, 3.5; 95% CI, 1.2-14.7) among men, for current smoking alone (adjusted OR, 2.9; 95% CI, 1.1-7.7), and a history of hypertension alone (adjusted OR, 2.6; 95% CI, 1.4-5.1) among women. CONCLUSIONS: Trends towards gender differences and synergism emerged in the relationship of cigarette smoking and a history of hypertension of the risk of SAH provides useful information for targeting individuals/populations in programs for the primary prevention of SAH by gender.

Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan.

BACKGROUND: Few epidemiologic studies have examined the role of nutrient intake in the development of pancreatic cancer in Japan. We addressed this association in a population-based case-control study. METHODS: The cases were 109 patients who were newly diagnosed with pancreatic cancer between January 2000 and March 2002, and controls were selected by a random procedure from the general population. Data on dietary intake were collected by in-person interview, with the use of a food-frequency questionnaire. The risk of pancreatic cancer associated with nutrient intake was estimated by using the odds ratios (ORs) and 95% confidence intervals (CIs) derived from a conditional logistic model. RESULTS: A statistically positive trend in risk was observed with increasing cholesterol intake, with subjects in the highest tertile experiencing a two fold increased risk (OR, 2.06; 95% CI, 1.11-3.85; Ptrend = 0.02). Vitamin C intake was negatively associated with risk of pancreatic cancer. The OR was 0.45 (95% CI, 0.22-0.94) for subjects in the highest tertile compared to the lowest tertile (Ptrend = 0.04). CONCLUSIONS: Our study indicates that high cholesterol intake is significantly associated with an increased risk of pancreatic cancer and that high vitamin C intake decreases the risk of pancreatic cancer.

Pharmacokinetic and pharmacodynamic analysis of systemic effect of topically applied timolol maleate ophthalmic gelling vehicle (Rysmon TG).

PURPOSE: The objective of this study was to evaluate the degree of systemic absorption and the systemic side effect after instillation of timolol maleate ophthalmic gelling vehicle in human. METHODS: A volunteer study was employed, and a randomized crossover design with the two phases was used. In one phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic gelling vehicle; in the other phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic solution. The plasma concentration of timolol and the heart rates were studied during the following 120 min and 60 min, respectively. RESULTS: The area under the blood concentration time curve (AUC) in timolol maleate ophthalmic gelling vehicle was lower than that in timolol maleate ophthalmic solution (p < 0.05). No differences were observed in heart rates between ophthalmic gelling vehicle and ophthalmic solution. The correlation between the calculated occupancy of beta-adrenergic receptors and the systemic side effects after instillation could be successfully analyzed with a pharmacokinetic and pharmacodynamic model, showing the predictability of the model for the systemic side effects of timolol. CONCLUSIONS: The result of our analysis clearly shows that timolol maleate ophthalmic gelling vehicle reduced the systemic absorption below that of ophthalmic solution, but the degree in difference of systemic effects was negligible.