Yasutomi Kinosada

Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy

We prepared fast dissolving oral thin film that contains dexamethasone and base materials, including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose. This preparation showed excellent uniformity and stability, when stored at 40 degrees C and 75% in humidity for up to 24 weeks. The film was disintegrated within 15s after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5 min. Subsequently, pharmacokinetic properties of dexamethasone were compared in rats with oral administration of 4 mg dexamethasone suspension or topical application of the film preparation containing 4 mg dexamethasone to the oral cavity. Pharmacokinetic parameters were similar between the two groups in which C(max) (h), T(max) (microg/mL), AUC (microg/mL/h) and half-life (h) were 12.7+/-6.6 (mean+/-SD, N=10), 3.4+/-1.4, 93.6+/-37.8 and 1.66+/-0.07, respectively, for oral suspension and 13.3+/-4.0, 3.2+/-1.0, 98.0+/-22.3 and 1.65+/-0.06, respectively, for film preparation. These findings suggest that the fast dissolving oral thin film containing dexamethasone is likely to become one of choices of dexamethasone preparations for antiemesis during cancer chemotherapy.

Analysis of the Interaction between Clopidogrel, Aspirin, and Proton Pump Inhibitors Using the FDA Adverse Event Reporting System Database

Clopidogrel is an antiplatelet agent widely used in combination with aspirin to limit the occurrence of cardiovascular (embolic/thrombotic) events. Consensus guidelines recommend proton pump inhibitors (PPIs) as a gastrointestinal (GI) prophylactic measure for all patients receiving dual antiplatelet therapy with clopidogrel and aspirin. The objective of this study was to analyze the effect of the simultaneous use of clopidogrel, aspirin, and PPIs on hemorrhagic and embolic/thrombotic events using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Reports of hemorrhagic and embolic/thrombotic events between 2004 and 2013 were analyzed with a reporting odds ratio (ROR) algorithm and logistic regression methods. The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify such events. Regarding hemorrhagic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 4.40 (95% confidence interval [CI], 4.02-4.81) and 3.40 (95% CI, 2.84-4.06), respectively. For embolic/thrombotic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 2.37 (95% CI, 2.16-2.59) and 2.38 (95% CI, 2.00-2.84), respectively. Among patients included in the FAERS database, the concurrent use of aspirin and clopidogrel with PPIs reduced the adjusted ROR of GI hemorrhagic events. PPIs had little influence on the adjusted ROR of embolic/thrombotic events. These results support the use of PPIs as a preventive measure against GI hemorrhagic events for patients receiving clopidogrel and aspirin.

Equivalent cross-relaxation rate imaging in the synthetic copolymer gels and invasive ductal carcinomas of the breast

The values of equivalent cross-relaxation rate (ECR) correlated well with [i] water conditions in various copolymer gels and [ii] nature of malignant cells with regard to nuclear dysplasia and mitotic potential in breast carcinomas. The synthetic copolymer gels composed of any two or three monomers among 2-hydroxyethyl methacrylate (HEMA), glycidyl methacrylate (GMA), N-vinyl-2-pyrrolidinone (N-VP), methyl methacrylate (MMA) and benzyl methacrylate (BMA). The ECR measurement was performed by using an off-resonance saturation pulse under conventional field-echo imaging at frequency within +/- 75 ppm apart from the water resonance frequency. The ECR values were readily to determine and non-time consuming parameter for cross relaxation rate. The ECR values at the frequency offset by 7-ppm (ECR-7) were divided the sample gels two classes, which must correspond to hydrophilic or hydrophobic ones. The sensitivity in the gels was nearly equivalent to the cross-relaxation rate itself. In the breast carcinomas, the ECR-7 correlates with the nature of malignant cells with regard to nuclear dysplasia and mitotic potential. The ECR-7 is better or more accurate than the STR-7 because the SDNRs between carcinoma and glandular tissue increased by approximately 50% on the ECR-7 compared with the STR-7. Thus the ECR values could be a new parameter for malignancy and cell proliferative activity of the breast carcinomas with non-invasive modalities by magnetic resonance imaging.

Evaluation of Dabigatran- and Warfarin-Associated Hemorrhagic Events Using the FDA-Adverse Event Reporting System Database Stratified by Age

Dabigatran and warfarin are oral anticoagulant drugs widely used for the prevention of stroke in patients with atrial fibrillation. The objective of this study was to evaluate the interaction between aging and dabigatran- and warfarin-induced gastrointestinal (GI) and nervous system hemorrhage using data available in the FDA Adverse Event Reporting System (FAERS) database. We analyzed reports of hemorrhagic events in the GI and nervous system recorded in the FAERS database between 2004 and 2014 using an adjusted reporting odds ratio (ROR). We demonstrated that dabigatran-associated GI hemorrhage was significantly increased in patients over the age of 80 years. The RORs of dabigatran increased with increasing age, although aging had little effect on warfarin-associated GI hemorrhage. The ROR for anticoagulant-associated nervous system hemorrhage was not significantly affected by aging, as compared to GI hemorrhage. Our results indicate that the excretion of dabigatran may be affected by aging, as compared to warfarin, likely due to renal function decline. Our results emphasize the need for physicians to closely monitor GI bleeding in aging patients, because it is closely related to renal function deterioration.

Equivalent cross-relaxation rate imaging of breast cancer.

To determine whether equivalent cross‐relaxation rate (ECR) imaging is a feasible method for demonstrating breast cancer.

Time-to-Onset Analysis of Drug-Induced Long QT Syndrome Based on a Spontaneous Reporting System for Adverse Drug Events

Long QT syndrome (LQTS) is a disorder of the heart’s electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database. For signal detection, we used the reporting odds ratio (ROR). Furthermore, we analyzed the time-to-onset data and assessed the hazard type using the Weibull shape parameter. The RORs (95% confidence interval) for bepridil, amiodarone, pilsicainide, nilotinib, disopyramide, arsenic trioxide, clarithromycin, cibenzoline, donepezil, famotidine, sulpiride, and nifekalant were 174.4 (148.6–204.6), 17.3 (14.7–20.4), 52.0 (43.4–62.4), 13.9 (11.5–16.7), 69.3 (55.3–86.8), 54.2 (43.2–68.0), 4.7 (3.8–5.8), 19.9 (15.9–25.0), 8.1 (6.5–10.1), 3.2 (2.5–4.1), 7.1 (5.5–9.2), and 254.8 (168.5–385.4), respectively. The medians and quartiles of time-to-onset for aprindine (oral) and bepridil were 20.0 (11.0–35.8) and 18.0 (6.0–43.0) days, respectively. The lower 95% confidence interval of the shape parameter β of bepridil was over 1 and the hazard was considered to increase over time.Our study indicated that the pattern of LQTS onset might differ among drugs. Based on these results, careful long-term observation is recommended, especially for specific drugs such as bepridil and aprindine. This information may be useful for the prevention of sudden death following LQTS and for efficient therapeutic planning.

Hyperglycemic adverse events following antipsychotic drug administration in spontaneous adverse event reports

BackgroundAntipsychotics are potent dopamine antagonists used to treat schizophrenia and bipolar disorder. The aim of this study was to evaluate the relationship between antipsychotic drugs and adverse hyperglycemic events using the FDA Adverse Event Reporting System (FAERS) database. In particular, we focused on adverse hyperglycemic events associated with atypical antipsychotic use, which are major concerns.FindingsWe analyzed reports of adverse hyperglycemic events associated with 26 antipsychotic drugs in the FAERS database from January 2004 to March 2013. The Standardized Medical Dictionary for Regulatory Activities Queries (SMQ) preferred terms (PTs) was used to identify adverse hyperglycemic events. The number of adverse hyperglycemic reports for the top eight antipsychotic drugs, quetiapine, olanzapine, risperidone, aripiprazole, haloperidol, clozapine, prochlorperazine, and chlorpromazine was 12,471 (28.9%), 8,423 (37.9%), 5,968 (27.0%), 4,045 (23.7%), 3,445 (31.5%), 2,614 (14.3%), 1,800 (19.8%), and 1,003 (35.7%), respectively. The reporting ratio increased with co-administration of multiple antipsychotic drugs. For example, adverse hyperglycemic events represented 21.6% of reports for quetiapine monotherapy, 39.9% for two-drug polypharmacy, and 66.3% for three-drug polypharmacy.ConclusionAntipsychotic drug polypharmacy may influence signal strength, and may be associated with hyperglycemia. After considering the causality restraints of the current analysis, further robust epidemiological studies are recommended.

Stevens–Johnson syndrome and toxic epidermal necrolysis: The Food and Drug Administration adverse event reporting system, 2004–2013

StevenseJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are severe cutaneous adverse reactions, are associated with fatal disorders.1 Although many causes of SJS/TEN have been proposed, their pathogenesis is not fully understood. Hypersensitivity to medications accounts for the majority of cases of SJS/ TEN.2 Several research groups have presented reports on drugs implicated in SJS/TEN (selective cyclooxygenase-2 inhibitors, lamotrigine, anti-epileptic drugs, sulfonamide antibiotics, and allopurinol, etc.).3,4 SJS associated with Mycoplasma pneumoniae infection is observed mainly in children,5,6 while another group reported the effects of the genetic background of patients.7 The relationship between aging and SJS/TEN is still not clear. Since SJS/TEN are very rare diseases,1 the implementation phase of epidemiologic research is fraught with difficulties. The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) is the largest and most well-known database worldwide, and it reflects the realities of clinical practice.8 FAERS, therefore, is one of the primary tools used in pharmacovigilance. We examined the incidence of SJS/TEN in the FAERS database from January 2004 to March 2013. To extract case reports of SJS/ TEN from the FAERS database, SJS/TEN were coded according to the terminology preferred by the Medical Dictionary for Regulatory Activities 16.0. We used the following three preferred terms to match SJS and TEN: SJS/PT10042033, oculomucocutaneous syndrome/PT10030081, and TEN/PT10044223. To detect SJS/TEN incidences, we calculated the reporting odds ratio (ROR), which is established for pharmacovigilance by using a disproportionality analysis.8 The ROR is an applicable technique that allows for adjustment through logistic regression analysis and offers the advantageous possibility of controlling for covariates.9 We refined the results with a dedicated correction to detect possible confounders present in the database. The reports were stratified by age as follows: 17 years, 18e39 years, 40e59 years, 60e79 years, and 80 years. The RORs were adjusted for gender, reporting year, and stratified age group. The following logistic model was used:

Computer-aided diagnosis scheme for classification of lacunar infarcts and enlarged Virchow-Robin spaces in brain MR images

The detection of asymptomatic lacunar infarcts on magnetic resonance (MR) images is important because their presence indicates an increased risk of severe cerebral infarction. However, accurate identification of lacunar infarcts on MR images is often hard for radiologists because of the difficulty in distinguishing lacunar infarcts and enlarged Virchow-Robin spaces. Therefore, we developed a computer-aided diagnosis (CAD) scheme for the classification of lacunar infarcts and enlarged Virchow-Robin spaces. Our database consisted of T1- and T2- weighted images obtained from 109 patients. The locations of lacunar infarcts and enlarged Virchow-Robin spaces were determined by an experienced neuroradiologist. It included 89 lacunar infarcts and 20 enlarged Virchow-Robin spaces. We first enhanced the lesions in T2-weighted image by using the white top-hat transformation. A gray-level thresholding was then applied to the enhanced image for the segmentation of lesions. From the segmented lesions, we determined image features, such as size, shape, location, and signal intensities in T1- and T2- weighted images. A neural network was then employed for distinguishing between lacunar infarcts and enlarged Virchow-Robin spaces. Our computerized method was evaluated by using a leave-one-out method. The result indicated that the area under the ROC curve was 0.945. Therefore, our CAD scheme would be useful in assisting radiologists for diagnosis of silent cerebral infarctions in MR images.

Equivalent cross‐relaxation rate imaging of axillary lymph nodes in breast cancer

To determine whether equivalent cross‐relaxation rate (ECR) imaging (ECRI) is a feasible method for optimization of axillary lymph node dissection (ALND) and thereby improve quality‐of‐life (QOL).