MR Imaging Detection of CNS Lesions in Tuberous Sclerosis Complex: The Usefulness of T1WI with Chemical Shift Selective Images.

BACKGROUND AND PURPOSE: CNS lesions of tuberous sclerosis complex are diagnosed mainly by T2WI, FLAIR, and sometimes T1WI with magnetization transfer contrast. The usefulness of T1WI with chemical shift selective images was recently reported in focal cortical dysplasia type IIb, which has histopathologic and imaging features similar to those of tuberous sclerosis complex. We investigated the usefulness of the T1WI with chemical shift selective images in detecting CNS lesions of tuberous sclerosis complex. MATERIALS AND METHODS: We retrospectively reviewed 25 consecutive patients with tuberous sclerosis complex (mean age, 11.9 [SD, 8.9] years; 14 males) who underwent MR imaging including T1WI, T1WI with magnetization transfer contrast, T1WI with chemical shift selective, T2WI, and FLAIR images. Two neuroradiologists assessed the number of CNS lesions in each sequence and compared them in 2 steps: among T1WI, T1WI with magnetization transfer contrast and T1WI with chemical shift selective images, and among T2WI, FLAIR, and T1WI with chemical shift selective images. We calculated the contrast ratio of the cortical tubers and of adjacent normal-appearing gray matter and the contrast ratio of radial migration lines and adjacent normal-appearing white matter in each sequence and compared them. RESULTS: T1WI with chemical shift selective images was significantly superior to T1WI with magnetization transfer contrast for the detection of radial migration lines and contrast ratio of radial migration lines. There was no significant difference between T1WI with chemical shift selective images and T1WI with magnetization transfer contrast for the detection of cortical tubers and the contrast ratio of the cortical tubers. Both T2WI and FLAIR were statistically superior to T1WI with chemical shift selective images for the detection of cortical tubers. T1WI with chemical shift selective images was significantly superior to T2WI and FLAIR for the detection of radial migration lines. CONCLUSIONS: The usefulness of T1WI with chemical shift selective images in detecting radial migration lines was demonstrated. Our findings suggest that the combination of T1WI with chemical shift selective images, T2WI, and FLAIR would be useful to evaluate the CNS lesions of patients with tuberous sclerosis complex in daily clinical practice.

Organ Impairment-Drug-Drug Interaction Database: A Tool for Evaluating the Impact of Renal or Hepatic Impairment and Pharmacologic Inhibition on the Systemic Exposure of Drugs.

The organ impairment and drug-drug interaction (OI-DDI) database is the first rigorously assembled database of pharmacokinetic drug exposure data from publicly available renal and hepatic impairment studies presented together with the maximum change in drug exposure from drug interaction inhibition studies. The database was used to conduct a systematic comparison of the effect of renal/hepatic impairment and pharmacologic inhibition on drug exposure. Additional applications are feasible with the public availability of this database.

Effect of articulatory rehabilitation after oral cancer surgery on higher brain activation.

The present study aimed to verify the importance of postoperative articulatory rehabilitation in patients with oral cancer and to clarify the neurological changes underlying articulatory functional recovery. A longitudinal assessment of oral function and accompanying brain activity was performed using non-invasive functional magnetic resonance imaging (fMRI). We assessed 13 patients with cancers of the tongue and oral floor before and after ablative surgery. Articulatory function was assessed preoperatively and postoperatively using a conversation intelligibility test and the Assessment of Motor Speech for Dysarthria test. Patients also performed a verbal task during fMRI scans. The assessments were then repeated after the patients had undergone 4-6 months of articulatory rehabilitation therapy. Compared to pretreatment levels, articulatory rehabilitation resulted in a significant increase in activation in the supplementary motor cortex, thalamus, and cingulate cortex. The present study offers a quantitative assessment of the effects of speech rehabilitation by investigating changes in brain activation sites.

Assessment of factors associated with dose differences between Japan and the United States.

Although it is well known that there are differences in approved doses between Japan and the United States, there has been no comprehensive research into the causes thereof. This study furthers the discussion of our previous investigation in 2010, with particular focus on pharmaceutical industry strategy and regulatory policy, among drugs approved in Japan between 2001 and 2009. Dose differences were observed in 73 of 190 drugs. Non-Japanese firms were more likely to have a similar dose approved between Japan and the United States, the association being more pronounced when limiting the analysis to drugs for which a Japanese dose-finding study was not conducted. Furthermore, dose differences were less frequent when non-Japanese efficacy data were included in the application data package. No relation between potential intrinsic ethnic difference and dose difference could be identified. The results suggest that the pathway of drug development is more strongly associated with dose difference than are drug characteristics.

Different contributions of internal reviewers and external experts to labelling decisions on therapeutic indications in new drug reviews in Japan.

WHAT IS KNOWN AND OBJECTIVE: External experts play an important role in shaping regulatory decisions in the new drug review process in the United States, Europe and Japan. No rigorous study has been performed addressing how and to what extent external experts, in contrast to internal reviewers in the agency, influence the regulatory decisions during new drug reviews. We examined their contributions in Japanese regulatory reviews in contrast to the internal reviewers, focusing on the labelling decision on therapeutic indications. METHODS: With the data set of 219 new molecular entities (NMEs) approved in Japan from 2000 to 2009, we observed how proposed indications in labelling were modified in a stepwise manner during the review process and conducted multinomial logistic analysis to examine the possible mechanism behind. RESULTS AND DISCUSSION: We found that interim assessment of indications by the internal reviewers was modified substantially by the influence of the external experts in about 20% of the 219 NMEs. Our analysis suggested that internal reviewers provided their opinion mainly based on strict review discipline, whereas external experts added flexibility and reality to their reviews. Our analysis revealed different evaluations between internal reviewers and external experts during regulatory discussions in new drug reviews and how the external panel contributes to changing internal decisions. WHAT IS NEW AND CONCLUSION: This study provides a new and quantitative approach to better label setting by emphasizing the contributions of each stakeholder in new drug reviews, which would improve the efficiency, quality and transparency of new drug reviews to enhance public health.

Involvement of prolactin-releasing peptide in the activation of oxytocin neurones in response to food intake.

Food intake activates neurones expressing prolactin-releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. In the present study, we investigated whether the activation of oxytocin neurones following food intake is mediated by PrRP. We first examined the expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated the release of oxytocin and vasopressin. In mice, re-feeding increased the expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or i.p. administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor-deficient mice showed an increased meal size, as reported in PrRP-deficient mice and in CCKA receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, the activation of oxytocin neurones in response to food intake, and that the CCK-PrRP-oxytocin pathway plays an important role in the control of the termination of each meal.

Effect of local anesthesia on trigeminal somatosensory-evoked magnetic fields.

For objective neurophysiological evaluation of the function of the trigeminal system, magnetoencephalography- based TSEF (trigeminal somatosensory-evoked field) assessment would be valuable in providing spatial and temporal profiles of cortical responses. However, this necessitates knowledge of how TSEF varies with trigeminal nerve dysfunctions. We introduced a conduction block of the trigeminal nerve using local anesthesia (lidocaine) to temporally mimic nerve dysfunctions, and monitored TSEF changes. Following an electrical stimulation of the lower lip, a magnetic response with peak latency of approximately 20 ms was identified in all participants. Dipole for the peak was estimated on the post-central gyrus in the participant's own magnetic resonance image. After normalization to Montreal Neurological Institute (MNI) space and inter-participant data integration, the summary equivalent current dipole localization among participants remained in the post-central gyrus, suggesting validity of the use of MNI space. Partial anesthesia of the lower lip led to a loss of the waveform characteristics of TSEF for electrical stimulation to the trigeminal nerve. We verified that the 20-ms latency cortical response of TSEF components localized at the primary sensory cortex can serve as a robust neurofunctional marker of experimental trigeminal nerve dysfunction.

Analysis of regulatory review times of new drugs in Japan: association with characteristics of new drug applications, regulatory agency, and pharmaceutical companies.

WHAT IS KNOWN AND OBJECTIVE: Various factors have been reported to be associated with the duration of regulatory review of new drug applications (NDAs). We investigated potential links between the review times in Japan and the attributes of NDAs, the regulatory agency and pharmaceutical companies. METHODS: We analysed new drugs approved in 2000-2009 in Japan using a proprietary database collected through annual surveys to pharmaceutical companies. Regression models in which individual firms were treated as either a fixed effect or a random effect were applied to examine factors associated with the overall review time and the duration of each step of the review. RESULTS AND DISCUSSION: The fixed effect model analysis using variations within each firm indicated that new molecular entities that were submitted to the Pharmaceuticals and Medical Devices Agency (PMDA), priority reviews and pre-NDA consultations were associated with a shorter overall review time, whereas additional studies during the review resulted in a longer review. In the random effect model analysis using both within- and between-firm variations, use of end-of-phase 2 consultations and foreign clinical data also had negative coefficients, suggesting the effect of these two vary among firms. Analysis of each step of the review process revealed NDAs reviewed by the Committee on Drugs under the Ministry of Health, Labour and Welfare, and the number of NDAs assigned to a review team were significantly linked with their duration, whereas consultation services and the number of reviewers had no relation. WHAT IS NEW AND CONCLUSION: Factors associated with each step of the review process as well as the differences in attributes and strategies among pharmaceutical companies should be considered to further improve the speed, quality and efficiency of the regulatory review.

Analysis of labeling decisions regarding therapeutic indications during new drug application reviews in Japan.

We analyzed regulatory reviews in Japan to study the modifications made in drug labeling with respect to proposed therapeutic indications, and investigated factors associated with these changes so as to gain insight into the reasons behind the decisions. Of 220 new molecular entities (NMEs) approved in Japan from 2000 to 2009, 70 received more restricted indications and 14 received more expanded indications than those proposed by the applicants. Multinomial regression analysis suggested that the presence of competitive drugs in the market, higher estimated peak sales, and higher complexity of the proposed indication were factors that significantly increased the likelihood of the indications being restricted on review, in addition to factors related to adequacy of efficacy data. Our results give us a clue to how the approved therapeutic indications reflect the characteristics of the applicants, drugs, review areas (RAs), and clinical evidence in the submitted data package, as well as to the principle behind the decisions.

Clinical development and review times for new drugs in Japan: associated factors.

The length of clinical development and review procedures related to new drugs approved in Japan in 2000-2009 were analyzed. The length of time taken for clinical development varied depending on diversification of strategies, and the review times showed a decline during this period. Regression analyses suggested that clinical development times were significantly shorter for non-new molecular entities (non-NMEs), priority reviews, conditional approvals, and drugs utilizing foreign clinical data. The review times were shorter for new drug applications (NDAs) submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) and for priority reviews. The effects of pre-NDA consultations were mixed; the review time was shorter, but the clinical development period was prolonged.

Exploring differences in drug doses between Japan and Western countries.

Japan is unique among Asian countries in that it requires inclusion of substantial domestic clinical trial data in new drug application data packages. Some question the need for this and call for globalization of approved doses. The current study examines international differences in maximum daily dose of drugs approved in Japan between 2001 and 2007, and for all cardiovascular system (CVS) and central nervous system (CNS) drugs marketed in Japan. For 32% of the drugs approved in Japan between 2001 and 2007, the maximum recommended dose in the United States was > or =2 times higher than the maximum dose approved in Japan. Dose differences were rare for antitumor and antiviral drugs and also for priority-review and orphan drugs. Of all the price-listed CVS drugs currently available in Japan, 65% had maximum doses that were > or =2 times higher in the Netherlands than in Japan; similarly, 57% of the drugs had maximum doses that were > or =2 times higher in the United States than in Japan. For CNS drugs, these figures were 32% (the Netherlands) and 29% (United States). These results underscore the necessity to carry out quantitative analyses to determine the causes of these differences.

Delays in new drug applications in Japan and industrial R&D strategies.

The gap between Japan and both the United States (US) and the European Union (EU) with regard to access to new drugs is becoming a major issue in Japan. We analyzed the time lags involved in new drug application (NDA) and biological license application submissions in Japan, the US, and the EU in order to identify the causes of delayed access. The time lag related to submission of applications ("submission lag") was longer for in-licensed products and for non-Japanese companies. Factors related to costs of clinical studies and potential volumes of sales were not associated with the submission lag. A bridging strategy (extrapolative use of foreign clinical data in the clinical data package based on International Conference on Harmonisation guideline E5) seemed to reduce submission lag, but the association between the two diminished when the cause-and-effect relationship was specifically investigated. These results suggest that multinational companies are likely to place more emphasis on the choice of development strategies that successfully lead to their goal rather than on direct costs and expected sales when deciding to introduce their pharmaceutical products in Japan. Our findings indicate that the clinical development guidances that helps pharmaceutical companies decide on investment and strategies are also the key to narrowing the gap in access to new drugs.

Nicotine enhances skin necrosis and expression of inflammatory mediators in a rat pressure ulcer model.

BACKGROUND: Many bedridden patients develop pressure ulcers, not only in hospital but also at home. Clinical studies have indicated cigarette smoking to be a risk factor for pressure ulcers. However, the contribution of nicotine to pressure ulcer formation has not been identified. OBJECTIVES: We aimed to clarify the effect of nicotine on pressure ulcer formation, and its mechanism. METHODS: Ischaemia-reperfusion (I/R) was performed in rat dorsal skin to induce pressure ulcers. The extent of the resulting necrotic area was determined. To clarify the mechanism of the effect of nicotine, mRNA levels of cyclooxygenase-2 (COX-2), interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase (iNOS) and protein expression of COX-2 and iNOS in the necrotic area were investigated by real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. Furthermore, the effects of the COX-2 inhibitor NS-398 and the iNOS inhibitor aminoguanidine on necrosis were examined. RESULTS: Skin necrosis in the I/R-treated area was significantly increased by intraperitoneal administration of nicotine (0.175 mg kg(-1) daily). Repeated nicotine administration had little effect on systolic and diastolic blood pressure. I/R treatment increased mRNA levels of COX-2, IL-1beta, IL-6 and iNOS, which were further augmented by nicotine in a dose-dependent manner. Correspondingly, nicotine (0.35 mg kg(-1) daily) markedly enhanced the protein expression of COX-2 and iNOS. Moreover, NS-398 and aminoguanidine showed a tendency to abrogate the increase of I/R-induced skin necrosis caused by nicotine. CONCLUSIONS: These results suggest that the increased risk of pressure ulcers due to cigarette smoking is mediated, in part, by nicotine. They also indicated that the effect of nicotine is not mediated by a change in blood pressure, but is elicited via an increase of inflammatory mediators in the I/R-treated skin.

Increased expression and activation of matrix metalloproteinase-2 (MMP-2) in O-1N: hamster oral squamous cell carcinoma with high potential lymph node metastasis.

Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers with poor clinical outcome. MMP-2 was implied to contribute to the invasiveness and metastatization of various malignancies because of the degradation of type IV collagen. In this experiment, ELISA, Western blot and Q-RT-PCR was performed to investigate the expression and activation of MMP-2 in serum and tumor from hamster oral cancer model with high lymph node metastasis based on the various stages of OSCC development. Active MMP-2 in the serum was found elevated during oral cancer progression. In the metastatic stage, total MMP-2 level was 46% higher than it in the expansive stage, while active MMP-2 level increased 6-fold than it in the expansive stage. MMP-2 serum activation ratio was significantly enhanced in the metastatic stage than before tumor transplantation and that in the expansive stage. MMP-2 protein and MMP-2 mRNA was found to be increased during oral cancer development in hamster models. The increase of MMP-2 expression and activation starts prior to the metastasis occurrence, indicating the important role of MMP-2 in the early phase of oral cancer progression. Active MMP-2 level in serum may be a useful indicator for monitoring oral cancer progression.

Immobilization stress induces BDNF in rat submandibular glands.

Brain-derived neurotrophic factor (BDNF) promotes survival and differentiation of the cells of the central and peripheral nervous systems. BDNF has been identified in non-neural tissue, including the heart, lung, platelets, lymphocytes, and lacrimal glands. Immobilization stress modifies BDNF mRNA expression in some organs. The present study examines the effect of immobilization stress on BDNF, and its receptor TrkB, in male rat submandibular glands. Increased BDNF mRNA and protein expression were observed in duct cells as a result of immobilization stress, as demonstrated by real-time PCR, Western blot, immunohistochemistry, and analysis by microdissection. TrkB mRNA was not detected in salivary gland tissue, or oral or esophageal mucosa, by RT-PCR. Rat submandibular gland was thus identified as an organ which expresses BDNF. Furthermore, the results of this study suggest that increased salivary BDNF expression occurs following immobilization stress.

Deep lamellar keratoplasty by deep parenchyma detachment from the corneal limbs.

AIM: To improve the deep lamellar keratoplasty technique. METHOD: For the easy and reliable perfomance of deep lamellar keratoplasty (DLKP), detachment of Descemet's membrane through the corneal limber flap was improved. To expose Descemet's membrane, the parenchyma was detached by hydrodelamination through a sclerocorneal flap made in the corneal limbs. The parenchyma was removed after the pseudochamber between it and Descemet's membrane was maintained with viscoelastic material. The corneal graft was placed with a running suture. 22 eyes were treated. RESULTS: Complete exposure of Descemet's membrane was obtained in 20 of the 22 eyes (91%). The membrane was perforated in five of the 22 eyes (23%) during surgery, and two of the 22 eyes (9%) were converted to penetrating keratoplasty. These two eyes developed keratoconus after acute corneal hydrops. CONCLUSION: Compared with the conventional procedure, this new method provides easy, reliable exposure of Descemet's membrane.

Update results of FEC followed by docetaxel neoadjuvant trials for primary breast cancer.

This study has been initiated to evaluate the safety, clinical and pathologic response as well as the relation of response (pCR or non-pCR) and survival (overall and relapse-free) of fluorouracil, epirubicin and cyclophosphamide (FEC) followed by docetaxel (DOC) as preoperative chemotherapy in patients with operable breast cancer. Japanese patients with primary breast cancer, Tlc-3N0M0 or T1-3NIM0, age 20-60, PS 0-1 were included in this study. Preoperative chemotherapy consisted of 4 cycles of FEC (500 mg/m(2), 100 mg/m(2), 500 mg/m(2)) every 3 weeks followed by 4 cycles of DOC (75 mg/m(2)) every 3 weeks. Since June 2002, 200 patients were enrolled in this study, and the time of this interim analysis, 80 patients were evaluable for safety and clinical efficacy. The overall clinical response rate was 71.4% (14% CR, 44% PR, 42% SD/PD), and the only G3,4 toxicities, neutropenia and febrile neutropenia were observed in 54% and 14% of patients, respectively. Eighty nine patients were evaluable for pathologic response by central review. Pathologic response was evaluated among invasive tumors on multiple cross-section specimens based on a modified version of the Japanese grading system for Japanese Breast Cancer Society. The pathologic response rate was 17%. In this ongoing trial, FEC followed by DOC was active and well tolerated.

Effects of toremifene (TOR) and tamoxifen (TAM) on serum lipids in postmenopausal patients with breast cancer.

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher (p < 0.01) and TG was significantly lower (p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.

Effect of hematocrit on pharmacokinetics of tacrolimus in adult living donor liver transplant recipients.

OBJECTIVE: Plasma drug concentrations are generally considered to reflect efficacy and pharmacokinetics more directly than those in whole blood. However, whole blood has been selected as the matrix to monitor concentrations of tacrolimus (FK506), because it is difficult to accurately measure plasma FK506 concentrations. Because FK506 highly and saturably binds in blood cells, a change in hematocrit value (Hct) may affect FK506 pharmacokinetics. Therefore, we investigated effects of Hct on FK506 pharmacokinetics. METHODS: First, we analyzed data on FK506 distribution among human blood cells in vitro. Briefly, we employed an equation, which describes saturable binding of FK506 to blood cells, and simulated plasma FK506 concentrations and clearances using the above equation with respect to a variable Hct. Subsequently, we retrospectively analyzed dosages and whole blood FK506 concentrations to predict plasma FK506 concentrations in living donor transplant recipients. RESULTS: In the simulation study, the Hct changed plasma FK506 concentrations and clearances based in whole blood. In living donor liver transplant recipients, whole blood FK506 concentrations were maintained within a therapeutic range, while the Hct varied after transplantation. The correlation of Hct with the ratio of dose/trough concentrations of FK506 (D/C) in plasma (D/Cp) (R = -0.23, n = 343) was weaker than that for D/C in whole blood (D/CWB) (R = -0.53, n = 343). CONCLUSION: Hct may be an important factor affecting the pharmacokinetics of FK506 in living donor liver transplantation recipients. It may be necessary to take Hct into consideration in the FK506 dosing regimen, especially when the Hct is low.