Quantification of Unencapsulated Drug in Target Tissues Demonstrates Pharmacological Properties and Therapeutic Effects of Liposomal Topotecan (FF-10850).

PURPOSE: Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen. METHODS: We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration-time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model. RESULTS: FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage. CONCLUSIONS: Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens.

Endoplasmic Protein Nogo-B (RTN4-B) Interacts with GRAMD4 and Regulates TLR9-Mediated Innate Immune Responses.

TLRs are distributed in their characteristic cellular or subcellular compartments to efficiently recognize specific ligands and to initiate intracellular signaling. Whereas TLRs recognizing pathogen-associated lipids or proteins are localized to the cell surface, nucleic acid-sensing TLRs are expressed in endosomes and lysosomes. Several endoplasmic reticulum (ER)-resident proteins are known to regulate the trafficking of TLRs to the specific cellular compartments, thus playing important roles in the initiation of innate immune responses. In this study, we show that an ER-resident protein, Nogo-B (or RTN4-B), is necessary for immune responses triggered by nucleic acid-sensing TLRs, and that a newly identified Nogo-B-binding protein (glucosyltransferases, Rab-like GTPase activators and myotubularins [GRAM] domain containing 4 [GRAMD4]) negatively regulates the responses. Production of inflammatory cytokines in vitro by macrophages stimulated with CpG-B oligonucleotides or polyinosinic:polycytidylic acid was attenuated in the absence of Nogo-B, which was also confirmed in serum samples from Nogo-deficient mice injected with polyinosinic:polycytidylic acid. Although a deficiency of Nogo-B did not change the incorporation or delivery of CpG to endosomes, the localization of TLR9 to endolysosomes was found to be impaired. We identified GRAMD4 as a downmodulator for TLR9 response with a Nogo-B binding ability in ER, because our knockdown and overexpression experiments indicated that GRAMD4 suppresses the TLR9 response and knockdown of Gramd4 strongly enhanced the response in the absence of Nogo-B. Our findings indicate a critical role of Nogo-B and GRAMD4 in trafficking of TLR9.

Responses of macrophages to the danger signals released from necrotic cells.

The immune system maintains homeostasis by recognizing and responding to cell death caused by various stresses. The immune response is considered to be elicited by 'danger signals' released from necrotic cells. However, the identity of the danger signals remains elusive. In this study, we focused on the expression of chemokines by macrophages stimulated with necrotic cells. In mouse bone-marrow-derived macrophages, the chemokine monocyte chemoattractant protein (MCP)-3 was induced at both the mRNA and protein levels in response to heat-killed murine cells. The induction of MCP-3 was also observed in MyD88-deficient macrophages, indicating that Toll-like receptors and the IL-1 receptor are not involved in this response. Consistent with this observation, the activation of NF-κB was not detected in RAW264.7 macrophages stimulated with necrotic cells. Treatments with proteinase K, DNaseI or RNaseA did not affect the ' STIMULATING ACTIVITY': of necrotic cells. In contrast, treatment with apyrase, which removes phosphates from nucleoside tri- and di-phosphates, abolished the inducing activity. Purified UDP at 30 µM concentration elicited similar induction of MCP-3 in RAW264.7 macrophages. Small interfering RNA-mediated knock-down of the UDP receptor P2Y6 in RAW264.7 cells significantly reduced the induction of MCP-3 in response to necrotic cells, but not its induction by lipopolysaccharide. Furthermore, ectopic expression of the P2Y6 receptor in HEK293 cells conferred responsiveness to necrotic cells. These results suggest that UDP released by necrotic cells plays a critical role as an endogenous danger signal and that P2Y6 is required for the induction of MCP-3 in response to necrotic cells.

FF-10850, a Novel Liposomal Topotecan Achieves Superior Antitumor Activity via Macrophage- and Ammonia-Mediated Payload Release in the Tumor Microenvironment.

Topotecan, an approved treatment for refractory or recurrent ovarian cancer, has clinical limitations such as rapid clearance and hematologic toxicity. To overcome these limitations and maximize clinical benefit, we designed FF-10850, a dihydrosphingomyelin-based liposomal topotecan. FF-10850 demonstrated superior antitumor activity to topotecan in ovarian cancer cell line-based xenograft models, as well as in a clinically relevant DF181 platinum-refractory ovarian cancer patient-derived xenograft model. The safety profile was also improved with mitigation of hematologic toxicity. The improved antitumor activity and safety profile are achieved via its preferential accumulation and payload release triggered in the tumor microenvironment. Our data indicate that tumor-associated macrophages internalize FF-10850, resulting in complete payload release. The release mechanism also appears to be mediated by high ammonia concentration resulting from glutaminolysis, which is activated by tumor metabolic reprogramming. In ammonia-rich conditions, FF-10850 released payload more rapidly and to a greater extent than liposomal doxorubicin, a currently approved treatment for ovarian cancer. FF-10850 significantly enhanced antitumor activity in combination with carboplatin or PARP inhibitor without detrimental effects on body weight in murine xenograft models, and demonstrated synergistic antitumor activity combined with anti-PD-1 antibody with the development of tumor antigen-specific immunity. These results support phase I investigation of FF-10850 for the treatment of solid tumors including ovarian cancer (NCT04047251), and further evaluation in combination settings.

Waggle dance effect: dancing in autumn reduces the mass loss of a honeybee colony.

A honeybee informs her nestmates about the location of a profitable food source that she has visited by means of a waggle dance: a round dance and a figure-of-eight dance for a short- and long-distance food source, respectively. Consequently, the colony achieves an effective collection of food. However, it is still not fully understood how much effect the dance behavior has on the food collection, because most of the relevant experiments have been performed only in limited locations under limited experimental conditions. Here, we examined the efficacy of the waggle dances by physically preventing bees from dancing and then analyzing the changes in daily mass of the hive as an index of daily food collection. To eliminate place- and year-specific effects, the experiments were performed under fully natural conditions in three different cities in Japan from mid September to early October in three different years. Because the experiments were performed in autumn, all six of the tested colonies lost mass on most of the experimental days. When the dance was prevented, the daily reduction in mass change was greater than when the dance was allowed, i.e. the dance inhibited the reduction of the hive mass. This indicates that dance is effective for food collection. Furthermore, clear inhibition was observed on the first two days of the experiments; after that, inhibition was no longer evident. This result suggests that the bee colony adapted to the new environment.

Safety of daprodustat in patients with anemia of chronic kidney disease: A pooled analysis of phase 3 studies in Japan.

INTRODUCTION: Daprodustat is an approved treatment for anemia of chronic kidney disease (CKD) in Japan. METHODS: This post hoc analysis evaluated pooled safety data for daprodustat from 3 phase 3 Japanese studies in dialysis-dependent and nondialysis patients with anemia of CKD. RESULTS: Median drug exposure duration was 365 days for both daprodustat (N = 369) and injectable erythropoiesis-stimulating agent (ESA, N = 285). The incidence per 100 patient-years of on-therapy adverse events (AEs) was 363.1 and 306.4 in the daprodustat and ESA groups, respectively. The incidence per 100 patient-years of thromboembolic and retinal events were 5.55 and 6.91 (daprodustat) and 6.28 and 7.46 (ESA), respectively. Cardiovascular and malignancy events were similar between groups, although analysis of these were limited by sample size and study duration. CONCLUSION: The safety of daprodustat was comparable to ESA in this pooled analysis, although further large-scale research is needed to evaluate long-term risks including cardiovascular and malignancy events.

A physiologically based pharmacokinetic and pharmacodynamic model for disposition of FF-10832.

This study aimed to quantitatively clarify the critical factors responsible for the superior antitumor efficacy of a liposomal gemcitabine (2,2-difluorodeoxycytidine; dFdC) formulation, FF-10832, compared with dFdC. The underlying hypothesis is the different exposure of tumors to its active metabolite, dFdC triphosphate (dFdCTP), between the two formulations. Therefore, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models for encapsulated and unencapsulated dFdC were constructed considering the tumor dFdCTP concentration as an index of antitumor activity. To estimate drug the parameters, the time profiles of encapsulated and unencapsulated dFdC in the blood and those of dFdC and dFdCTP in tumors were measured following the intravenous bolus administration of FF-10832 or dFdC. dFdC metabolism and transport in the liver S9 fraction and isolated hepatocytes, respectively, were experimentally determined. The tumor growth curve in a mouse xenograft model following the administration of FF10832 and dFdC was also used to construct the PD model. The sensitivity analysis of the PBPK/PD model revealed the critical factors affecting antitumor efficacy, which included the total and intratumor tissue uptake clearances for liposomal formulation and the cytidine deaminase and deoxycytidine deaminase activities in tumors. Thus, these parameters are potential biomarkers for predicting the efficacy of the liposomal formulation of dFdC.

Antenna Cleaning Is Essential for Precise Behavioral Response to Alarm Pheromone and Nestmate-Non-Nestmate Discrimination in Japanese Carpenter Ants (Camponotus japonicus).

Self-grooming of the antennae is frequently observed in ants. This antennal maintenance behavior is presumed to be essential for effective chemical communication but, to our knowledge, this has not yet been well studied. When we removed the antenna-cleaning apparatuses of the Japanese carpenter ant (C. japonicus) to limit the self-grooming of the antennae, the worker ants demonstrated the self-grooming gesture as usual, but the antennal surface could not be sufficiently cleaned. By using scanning electron microscopy with NanoSuit, we observed the ants' antennae for up to 48 h and found that the antennal surfaces gradually became covered with self-secreted surface material. Concurrently, the self-grooming-limited workers gradually lost their behavioral responsiveness to undecane-the alarm pheromone. Indeed, their locomotive response to the alarm pheromone diminished for up to 24 h after the antenna cleaner removal operation. In addition, the self-grooming-limited workers exhibited less frequent aggressive behavior toward non-nestmate workers, and 36 h after the operation, approximately half of the encountered non-nestmate workers were accepted as nestmates. These results suggest that the antennal sensing system is affected by excess surface material; hence, their proper function is prevented until they are cleaned.

Prevalence of Comorbid Anxiety Disorders and Their Associated Factors in Patients with Bipolar Disorder or Major Depressive Disorder.

OBJECTIVE: Comorbid anxiety disorders in patients with mood disorders have a negative impact on outcomes, such as persistence of depressive symptoms, deterioration of quality of life (QoL), increased suicide risk, mood instability with antidepressant treatment, but often go underrecognized in clinical practice. To identify features useful for supporting the confirmation of comorbid anxiety disorders, we investigated the prevalence of comorbid anxiety disorders and their associated factors in Japanese patients with mood disorders using data from our previously reported JET-LMBP study. PATIENTS AND METHODS: Patients with bipolar disorder (BD; n=114) and patients with major depressive disorder (MDD; n=334), all with major depressive episodes (DSM-IV-TR) were analyzed. Comorbid anxiety disorders were confirmed using the Mini-International Neuropsychiatric Interview. Demographic and clinical features were assessed using patient background forms, including the Quick Inventory of Depressive Symptomatology-Self Report Japanese version, 36-Item Short-Form Health Survey (SF-36), and Child Abuse and Trauma Scale (CATS). Multivariate logistic regression analysis adjusted for age, sex, and severity of depressive symptoms was used to identify factors associated with comorbid anxiety disorders (post hoc analysis). RESULTS: The prevalence of comorbid anxiety disorders was significantly higher in patients with BD (53.2%) than in patients with MDD (37.2%). Factors associated with comorbid anxiety disorders in BD included no spouse, interpersonal rejection sensitivity, higher CATS sexual abuse scores, and lower SF-36 mental component summary scores. In MDD, factors included hypersomnia, pathological guilt feelings, higher CATS neglect scores, and lower SF-36 physical component summary scores. CONCLUSION: Comorbid anxiety disorders were commonly seen in Japanese patients with mood disorders. Childhood abuse, atypical depression symptoms, and deterioration of health-related QoL were commonly associated with comorbid anxiety disorders in BD and MDD, suggesting that the presence of these features may be useful to support the confirmation of comorbid anxiety disorders in these patients.

Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: a potential treatment for psychotic disorders.

We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1mg/kg in an animal model.

Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist.

We identified 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide 27 as a potent mGluR1 antagonist. The compound possessed excellent subtype selectivity and good PK profile in rats. It also demonstrated relatively potent antipsychotic-like effects in several animal models. Suitable for development as a PET tracer, compound 27 would have great potential for elucidation of mGluR1 functions in human.

Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide].

The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.

Discovery and biological profile of 4-(1-aryltriazol-4-yl)-tetrahydropyridines as an orally active new class of metabotropic glutamate receptor 1 antagonist.

We describe here the discovery and the structure-activity relationship (SAR) of a series of 4-(1-Aryltriazol-4-yl)-tetrahydropyridines as novel mGluR1 antagonists. Our extensive chemical modification of lead compound 2 successfully led to fluoropyridine analogs 7j and 1 with improved in vivo antagonistic activities. Among the evaluated compounds, chemically stable urea analog 1 showed oral antagonistic activity at dose ranges of 10-30mg/kg in an animal model.

Properties of blocking and non-blocking monoclonal antibodies specific for human macrophage galactose-type C-type lectin (MGL/ClecSF10A/CD301).

Monoclonal antibodies (mAbs) specific for the human macrophage galactose-type calcium-type lectin (MGL) were established. The recombinant extracellular domain of MGL was used to immunize a mouse, and 10 hybridoma clones were obtained. Binding of recombinant MGL to asialo-bovine submaxillary mucin was shown to be blocked by mAbs MLD-1, 4 and 6. Immunoprecipitation of MGL from lysates of COS-1 cells transfected with MGL cDNA (form 6A) was achieved with mAbs MLD-1, 4, 7, 8 and 16. Chimeric recombinant proteins between human MGL and mouse MGL1 were used to determine the location of the epitopes for these mAbs. mAbs MLD-8, 13, 15 and 16 interacted with the amino terminal side of the conserved WVDGTD sequence immediately upstream of QPD, whereas mAbs MLD-7, 12 and 17 interacted with the other side. mAbs MLD-1, 4, and 6 apparently required both sides of this boundary. mAbs MLD-15 and 16 were shown to recognize the protein products of alternatively spliced mRNA 6A/8A and 6C/8A, having deletions at the boundary of exons 7 and 8, in addition to full length and other spliced forms of MGL (6A, 6B and 6C), whereas the other mAbs bound only full length and forms 6A, 6B and 6C.

Preventive Effects of Lamotrigine in Bipolar II Versus Bipolar I Disorder.

OBJECTIVE: The preventive effects of mood stabilizers on recurrence/relapse in bipolar disorders have been investigated mostly in bipolar I disorder (BPI) patients, with limited reports on bipolar II disorder (BPII) patients. Here, we conducted an explorative data analysis to investigate whether the preventive effect of lamotrigine on recurrence /relapse in BPII is better than in BPI. METHODS: Data from Japanese patients with a diagnosis of BPI or BPII according to DSM-IV-TR were analyzed in an open-label, noninterventional, naturalistic, prospective postmarketing surveillance study of lamotrigine. This study was carried out from October 2011 to November 2014, and each patient was observed for 1 year. The time to recurrence/relapse of mood episodes after commencement of lamotrigine treatment was evaluated as a primary endpoint. Kaplan-Meier curves were generated to compare the time to recurrence/relapse of mood episodes in BPI with in BPII using a log-rank test. RESULTS: Lamotrigine was associated with a significantly longer time to recurrence/relapse of mood episodes in BPII than in BPI (log-rank test, P = .0103). Lamotrigine also prolonged time to recurrence/relapse of mania-related episodes, including hypomanic episodes, more in BPII than in BPI (P = .0110). CONCLUSIONS: Although the preventive effect of lamotrigine on recurrence/relapse of mood episodes in BPI has been established in a variety of clinical studies, the present study suggests that lamotrigine may be more suitable for maintenance treatment in BPII than in BPI.

Assessment of safety and efficacy of lamotrigine over the course of 1-year observation in Japanese patients with bipolar disorder: post-marketing surveillance study report.

BACKGROUND: A post-marketing surveillance (PMS) study was conducted with a 1-year observation period to assess the safety and efficacy of lamotrigine in routine clinical practice in patients with bipolar disorder (BD). PATIENTS AND METHODS: Central enrollment method was used to recruit patients diagnosed with BD who were being treated for the first time with lamotrigine to prevent the recurrence/relapse of BD mood episodes. Adverse drug reactions (ADRs) and recurrence/relapse were assessed. Improvement of mania and depression was also assessed using the Hamilton's Rating Scale for Depression (HAM-D) and the Young Mania Rating Scale (YMRS) at treatment initiation, 4-6 months post treatment initiation, and 10-12 months post treatment initiation. RESULTS: A total of 237/989 patients (24.0%) reported ADRs, most commonly rash (9.1%), and the incidence of serious ADRs was 3.3% (33/989 patients). Skin disorders occurred in 130 patients (13.1%), mostly within 8 weeks post treatment. A total of 237/703 patients (33.7%) experienced recurrence/relapse of mood episodes. The 25th percentile of the time to recurrence/relapse of mood episodes was 105 days. Remission of depression symptoms (HAM-D ≤7) occurred in 147/697 patients (21.1%) at treatment initiation, rising to 361 patients (67.4%) at 10-12 months post treatment. Remission of manic symptoms (YMRS ≤13) occurred in 615/676 patients (91.0%) at treatment initiation, rising to 500 patients (97.3%) at 10-12 months post treatment. CONCLUSION: The results of this PMS study suggest that lamotrigine is a well-tolerated and effective drug for preventing recurrence/relapse of BD in clinical practice.

Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity.

Identification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M(3) selective antagonist that had >100-fold selectivity versus the M(1), M(2), M(4), and M(5) receptors (M(3): K(i) = 0.30 nM, M(1)/M(3) = 570-fold, M(2)/M(3) = 1600-fold, M(4)/M(3) = 140-fold, M(5)/M(3) = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M(3) antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M(3) receptors.

Prevalence and predictors of bipolar disorders in patients with a major depressive episode: the Japanese epidemiological trial with latest measure of bipolar disorder (JET-LMBP).

BACKGROUND: For patients with a major depressive episode, early differential diagnosis of bipolar disorder and subsequent appropriate treatment are critical. This study, conducted in clinical settings in Japan, examined patients with a major depressive episode to investigate the prevalence and predictors of bipolar disorders. METHODS: A total of 448 patients with a major depressive episode were interviewed using the Mini-International Neuropsychiatric Interview to determine the presence of mood episodes and psychiatric comorbidities. The diagnosis of bipolar disorder was based on the collected information according to the DSM-IV-TR. RESULTS: Of the 448 patients with a major depressive episode, 114 patients (25.4%) were diagnosed with bipolar disorder. Multivariate logistic regression identified five predictors that were significantly correlated with bipolar disorder: antidepressant-related switch to mania/hypomania, mixed depression, two or more previous mood episodes within the past year, early age at the onset of a major depressive episode (<25 years), and a history of suicide attempts. The area under the curve of receiver operating characteristic analysis based on the multivariate logistic regression of the five predictors was 0.849. LIMITATIONS: The diagnosis of bipolar disorder in patients was already conclusively confirmed by long illness observations but was not confirmed by a prospective study. CONCLUSIONS: In patients with a major depressive episode, the differential diagnosis of bipolar disorder and major depressive disorder, which exhibit similar depressive symptoms, is essential. Several predictors identified in the present study may be useful in supporting a differential diagnosis of these disorders in routine clinical practice.

Safety and effectiveness of controlled-release paroxetine in routine clinical practice: results of a postmarketing surveillance study of patients with depression.

OBJECTIVE: Selective serotonin reuptake inhibitors are commonly used in the pharmacotherapy of depression. However, adverse events can lead to their early discontinuation. This study evaluated the safety and effectiveness of paroxetine controlled-release (CR) tablets in Japanese patients with depression/depressive state (hereafter referred to as depression) in routine clinical practice in Japan. PATIENTS AND METHODS: This was an open-label, noninterventional, prospective, postmarketing surveillance study. A total of 3,213 patients aged 12-92 years with depression were prescribed paroxetine CR for 8 weeks at the physician's discretion. Safety was evaluated on the basis of the reporting of adverse drug reactions. Effectiveness was evaluated on the basis of the physician's assessment using the Clinical Global Impression-Global Improvement (CGI-GI) and the Clinical Global Impression-Severity of Illness (CGI-SI) scales, as well as on the basis of the patients' self-reported satisfaction. The primary effectiveness outcome was the improvement rate based on the physician's assessment using the CGI-GI. RESULTS: The incidence of adverse drug reactions was 11.2% (359/3,213; 95% confidence interval [CI]: 10.1%-12.3%). The common adverse drug reactions that accounted for 1.0% or more of the incidence were nausea (3.5%) and somnolence (2.7%). The proportion of patients who continued paroxetine CR at week 8 was 80.2% (2,577/3,213; 95% CI: 78.8%-81.6%). The improvement rate at week 8 (last observation carried forward) was 72.8% (2,132/2,927; 95% CI: 71.2%-74.4%). The proportion of patients with CGI-SI scores of moderately or severely ill decreased from 63.6% at baseline to 17.9% at week 8. The proportion of patients who were satisfied with paroxetine CR treatment was 69.8% (2,040/2,921; 95% CI: 68.1%-71.5%). CONCLUSION: The results of this study suggest that paroxetine CR is a well-tolerated and efficacious treatment for depression in routine clinical practice.

Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.

To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).