Clinical features of pasteurellosis without an animal bite or scratch in comparison with bite/scratch pasteurellosis.

Pasteurellosis is a common zoonotic infection that occurs after an animal bite or scratch (B/S). We compared the clinical features of six patients with non-B/S pasteurellosis with those of 14 patients with B/S infections. Pasteurella multocida was identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all six non-B/S infections, whereas 13 of the 14 B/S infections were identified with diagnostic kits. The non-B/S infections were pneumonia (n = 3), skin and soft tissue infections (n = 2), and bacteremia (n = 1). Pneumonia occurred in two patients with underlying pulmonary disease, whereas ventilator-associated pneumonia developed in one patient with cerebral infarction. Pasteurella multocida was isolated from a blood specimen and nasal swab from a patient with liver cirrhosis (Child-Pugh class C) and diabetes. Cellulitis developed in one patient with diabetes and normal-pressure hydrocephalus, who had an open wound following a fall, and in one patient with diabetes and a foot ulcer. Three patients with non-B/S infections had no pet and no episode of recent animal contact. The rate of moderate-to-severe comorbidities was significantly higher in patients with non-B/S infections than in those with B/S infections (100% and 14.3%, respectively, p < 0.001). In conclusion, non-B/S infections can develop in patients with chronic pulmonary disease, invasive mechanical ventilation, or open wounds, or who are immunocompromised, irrespective of obvious animal exposure. In contrast to B/S infections, non-B/S pasteurellosis should be considered opportunistic.

Efficacy and safety of nivolumab with ipilimumab for recurrent malignant pleural mesothelioma after primary surgical intervention.

BACKGROUND: Treatment of recurrent malignant pleural mesothelioma (MPM) remains challenging. Our study examined the efficacy, tolerability, and safety of nivolumab with ipilimumab treatment for recurrent MPM after primary curative-intent surgery. METHODS: Treatment comprised 360 mg nivolumab every 3 weeks and 1 mg/kg of ipilimumab every 6 weeks, both administered intravenously. Both were discontinued for progressive disease or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), post-treatment survival, progression-free survival (PFS), and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Survival analysis was estimated using a Kaplan-Meier plot. Feasibility analysis was performed using the National Cancer Institute Common Terminology Criteria for AEs version 5.0. RESULTS: Forty-one patients received nivolumab with ipilimumab for recurrent MPM after primary curative-intent surgery (median follow-up, 10.4 months; median treatment, 5.1 months). Overall, 18 patients exhibited partial response, 13 exhibited stable disease, and 10 had documented progressive disease. ORR and DCR were 43.9 and 75.6%, respectively. The 12-month post-treatment survival rate and PFS rate were 74.2 and 40.0%, respectively (median survival, not calculated; median PFS, 7.3 months). Further, 47 AEs were reported in 29 patients (70.7%), including grade 3-4 AEs in 14 patients (34.1%). Grade 4 hepatobiliary disorders were observed in 2 patients and grade 4 neutropenia was observed in 1. CONCLUSION: Nivolumab with ipilimumab treatment in patients with recurrent MPM after primary surgical treatment may be clinically efficacious, although serious AEs may be frequently observed.

Renadirsen, a Novel 2'OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients' DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2'-O,4'-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2'-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2'OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.

Complications and Predictive Factors for Air Leak > 10 Days with Neoadjuvant Chemotherapy Followed by Pleurectomy/Decortication for Malignant Pleural Mesothelioma.

BACKGROUND: A few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D). OBJECTIVE: The aim of this study was to assess the details of complications and predictive factors of particularly durable air leak with P/D. METHODS: Data on 163 consecutive patients who underwent neoadjuvant chemotherapy (NAC) followed by P/D for malignant pleural mesothelioma between September 2012 and May 2020 at our institution were retrospectively analyzed. Postoperative complications and the significance of various preoperative risk factors for air leak > 10 days (AL10) to identify the group having a higher risk for particularly durable air leak were investigated. Risk factors for AL10 were sought using univariate and multivariate analyses. RESULTS: Of 163 patients, 30- and 90-day mortality was 0.6% and 2.5%, respectively. Eighty-four (51.4%) patients experienced grade III or worse postoperative complications according to the Clavien-Dindo classification. The median duration of air leak was 7 postoperative days. AL10 occurred in 53 (32.5%) patients. Fifty-eight patients (35.6%) underwent pleurodesis and five patients (3.1%) underwent reoperation to control the air leak. On univariate analysis, performance status (PS; p = 0.003), prognostic nutritional index (p = 0.01), and pleural effusion (p = 0.04) were statistically significant risk factors for AL10, while on multivariate analysis, PS (odds ratio 4.0, 95% confidence interval 1.3-12.7; p = 0.02) remained the only variable predicted for AL10. CONCLUSIONS: Recent postoperative mortality rates in NAC followed by P/D are quite acceptable. Approximately one in every three patients experienced AL10, and PS may be a risk factor associated with AL10.

Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study.

BACKGROUND: Cisplatin-pemetrexed combination chemotherapy is the current standard primary treatment for malignant pleural mesothelioma (MPM). It was first approved for untreated and unresectable MPM in the 2003 National Comprehensive Cancer Network (NCCN) guidelines. However, to date, standard treatments for patients with MPM who previously underwent chemotherapy, as recommended by the NCCN Malignant Pleural Mesothelioma guidelines, have been inadequate. To explore treatment options for such patients, we performed this retrospective study of patients who received irinotecan plus gemcitabine as second-line therapy for MPM. METHODS: We investigated 62 patients diagnosed with unresectable MPM between January 2008 and October 2017 who experienced recurrence following cisplatin treatment (or carboplatin) plus pemetrexed or pemetrexed monotherapy as first-line treatment, and who underwent irinotecan plus gemcitabine combination therapy as second-line treatment. Irinotecan (60 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1 and 8 every 3 weeks, including a 1-week washout period. Our endpoints were efficacy, survival period, and toxicity. RESULTS: patients' median age was 65 years (range 50-79), and the histological MPM types were epithelioid (n = 48), sarcomatoid (n = 6), biphasic (n = 6), and desmoplastic (n = 2). One patient experienced a partial response, 40 had stable disease, and 21 had progressive disease. The disease control rate was 66.1% and the response rate 2.1%. Additionally, the median progression-free and overall survival time were 5.7 and 11.3 months, respectively. The most common adverse events were neutropenia (32.2%), loss of appetite (16.1%), nausea/diarrhea (11.3%), and thrombocytopenia/phlebitis (9.7%). Grade 3 adverse events included neutropenia (12.9%) and thrombocytopenia/phlebitis (2.1%); however, all adverse events were managed with symptomatic therapy. CONCLUSIONS: Despite the fact that second-line irinotecan plus gemcitabine combination therapy did not produce marked tumor shrinkage, it achieved a relatively high disease control rate of >65% with an acceptable toxicity profile. Hence, the combination of irinotecan plus gemcitabine may be considered for MPM treatment, with consideration of combination with immune checkpoint inhibitors as a potential next step.

Clinicopathological features of radiological early malignant pleural mesothelioma with no apparent tumor or pleural thickening.

BACKGROUND: We occasionally encounter malignant pleural mesothelioma (MPM) of no apparent tumor or pleural thickening that is radiological early MPM. This study aimed to examine the clinicopathological outcomes of radiological early MPM. METHODS: Patients with MPM treated with neoadjuvant chemotherapy and planned surgery at the time of diagnosis between July 2004 and December 2019 were retrospectively examined. Pretreatment maximal pleural thickness of all patients was measured on chest computed tomography. We extracted and investigated the patients who exhibited a lack of pleural thickening or visible tumor, which was defined as radiological early MPM. Survival was analyzed by the Kaplan-Meier method. RESULTS: Of 296treated patients, 16 (5.4%) exhibited radiological early MPM. Fourteen (87.5%) of these patients underwent pleurectomy/decortication and 2 (12.5%) underwent extrapleural pneumonectomy. Pathological stage T1 disease was diagnosed in 14 (87.5%) patients; 2 (12.5%) exhibited pulmonary parenchymal invasion (pathological stage T2). Lymphatic invasion was detected in only 1 patient. Lymph node metastases and vascular invasion were not detected. Median follow-up was 42 months. Median progression-free survival and median overall survival were 40.7 and 56.1 months, respectively. The 3-year progression-free survival and overall survival rates were 84.8% and 83.6%, respectively. CONCLUSIONS: Radiological early MPM occurs in approximately 1 of every 20 patients treated with neoadjuvant chemotherapy and surgery planned at the time of diagnosis in an experienced center. Radiological early MPM was associated with early pathological stage and long-term survival.

The utility of 68F-FDG PET/CT for evaluation of tumor response to immune checkpoint inhibitor therapy and prognosis prediction in patients with non-small-cell lung cancer.

OBJECTIVE: To compare three fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) (EORTC criteria and PERCIST) and computed tomography (CT) (RECIST1.1) for response evaluation and prognosis prediction in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitor (ICI) monotherapy. SUBJECTS AND METHODS: Forty NSCLC patients underwent 18F-FDG PET/CT scans at baseline and after 4 to 8 cycles of nivolumab or pembrolizumab. Therapeutic response was evaluated according to EORTC criteria, PERCIST, and RECIST1.1,then concordance among those was assessed using Cohen's κ coefficient. Progression-free survival (PFS) and overall survival (OS) was examined using log-rank and Cox methods. RESULTS: The number of complete metabolic response (CMR)/partial metabolic response (PMR)/stable metabolic disease (SMD)/progressive metabolic disease (PMD) were 8/10/4/18 for EORTC criteria and 9/9/4/18 for PERCIST. Using RECIST1.1, those of CR/PR/SD/PD were 4/10/12/14. Although there was high concordance between PERCIST and EORTC (92.5% of patients; κ=0.924), that between PERCIST and RECIST1.1 was substantial (65.0%; κ=0.560) and that between EORTC and RECIST1.1 (65.0%; κ=0.574). After a median 23.2 months (range 7.2 to 51.8 months), 32 patients had documented progression and 24 patients died from NSCLC. According to both PET and CT, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and OS than PMD or PD patients (EORTC: P<0.0001 and P<0.0001, respectively, PERCIST: P<0.0001 and P=0.0001, respectively, RECIST1.1: P<0.0001 and P<0.0001, respectively). In a univariate analysis total MTV (P=0.042) on pre-ICI treatment 18F-FDGPET/CT scans was significantly associated with progression. Highest SUVmax (P<0.0001), total MTV (P=0.0062), total TLG (P<0.0001), highest SULpeak (P<0.0001), and total TLGL (P<0.0001) on post-ICI treatment 18F-FDG PET/CT scans were also were significantly associated with progression. Moreover, the change rate of highest SUVmax (P<0.0001), total metabolic tumor volume (MTV) (P<0.0001), total lesion glycolysis(TLG) (P<0.0001), highest SULpeak (P<0.0001), total TLGL (P<0.0001), size (P=0.0012), EORTC (P<0.0001), PERCIST (P<0.0001), and RECIST 1.1 (P<0.0001) on two PET/CT scans were significantly associated with progression. A multivariate analysis confirmed the change rate of total MTV (P=0.034), and total TLGL (P=0.0027), EORTC (P=0.018), PERCIST (P=0.045), and RECIST1.1 (P=0.0037) as independent negative PFS predictors. CONCLUSION: Both 18F-FDG PET (EORTC criteria and PERCIST) and CT (RECIST1.1) after 4 to 8ICI monotherapy cycles are accurate for evaluation of tumor response and predicting prognosis in NSCLC patients.

A High Plasma Lamotrigine Concentration at Week 2 as a Risk Factor for Lamotrigine-Related Rash.

BACKGROUND: Reportedly, a high plasma concentration of lamotrigine plays a role in the development of lamotrigine-related rash. The relationship between plasma concentrations of lamotrigine at week 2 and the lamotrigine-related rash was prospectively studied in 84 patients (22 males and 62 females) with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation. METHODS: Eighty-four depressed patients with an insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics, were included. The diagnoses were major depressive disorder (n = 39), bipolar I disorder (n = 10), and bipolar II disorder (n = 35). The final doses of lamotrigine were 100 mg/d for 57 subjects who were not taking valproate and 75 mg/d for 27 subjects taking valproate. Blood sampling was performed at week 2. Lamotrigine plasma concentrations were measured using high-performance liquid chromatography. The development of lamotrigine-related rash was assessed during the 8-week treatment. RESULTS: Six females developed lamotrigine-related rash. The mean plasma lamotrigine concentrations at week 2 were significantly (P = 0.009) higher in the rash group (4.81 ± 1.23 µmol/L) than in the nonrash group (3.35 ± 1.39 µmol/L). Receiver-operating characteristic analysis indicated that a plasma lamotrigine concentration of 4.38 µmol/L or greater at week 2 was significantly (P < 0.0001) predictive of lamotrigine-related rash. The proportion of patients with a lamotrigine concentration of 4.38 µmol/L or greater was significantly divided by the cutoff point into the rash group and the nonrash group (5/1 versus 13/65, P = 0.001). CONCLUSIONS: This study suggests that a high plasma lamotrigine concentration during week 2 is a risk factor for lamotrigine-related rash and a plasma lamotrigine concentration of 4.38 µmol/L may be a considered a threshold for rash in treatment-resistant depressive disorder.

Initial evaluation of nivolumab in patients with post-operative recurrence of malignant pleural mesothelioma.

BACKGROUND: Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM in a real-world setting. METHODS: This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan-Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1-14 months), and median of 8 cycles (range: 2-32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed. CONCLUSION: Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy.

Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy.

BACKGROUND: In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. METHODS: The subjects were 103 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses. RESULTS: There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication. CONCLUSIONS: This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Poor Prognostic Factors in Patients with Malignant Pleural Mesothelioma Classified as Pathological Stage IB According to the Eighth Edition TNM Classification.

INTRODUCTION: The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group. METHODS: Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery [pleurectomy decortication n = 57 (64.1%), extrapleural pneumonectomy n = 32 (35.9%)] at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models. RESULTS: Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1) < 2000 ml. Patients with no, one, and two of these risk factors showed 3-year overall survival probabilities of 94.7, 62.5, and 0%, respectively. The 3-year survival of patients with one factor did not differ significantly from that of patients with stage III MPM, whereas that of patients with two factors was significantly shorter (p = 0.015). CONCLUSIONS: Independent poor prognostic factors for patients with stage IB MPM patients, allowing subgroups with poorer and more favorable prognoses to be identified. This should help personalize decisions on adjuvant chemotherapy.

Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6).

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.

Prediction of an Optimal Dose of Aripiprazole in the Treatment of Schizophrenia From Plasma Concentrations of Aripiprazole Plus Its Active Metabolite Dehydroaripiprazole at Week 1.

BACKGROUND: It has been suggested that a plasma trough concentration of aripiprazole plus its active metabolite, dehydroaripiprazole of 225 ng/mL is a threshold for a good therapeutic response in the treatment of acutely exacerbated patients with schizophrenia. The present study investigated whether or not an optimal dose of aripiprazole could be predicted from these concentrations at week 1. METHODS: The subjects were 26 inpatients with schizophrenia, who received aripiprazole once a day for 3 weeks. The daily doses were 12 mg for the first week and 24 mg for the next 2 weeks. No other drugs except biperiden and flunitrazepam were coadministered. Blood samples were taken at weeks 1 and 3 after the treatment. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. RESULTS: There was a significant linear relationship between the plasma concentrations of aripiprazole plus dehydroaripiprazole at weeks 1 (x) and 3 (y) (P < 0.001). Regression equation was y = 2.580x + 34.86 (R = 0.698). Based on the equation, a nomogram to estimate an optimal dose of aripiprazole could be constructed. CONCLUSIONS: The present study suggests that an optimal dose of aripiprazole for the treatment of patients with schizophrenia can be predicted from the plasma concentrations of the sum of the 2 compounds at week 1.

A Partial Response at Week 4 Can Predict Subsequent Outcome during Lamotrigine Augmentation Therapy in Treatment-Resistant Depressive Disorder: A Preliminary Study.

BACKGROUND/AIMS: The present study prospectively examined whether or not a partial response at week 4 predicts subsequent response at week 8 during lamotrigine augmentation therapy in 51 (16 males and 35 females) inpatients with treatment-resistant depressive disorder using an open-study design. METHODS: The subjects were 51 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 19), bipolar I disorder (n = 9), and bipolar II disorder (n = 23). The final doses of lamotrigine were 100 mg/day for 29 subjects who were not taking valproate and 75 mg/day for 22 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS) before the start of lamotrigine and then at week 4, and finally after the 8th week of treatment. RESULTS: A significant linear relationship was found between percent improvements in MADRS scores at weeks 4 and 8 (r = 0.492, y = 0.438x + 30.223, R2 = 0.226, p < 0.001). The receiver operating characteristics analysis indicated that a percent improvement of 16% or greater at week 4 was significantly (p < 0.01) predictive of response (50% or more reduction in the MADRS score). The patients were significantly divided by the cut-off point into the responders and the nonresponders (18/26 vs. 1/25, p < 0.001). CONCLUSION: The present study suggests that a partial response at week 4 can predict subsequent outcome at week 8 during lamotrigine augmentation therapy in patients with treatment-resistant depressive disorder, and that the absence of a partial improvement at week 4 is highly predictive of nonresponse.

Both Serum Brain-Derived Neurotrophic Factor and Interleukin-6 Levels Are Not Associated with Therapeutic Response to Lamotrigine Augmentation Therapy in Treatment-Resistant Depressive Disorder.

BACKGROUND/AIMS: Serum levels of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) were prospectively monitored in relation with therapeutic response to lamotrigine augmentation therapy in 46 (15 males and 31 females) inpatients with treatment-resistant depressive disorder during an 8-week treatment with lamotrigine using an open-study design. METHODS: The subjects were 46 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 19), bipolar I disorder (n = 6), and bipolar II disorder (n = 22). The final doses of lamotrigine were 100 mg/day for 26 subjects who were not taking valproate and 75 mg/day for 20 subjects taking valproate, respectively. Depressive symptoms were evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS) before and after the 8-week treatment. Blood sampling was performed before the start of lamotrigine treatment and at week 8. Serum BDNF and IL-6 levels were measured using quantitative sandwich enzyme immunoassays. RESULTS: No significant changes in serum BDNF or IL-6 levels during the 8-week lamotrigine treatment were observed in the total of subjects, responders or nonresponders. There was no significant correlation between the changes in serum BDNF or IL-6 levels and the percent improvement in MADRS scores in the overall subjects. CONCLUSION: The present study suggests that the acute effect of lamotrigine augmentation therapy for a major depressive episode is not related to either BDNF or IL-6, at least in patients with treatment-resistant depressive disorder.

Prediction of an Optimal Dose of Lamotrigine for Augmentation Therapy in Treatment-Resistant Depressive Disorder From Plasma Lamotrigine Concentration at Week 2.

BACKGROUND: The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 µmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2. METHODS: The subjects were 37 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. RESULTS: There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated. CONCLUSIONS: The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.

Ortho-phosphinobenzenesulfonate: a superb ligand for palladium-catalyzed coordination-insertion copolymerization of polar vinyl monomers.

Ligands, Lewis bases that coordinate to the metal center in a complex, can completely change the catalytic behavior of the metal center. In this Account, we summarize new reactions enabled by a single class of ligands, phosphine-sulfonates (ortho-phosphinobenzenesulfonates). Using their palladium complexes, we have developed four unusual reactions, and three of these have produced novel types of polymers. In one case, we have produced linear high-molecular weight polyethylene, a type of polymer that group 10 metal catalysts do not typically produce. Secondly, complexes using these ligands catalyzed the formation of linear poly(ethylene-co-polar vinyl monomers). Before the use of phosphine-sulfonate catalysts, researchers could only produce ethylene/polar monomer copolymers that have different branched structures rather than linear ones, depending on whether the polymers were produced by a radical polymerization or a group 10 metal catalyzed coordination polymerization. Thirdly, these phosphine-sulfonate catalysts produced nonalternating linear poly(ethylene-co-carbon monoxide). Radical polymerization gives ethylene-rich branched ethylene/CO copolymers copolymers. Prior to the use of phosphine-sulfonates, all of the metal catalyzed processes gave completely alternating ethylene/carbon monoxide copolymers. Finally, we produced poly(polar vinyl monomer-alt-carbon monoxide), a copolymerization of common polar monomers with carbon monoxide that had not been previously reported. Although researchers have often used symmetrical bidentate ligands such as diimines for the polymerization catalysis, phosphine-sulfonates are unsymmetrical, containing two nonequivalent donor units, a neutral phosphine, and an anionic sulfonate. We discuss the features that make this ligand unique. In order to understand all of the new reactions facilitated by this special ligand, we discuss both the steric effect of the bulky phosphines and electronic effects. We provide a unified interpretation of the unique reactivity by considering of the net charge and the enhanced back donation in the phosphine-sulfonate complexes.

Relationship between plasma concentrations of lamotrigine and its early therapeutic effect of lamotrigine augmentation therapy in treatment-resistant depressive disorder.

BACKGROUND: The relationship between plasma concentrations of lamotrigine and its therapeutic effects was prospectively studied on 34 (9 men and 25 women) inpatients with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation using an open-study design. METHODS: The subjects were depressed patients who had already shown insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 12), bipolar I disorder (n = 7), and bipolar II disorder (n = 15). The final doses of lamotrigine were 100 mg/d for 18 subjects who were not taking valproate and 75 mg/d for 16 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery Åsberg Depression Rating Scale (MADRS) before and after the 8-week treatment. Blood sampling was performed at week 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. RESULTS: There was a significant linear relationship between the plasma concentrations of lamotrigine and percentage improvements at week 8 (r = 0.418, P < 0.05). A stepwise multiple regression analysis showed that plasma lamotrigine concentrations alone had a significant effect on the percentage improvements at week 8 (standardized partial correlation coefficients = 0.454, P < 0.001). The receiver operating characteristics analysis indicated that a plasma lamotrigine concentration of 12.7 µmol/L or greater was significantly (P < 0.001) predictive of response (50% or more reduction in the MADRS score). The proportion of the responders was significantly higher in the groups with a lamotrigine concentration >12.7 µmol/L (11/15 versus 4/19, P < 0.01). CONCLUSIONS: The present study suggests that an early therapeutic response to lamotrigine is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 µmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder.

Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia.

BACKGROUND: We studied the effects of various factors, including genetic polymorphisms of the cytochrome P450 (CYP) 2D6, CYP3A5, and ABCB1, age, gender, and smoking habit on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in 89 patients with schizophrenia (46 males, 43 females). METHODS: All patients had been receiving fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 56) and 12 mg (n = 33). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. The CYP2D6 (CYP2D6*5, CYP2D6*10, and CYP2D6*14), CYP3A5 (CYP3A5*3), and ABCB1 (C3435T and G2677T/A) genotypes were identified by PCR analyses. RESULTS: The mean concentration/dose ratios of aripiprazole and the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with 1 (P < 0.01 and P < 0.01) or 2 (P < 0.001 and P < 0.05) mutated alleles for CYP2D6 than in those without mutated alleles. No differences were found in the values of dehydroaripiprazole among CYP2D6 genotypes. There were no differences in the values of aripiprazole, dehydroaripiprazole, and the sum of the 2 compounds among CYP3A5 or the 2 ABCB1 variants. Multiple regression analyses including these polymorphisms, age, gender, and smoking habit showed that only the number of mutated alleles for CYP2D6 was correlated with mean concentration/dose ratios of aripiprazole [standardized partial correlation coefficients (beta) = 0.420, P < 0.001] and the sum of the 2 compounds (standardized beta = 0.335, P < 0.01). CONCLUSIONS: The findings of this study suggest that CYP2D6 genotypes play an important role in controlling steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects, whereas CYP3A5 and ABCB1 genotypes seemed unlikely to have an impact.

Lack of correlation between the steady-state plasma concentrations of aripiprazole and haloperidol in Japanese patients with schizophrenia.

BACKGROUND: Both aripiprazole and haloperidol have been used in the treatment of schizophrenia, and are metabolized by the cytochrome P450 (CYP) 2D6 and CYP3A4. The authors studied the correlations between the steady-state plasma concentrations (Css) of aripiprazole and its active metabolite, dehydroaripiprazole, and those of haloperidol in 19 Japanese patients with schizophrenia, together with the effects of CYP2D6 genotypes on the steady-state kinetics of these compounds. METHODS: All the patients received first 24 mg/d of aripiprazole for 3 weeks and later received 6 mg/d of haloperidol for 2 weeks. Blood samplings were performed at least 2 weeks after the initiation of each treatment. The Css values of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection, and those of haloperidol were measured by using an enzyme immunoassay. CYP2D6 genotypes were determined by using polymerase chain reaction analysis. RESULTS: None of the correlations between the Css of aripiprazole (r = 0.286) or the sum of aripiprazole plus dehydroaripiprazole (r = 0.344) and those of haloperidol were significant. The mean Css of aripiprazole was significantly higher (P < 0.05) in the subjects with 1 *10 allele of CYP2D6 (n = 6) than in those with no mutated alleles (n = 13), whereas there were no significant differences in those of haloperidol between the 2 groups. CONCLUSIONS: This study suggests that the Css of aripiprazole and that of aripiprazole plus dehydroaripiprazole do not correlate with that of haloperidol in the same individual, because of the greater involvement of CYP2D6 in the metabolism of aripiprazole than in that of haloperidol.