Design and discovery of a high affinity, selective and ß-arrestin biased 5-HT7 Receptor Agonist.

Compound 1c, 5-chloro-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2,3-dihydro-1H-inden-1-one was previously reported from our laboratory showing high affinity binding to the 5-HT7 receptor (Ki = 0.5 nM). However, compound 1c racemizes readily upon enantiomeric separation. To prevent racemization, we have redesigned and synthesized methyl and carboxyethyl analogs, compounds 2 and 3 respectively, whose binding affinities were similar to those of compound 1c. Compounds 2 and 3 cannot undergo racemization since tautomerism was no longer possible and thus, compound 2 was selected for enantiomeric separation and further evaluation. Upon enantiomeric separation, the levorotatory enantiomer, (-)2 or 2a demonstrated a higher affinity (Ki = 1.2 nM) than the (+)2 or 2b enantiomer (Ki = 93 nM) and a ß-arrestin biased functional selectivity for the 5-HT7 receptor. Although 2a showed about 8 times less activity than 5-HT in the Gs pathway, it showed over 31 times higher activity than 5-HT in the ß-arrestin pathway. This constitutes a significant ß-arrestin pathway preference and shows 2a to be more potent and more efficacious than the recently published ß-arrestin biased 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine, the N-debenzylated analog of JNJ18038683 (Compound 7).

Nitrosamine removal: Pilot-scale comparison of advanced oxidation, nanofiltration, and biological activated carbon processes.

Removal of nitrosamines from water intended for consumption is an important topic due to the carcinogenic risks they pose to human health. In this study, we measure and compare nitrosamine removal by four individuals and three combinations of water treatments applied in situ as a pilot study and in the laboratory. Of the two advanced oxidation processes tested, UV irradiation at a wavelength of 254 nm was more effective in nitrosamine removal than ozonation; however, the efficacy of UV photolysis required a high dose (>635 mJ/cm2) for sufficient (>90%) removal of the contaminants. The biological activated carbon (BAC) process was also effective at removing nitrosamines, most of which were adsorbed onto the carbon. A small fraction (<10%) of nitrosamines were removed through biodegradation. Nanofiltration membranes were limited in removing nitrosamines, particularly N-nitrosodimethylamine, which is hydrophilic. Employing either UV or BAC treatments can warrant a high degree of elimination of nitrosamines; however, desorption of nitrosamines from BAC can occur due to variations in the quality of source water and the types of carbon filters used. Combined treatments using both UV and BAC processes offer promising alternative strategies for removing nitrosamines when treating water for human consumption.

Evaluation of SYA16263 as a new potential antipsychotic agent without catalepsy.

SYA16263 exhibited moderate radioligand binding affinity at the D2 receptor and produced inhibition of apomorphine-induced climbing behavior in mice with an ED50 value of 3.88 mg/kg IP, predicting potential antipsychotic effects in humans. Analysis of plasma and brains from rats injected IP with SYA16263 over the course of 24 h revealed a log [brain]/[plasma] (log BB) at Cmax observed equal to 1.08, indicating that SYA16263 enters the brain and is predicted to cross the blood brain barrier (BBB) readily. When tested in animal behavior tests for catalepsy, SYA16263 did not produce catalepsy at doses up to 19 times the apomorphine ED50 value predicting little or no extra-pyramidal (EPS) side effects in humans. This is similar to aripiprazole, which is associated with a low incidence of EPS in humans, but unlike haloperidol which is known to cause severe EPS in humans. Functional activities for SYA16263 show that it acts as a D2 agonist at both the Gi and ß-arrestin pathways, similar to, but better than aripiprazole, which could account for the absence of the catalepsy observed. Taken together, the receptor binding profile, the functional status, the animal behavioral tests and the log BB value, all provide evidence for further pre-clinical testing of SYA16263 as a potential antipsychotic agent with an interesting profile and a unique mechanism of action resulting in no EPS even up to 19 times the ED50 value.

Characteristic MR image finding of squatting exercise-induced rhabdomyolysis of the thigh muscles.

OBJECTIVE: To describe the characteristic MRI appearance of squatting-induced rhabdomyolysis involving the thigh muscles. METHODS: This study consisted of 10 cases obtained at 3 institutions from 2005 to 2015. A retrospective review was performed to obtain clinical information and MR scans for rhabdomyolysis of the thigh muscles. MRI was analyzed according to the distribution and degree of muscle involvement; the degree was assessed and graded as normal, mild or prominent. RESULTS: The mean patient age was 20.2 years (range, 15-24 years), and 7 of the 10 patients were male. All patients had history of excessive squatting action, suffered clinically from bilateral thigh pain and were confirmed to have rhabdomyolysis through analysis of serum creatine kinase (CK) levels. All of the patients (10/10) exhibited diffuse mild to prominent degree involvement of the anterior thigh muscles according to fluid-sensitive MR sequences. Among the anterior thigh muscles, the rectus femoris was spared in 8 patients (8/10) and mild degree involved in 2 patients (2/10). Thus, no cases exhibited prominent degree involvement of the rectus femoris muscle. CONCLUSION: Preservation of the rectus femoris muscle on MRI in squatting-induced rhabdomyolysis may be useful for differentiating rhabdomyolysis from other aetiologies. Advances in knowledge: Preservation of rectus femoris on MRI is distinguishable finding in squatting-induced rhabdomyolysis and reflects the functional anatomy of anterior thigh muscles.

Development of CNS multi-receptor ligands: Modification of known D2 pharmacophores.

Several known D2 pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing.

Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands.

5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.

Radioimmunotherapy with (131)I-rituximab for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL).

AIM: To evaluate the efficacy and safety of radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti-CD20 monoclonal antibody rituximab ((131)I-rituximab) for treating Korean patients with relapsed or refractory B-cell non-Hodgkin's lymphomas (NHL). METHODS: All patients received unlabeled rituximab 70 mg immediately prior to the administration of a therapeutic dose (median dose: 7.3 GBq) of (131)I-rituximab. The tumor response was evaluated 1 month later by contrast enhanced (18) F-fludeoxyglucose positron emission tomography-computed tomography. RESULTS: Between May 2004 and October 2006, 24 patients received single treatment with (131)I-rituximab. The overall response rate (ORR) was 29%; 46% (three complete responses, two partial responses (PR) for patients with low grade B-cell NHL (LGL) and 9% (one PR) for patients with diffuse large B-cell lymphoma (DLBCL). After a median follow-up of 55 months, the median progression-free survival (PFS) for all the patients was 2.2 months. The median overall survival (OS) was 11.3 months. There were statistically significant differences between the LGL and the DLBCL for the median PFS (4.5 months vs 1.3 months, respectively, P = 0.0007) and the median OS (30.3 months vs 6.5 months, respectively, P = 0.0295). Grades 3-4 thrombocytopenia and neutropenia occurred in 33% (8/24) and 21% (5/24) of the patients, respectively. CONCLUSION: RIT with (131)I-rituximab seems to be effective and tolerable for patients with refractory LGL, although this treatment had modest activity in patients with refractory DLBCL. Further studies are warranted to determine the efficacy of (131)I-rituximab for treating the patients with DLBCL.

Prognostic factors for classifying extranodal NK/T cell lymphoma, nasal type, as lymphoid neoplasia.

This study evaluated the applicability of prognostic factors commonly used for diagnosis of classical lymphoma outcomes to extranodal NK/T cell lymphoma, nasal type (NTCL). Clinical features and their associations with lactate dehydrogenase (LDH) were evaluated in 70 patients. RLDH was defined as the ratio of LDH to the upper normal limit. RLDH was associated with stage (I-II vs. III-IV), lymph node involvement (LNI), and International Prognostic Index score (<2 vs. > or =2). Poor performance status and advanced stage were common in patients with local tumor invasiveness (LTI). LDH level, classified into three levels (low, high, and very high) was associated with survival (P < 0.001). In multivariate analysis, the predictive values of LDH level, B symptom, performance status, and stage remained significant whereas those of LTI and LNI did not. Scoring was performed by weighting each factor with 0.5 or 1.0 according to its hazard ratio. Scores were classified into four groups. Groups with high scores were associated with unfavorable outcomes (P < 0.001). Current study suggests that prognostic factors for NHL may be useful to predict the outcome of NTCL but the model should take LDH level and the prognostic weight of each factor into account.

Clinical features and treatment outcomes of angioimmunoblastic T-cell lymphoma.

The objective of this retrospective study was to investigate clinical features and treatment outcomes in patients with angioimmunoblastic T-cell lymphoma (AITL), data of which were collected over a 15-year period. Sixty-five patients diagnosed with AITL were included in the study. About half of the patients (46.2%) presented with poor performance status (ECOG > or = 2); 72.3% of patients belonged to high intermediate or high-risk of IPI and same proportion belonged to Class 2 of PIT (Prognostic index for PTCL-U), and most patients (95.4%) were diagnosed at an advanced stage. At diagnosis, 27 patients (41.5%) presented with malignant pleural effusion, and 22 patients (33.8%) had skin involvement. Most of the initial chemotherapy regimens were anthracycline-based (88.2%). Overall response rate to initial chemotherapy was 86.2% (64.7% of complete response, 21.5% of partial response). The median progression-free survival and overall survival of all patients was 7.1 months (95% CI, 2.8 - 11.4) and 15.1 months (95% CI, 6.7 - 23.5), respectively. Age, performance status, and PIT scores were predictive prognostic factors for survival. In conclusion, although AITLs showed a good response to the initial chemotherapy, their response durations were short; therefore, chemotherapy for AITL should be modified or intensified as in high-dose chemotherapy.

Prognostic factor analysis and proposed prognostic model for conventional treatment of high-grade primary gastric lymphoma.

OBJECTIVES: We conducted a clinical risk factors analysis to define a prognostic model for high-grade primary gastric lymphoma (HG-PGL). METHODS AND RESULTS: The median event-free survival and overall survival of 214 HG-PGL patients were 54 and 104.5 months, respectively, after a median follow-up duration of 60 months. According to the prognostic factor analysis, survival, advanced age, male gender, higher LDH levels and the presence of ascites were identified as independent prognostic factors for HG-PGL. We identified four groups at different risk: group 1, no adverse effect; group 2, one factor; group 3, two factors; group 4, three or four factors. The new prognostic model showed excellent prognostic capacity to differentiate subgroups according to their risk stratification. CONCLUSIONS: The proposed new prognostic model for HG-PGL demonstrated a balanced distribution of patients into four groups with good prognostic capacity.