Eric C. Brown

Characteristics of geriatric patients seeking medication treatment for pathologic gambling disorder

This study was constructed to compare geriatric patients seeking medication treatment for pathologic gambling disorder (PGD) with younger pathologic gamblers. This comparison study assessed three groups with PGD accord ing to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition: 16 subjects over the age of 60 years, 11 subjects between the ages of 20 and 30 years, and 46 subjects between the ages of 40 and 50 years. All subjects were evaluated in terms of demographic characteristics, clinical features of PGD, and treatment history. Geriatric gamblers had a later age of onset of gambling and developed pathologic gambling over a longer period of time. Geriatric subjects were more likely to play slot machines and demonstrate less variety in their choice of gam bling activity. Geriatric gamblers were also more likely to gamble secondary to boredom. Geriatric subjects were as likely as the other age groups to report slight or no response to nonpharmacologic treatment. There appear to be some differences in the clinical features of PGD among geriatric subjects, and these differences may have treat ment implications. (J Geriatr Psychiatry Neurol 2001; 14:125-129).

Quetiapine in patients with borderline personality disorder: An open-label trial

BACKGROUND Quetiapine was assessed in patients diagnosed with borderline personality disorder (BPD) to examine its potential effect on symptoms and explore a tolerated dosing pattern. METHOD An open label case series with objective rating measures was undertaken. The study was of 8 weeks duration. RESULTS Sixteen research subjects received quetiapine and completed at least one rating. Nine subjects completed the entire 8 week trial. In the LOCF and completer analyses, significant improvement was noted on GAF, SCL-90, BIS, and SIB. Specifically for the LOCF analysis, GAF increased from 57.7 to 64.6 (p = 0.001), SCL-90 decreased from 120.1 to 78.4 (p = 0.004), BIS improved from 73.4 to 59.9 (p = 0.021), and the SIB started at 267.8 and ended at 202.3 (p < 0.001). The average dose of quetiapine for LOCF analysis was 223.4 mg/d and was 286.1 mg/d for the completers. Common side-effects were similar to those seen in schizophrenic patients--sedation and increased appetite. CONCLUSIONS Significant reductions in symptoms assessed by objective rating scales were observed in this pilot study of quetiapine administered to subjects with BPD. The dosing strategy in the study was well tolerated.

Infectivity-selective Oncolytic Adenovirus Developed by High-throughput Screening of Adenovirus-formatted Library

Adenovirus (Ad) is a potent gene-delivery vehicle and has frequently been used for designing oncolytic viruses. However, lack of selectivity on infection has hampered the achievement of sufficient in vivo efficiency. Here, we developed a novel oncolytic virus system, infectivity-selective oncolytic adenovirus (ISOAd), via direct high-throughput screening of a high-diversity targeting-ligand library in adenoviral format. Through our newly designed rescue virus system, the high-diversity Ad library carrying the random seven amino acid sequences ligand-library in the AB-loop of its fiber-knob region (5 × 10(9) diversity) was successfully generated. During the screening of this library with the cells expressing the target molecule (mesothelin, MSLN), the AB-loop sequence of the virus clones converged to one dominant sequence and a novel MSLN-targeting sequence was isolated. The virus with the isolated motif showed selective infectivity to MSLN-positive cells in vitro. In vivo, it exhibited a selective and potent antitumor effect resulted from the viral replication in MSLN-positive xenografts. The ISOAd is a novel class of oncolytic Ad, which has selectivity at the step of transduction. The selectivity at the stage of infection can open new perspectives in oncolytic Ad therapy for various diseases.

Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy

BACKGROUND Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated. METHODS Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens. RESULTS Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown. CONCLUSIONS Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer-specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients.

Investigational drugs for eating disorders.

The eating disorders anorexia nervosa, bulimia nervosa and binge eating disorder are common, significant public health problems which are treated with nutritional, psychotherapeutic and pharmacological interventions. A number of drugs (mostly antidepressant drugs) are currently used in their treatment to some benefit, but there is substantial room for improvement. A wide variety of compounds are listed as under investigation for the treatment of eating disorders. They have a diverse variety of mechanisms of action, reflecting the complex nature of the control of food intake. While none of these compounds are close to release at present, the diversity of mechanisms under study lend some optimism that more effective approaches will be identified.

Development of a method for effective amplification of human adenovirus 40

Human adenovirus 40 (Ad40) is an interesting candidate for vector construction because of its tropism for the gastrointestinal tract. Although effective preparation of the vector is necessary for its in vivo application, amplification of Ad40 has been very difficult. Ad40 E1 deletion mutants were detected by PCR in the viral DNA from Ad40 Dugan amplified by Ad5 E1-expressing human embryonic kidney (293) cells and in Ad40 Dugan plaques observed with Ad5 E1-expressing human retinoblastic cells. For the purpose of generating a single wild-type Ad40 clone, the entire Ad40 DNA was cloned into a plasmid by homologous recombination. A pure Ad40 was successfully generated by plasmid transfection and subsequently amplified with Ad5 E4orf6-inducible 293 (2V6.11) cells. 2V6.11 is an apposite cell line for effective Ad40 amplification and for future vector construction because Ad40 genetic integrity was maintained with this Ad5 E1 and E4orf6 trans-complementing cell line.

Structure–Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR

Pseudomonas aeruginosa is an opportunistic pathogen that coordinates the production of many virulence phenotypes at high population density via quorum sensing (QS). The LuxR-type receptor RhlR plays an important role in the P. aeruginosa QS process, and there is considerable interest in the development of chemical approaches to modulate the activity of this protein. RhlR is activated by a simple, low molecular weight N-acyl l-homoserine lactone signal, N-butanoyll-homoserine lactone (BHL). Despite the emerging prominence of RhlR in QS pathways, there has been limited exploration of the chemical features of the BHL scaffold that are critical to its function. In the current study, we sought to systematically delineate the structure-activity relationships (SARs) driving BHL activity for the first time. A focused library of BHL analogues was designed, synthesized, and evaluated in cell-based reporter gene assays for RhlR agonism and antagonism. These investigations allowed us to define a series of SARs for BHL-type ligands and identify structural motifs critical for both activation and inhibition of the RhlR receptor. Notably, we identified agonists that have ∼10-fold higher potencies in RhlR relative to BHL, are highly selective for RhlR agonism over LasR, and are active in the P. aeruginosa background. These compounds and the SARs reported herein should pave a route toward new chemical strategies to study RhlR in P. aeruginosa.