Self-reported cognitive problems predict employment trajectory in patients with bipolar I disorder.

BACKGROUND: Cognitive impairment in bipolar disorder has been associated with poor functional outcomes. We examined the relation of self-reported cognitive problems to employment trajectory in patients diagnosed with bipolar I disorder. METHODS: 154 bipolar I disorder patients were followed for 15-43months at the Bipolar Disorders Center for Pennsylvanians. Using a multinomial logistic regression we examined predictors of employment group including self-reported cognitive problems, mood symptoms, education and age. Cognitive functioning was measured via 4 self-report items assessing memory/concentration at baseline and termination. Employment status was recorded at baseline and termination. Employment was categorized as working (full-time, part-time, homemaker, volunteer) or not working (leave of absence, disability, unemployed, no longer volunteering) at each time point. Patients were categorized as good stable, improving, worsening and poor stable. RESULTS: Baseline self-reported concentration problems and years of education significantly predicted employment trajectory. LIMITATIONS: Post-hoc analyses of existing clinical data. CONCLUSIONS: Self-reported concentration problems assessed in the context of specific areas of functioning may serve as a sensitive predictor of functional outcome in patients diagnosed with bipolar I disorder.

Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 2. Selective and potent benzylamino cyclobutenediones.

A novel series of benzylamine, potassium channel openers (KCOs) is presented as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that the in vitro potency of (R)-4-[3,4-dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC(50) = 0.29 microM) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 31 (IC(50) = 0.14 microM)-a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered orally (31, ED(50) = 3 mg/kg) in a rodent model of bladder instability. Further modifications, particularly the replacement of the t-Bu amino substituent with a tert-amylamine, gave a similarly active compound 60 (IC(50) = 0.10 microM) which shows excellent in vivo efficacy (ED(50) = 0.6 mg/kg). Moreover, 60, 3-(2,4-dichloro-6-methyl-benzylamino)-4-(1, 1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (WAY-151616), shows excellent tissue selectivity for bladder K channels over arterial tissue (60, MAP ED(20) = 100 mg/kg; selectivity: MAP ED(20)/bladder ED(50) = 166). Other manipulations of the benzylamino cyclobutenediones, acylation of the benzylamine, conversion of the benzylamine substituent to a benzamide, homologation of the benzylamine to a phenethylamine, and incorporation of a methyl group at the benzyl carbon, all led to substantial loss of in vitro activity, although some in vivo activity was maintained in the acylated analogues. Compound 60 represents an attractive candidate for development in the treatment of UUI.

Novel and selective calcitonin-inducing agents.

A series of xanthine sulfonamides is presented as a class of calcitonin (CT) inducers - a potentially new method for treating diseases associated with postmenopausal bone loss such as osteoporosis. We have found that certain di-n-butylxanthine sulfonamides 4 upregulate CT transcription in a CT-luciferase reporter gene assay (CT-luci) and increase the production and release of CT in a CT secretion/RIA assay (CTS). In addition, these compounds do not have potent PDE4 inhibitory activity as do the related xanthine methylene ketones such as denbufyllene (2). One compound in particular (9) shows a transcription activation ratio (TAR) of 2.1 in CT-luci, a CTS increase of 3.6-fold, and a PDE4 (phosphodiesterase type IV) IC(50) = 4.1 microM. In addition, this compound showed a statistically significant 47% trabecular bone protection in ovariectomized-induced osteopenia (OVX) rats as determined by assay when administered for 4 weeks at 30 mg/kg/day, i. p. by quantitative computed tomography (QCT). When administered p.o., compound 9 shows 50% trabecular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. This compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.

The assessment of lamotrigine, an antiepileptic drug, in the treatment of tinnitus.

OBJECTIVE: Tinnitus is an extremely prevalent condition that currently has no satisfactory clinical treatment. Development of therapy has been hampered by the diversity of underlying conditions that give rise to the symptom of tinnitus. A drug that has multiple actions may have an improved chance of being effective. One such drug is lamotrigine, a recently developed antiepileptic agent that has both glutamate release inhibition and sodium channel antagonist activity. STUDY DESIGN: Lamotrigine was evaluated in a double-blind, placebo-controlled, crossover clinical trial. Patients initially were tested with an intravenous infusion of lidocaine (10 mg/mL) to a maximum of 100 mg or until a reduction in tinnitus. Lamotrigine or placebo tablets were taken once daily (25 mg) for 2 weeks, 50 mg for 2 weeks, and 100 mg for 4 weeks. SETTING: Patients were chosen from among volunteers from the tinnitus clinic in the local hospital without reference to underlying pathology. PATIENTS: Those patients whose tinnitus had been present for less than 6 months or whose tinnitus was likely to vary spontaneously were excluded. INTERVENTIONS: Perceived intensity and intrusiveness of tinnitus was assessed before entry onto the trial and at 4-week intervals throughout the trial. MAIN OUTCOME MEASURES: Assessment comprised questionnaires, visual analog scales, and a battery of audiologic measurements. RESULTS: There was no correlation between the response to lidocaine and the response to lamotrigine. There was good agreement between the questionnaires and visual analog scales in the reporting of perceived changes; however, this was not reflected as changes in the audiologic tests. CONCLUSIONS: Of the 31 participants who completed the trial, questionnaires indicated that lamotrigine was effective in a very few of these persons.

Identification and analysis of a class 2 alpha-mannosidase from Aspergillus nidulans.

A Class 2 alpha-mannosidase gene was cloned and sequenced from the filamentous fungus Aspergillus nidulans. A portion of the gene was amplified using degenerate oligonucleotide primers which were designed based on similarity between the Saccharomyces cerevisiae vacuolar and rat ER/cytosolic Class 2 protein sequences. The PCR amplification product was used to isolate the full length gene, and DNA sequencing revealed a 3383 bp coding region containing three introns. The predicted 1049 amino acid reading frame contained six potential N-glycosylation sites and encoded a protein of 118 kDa. The protein sequence did not appear to encode a typical fungal signal sequence or membrane spanning domain. Although the cellular location of the A.nidulans mannosidase was not determined, experimental evidence suggested that it was located within a subcellular organelle. The Matchbox sequence similarity matrix indicated that the A.nidulans protein sequence was more highly similar to the rat ER/cytosolic (Rij = 0.33) and S.cerevisiae vacuolar alpha-mannosidases (Rij = 0.43) than the rat and yeast sequences were to each other (Rij = 0.29). These three enzymes were found to be distantly related to other Class 2 sequences, and compose a third subgroup of Class 2 alpha-mannosidases, as shown by ClustalW sequence alignment.

Variations in the uptake of beta-carotene in the oral mucosa of individuals after 3 days of supplementation.

Variations in the response of individuals to beta-carotene supplementation were studied by measuring the accumulation of beta-carotene in oral mucosa cells. Beta-carotene was administered orally to 178 individuals for 3 consecutive days, exfoliated oral mucosa cells were collected by brushing the entire oral mucosa on the 7th day following supplementation, and the beta-carotene content was measured by HPLC analysis of the pronase-treated cells. The rise in beta-carotene levels in the oral mucosa following supplementation varied considerably. Significant differences in mean beta-carotene levels in the oral mucosa were observed in 4 population groups. After supplementation, beta-carotene levels increased by factors of 10.3 (100 Mile House), 7.8 (Williams Lake), 6.9 (Lytton) and 3.4 (Vancouver), respectively. This difference in mean beta-carotene values is due to there being different proportions of weak and strong responders in the various population groups. Neither peak levels nor increases in beta-carotene levels were correlated with base-line concentrations of beta-carotene in the pre-supplementation samples. A second supplementation was given to 54 individuals several months after the initial supplementation. Of 17 weak responders in the first supplementation study, 10 (58.8%) individuals again showed only a small increase. A time-course study revealed that low responders showed no significant changes in beta-carotene levels over the 21 days following supplementation. Particular attention should be paid to weak responders when results of intervention trials using beta-carotene are interpreted.

Defective production of leucocytic endogenous mediator (interleukin 1) by peripheral blood leucocytes of patients with systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and mixed connective tissue disease.

Leucocytic endogenous mediator is one of the activities ascribed to the cytokine or family of cytokines known as interleukin 1. In this study we have examined the ability of circulating blood leucocytes from patients with rheumatic diseases to produce this mediator in vitro. Leucocytic endogenous mediator production was found to be significantly decreased below normal values (mean 107 units, s.e.m. +/- 25) in systemic sclerosis (-6 units +/- 18), systemic lupus erythematosus (-25 units +/- 13), rheumatoid arthritis (-3 units +/- 13) and mixed connective tissue disease (-4 units +/- 40). A control group of ill patients with cancer produced 57 units +/- 8.