PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors?

The Peroxisome Proliferator-Activated Receptors-PPAR alpha, PPAR gamma, and PPAR delta--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders.

OBJECTIVE: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. METHODS: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. RESULTS: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. CONCLUSIONS: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

Deep Impact: observations from a worldwide Earth-based campaign.

On 4 July 2005, many observatories around the world and in space observed the collision of Deep Impact with comet 9P/Tempel 1 or its aftermath. This was an unprecedented coordinated observational campaign. These data show that (i) there was new material after impact that was compositionally different from that seen before impact; (ii) the ratio of dust mass to gas mass in the ejecta was much larger than before impact; (iii) the new activity did not last more than a few days, and by 9 July the comet's behavior was indistinguishable from its pre-impact behavior; and (iv) there were interesting transient phenomena that may be correlated with cratering physics.

Stress responsivity and socioeconomic status: a mechanism for increased cardiovascular disease risk?

AIMS: Low socioeconomic status is associated with increased cardiovascular disease risk. We hypothesized that psychobiological pathways, specifically slow recovery in blood pressure and heart rate variability following mental stress, partly mediate social inequalities in risk. METHODS AND RESULTS: Participants were 123 men and 105 women in good health aged 47-58 years drawn from the Whitehall II cohort of British civil servants. Grade of employment was the indicator of socioeconomic status. Cardiovascular measures were monitored during performance of two behavioural tasks, and for 45 min following stress. Post-stress return of blood pressure and heart rate variability to resting levels was less complete after 45 min in the medium and low than in the high grade of employment groups. The odds of failure to return to baseline by 45 min in the low relative to the high grade of employment groups were 2.60 (95% CI 1.20-5.65) and 3.85 (1.48-10.0) for systolic and diastolic pressure, respectively, and 5.19 (1.88-18.6) for heart rate variability, adjusted for sex, age, baseline levels and reactions to tasks. Subjective ratings of task difficulty, involvement and stress did not differ by socioeconomic status. CONCLUSIONS: Lower socioeconomic status is associated with delayed recovery in cardiovascular function after mental stress. Impaired recovery may reflect heightened allostatic load, and constitute a mechanism through which low socioeconomic status enhances cardiovascular disease risk.

Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in nursing home patients with Alzheimer's dementia.

BACKGROUND: Psychotic symptoms and behavioral disturbances are a leading cause of institutionalization in elderly patients with Alzheimer's disease (AD). OBJECTIVES: Elderly nursing home patients (n=105) with possible or probable AD were entered into a multicenter study to determine the long-term efficacy and safety of olanzapine in treatment of psychotic symptoms and behavioral disturbances due to AD. METHODS: Following a double-blind, 6-week exposure to fixed-dose olanzapine (5, 10, or 15 mg/d), patients entered an additional 18-week, open-label, flexible-dose treatment. Baseline was defined from the start of the extension phase. RESULTS: Patients improved significantly on the primary efficacy measure, defined a priori, which consisted of the sum of the Agitation/Aggression, Delusions, and Hallucinations items ('Core':) of the NPI/NH. Olanzapine also significantly improved scores for the NPI/NH total and the Core item-associated Occupational Disruptiveness of the NPI/NH, as well as the BPRS total and CGI Severity-of-Alzheimer's scores. Barnes Akathasia scores improved significantly from baseline, while Simpson-Angus and AIMS scores were not significantly changed. Treatment-emergent symptoms included somnolence, accidental injury, and rash. No significant changes were seen in ECGs, including QT(c) interval, nor in weight or vital signs, including orthostasis. CONCLUSIONS: Low-dose olanzapine appears to be effective and well tolerated for treatment of behavioral disturbances and psychotic symptoms due to AD in elderly patients.

Detection of molecular hydrogen in the atmosphere of Mars.

Four hydrogen (H2) lines have been detected in a spectrum of Mars observed with the Far Ultraviolet Spectroscopic Explorer. Three of those lines are excited by the solar Lyman beta photons. The line intensities correspond to a column H2 abundance of 1.17 (+/-0.13) x 10(13) per square centimeter above 140 kilometers on Mars. A photochemical model for the upper atmosphere that simulates the observed H2 abundance results in an H2 mixing ratio of 15 +/- 5 parts per million in the lower atmosphere. The H2 and HD mixing ratios agree with photochemical fractionation of D (deuterium) between H2O and H2. Analysis of D fractionation among a few reservoirs of ice, water vapor, and molecular hydrogen on Mars implies that a global ocean more than 30 meters deep was lost since the end of hydrodynamic escape. Only 4% of the initially accreted water remained on the planet at the end of hydrodynamic escape, and initially Mars could have had even more water (as a proportion of mass) than Earth.

The experiences and challenges of informal caregivers: common themes and differences among whites, blacks, and hispanics.

PURPOSE: This study examined commonalities and differences in the experiences and challenges of White, Black, and Hispanic informal caregivers in New York, NY. DESIGN AND METHODS: A randomly selected representative cross-section of 2,241 households was contacted through telephone interviews. Complete data were available for 380 eligible participants, who were classified as White (n = 164), Black (n = 129) and Hispanic (n = 87). Descriptive, bivariate, and multivariate analyses were conducted to examine differences in caregiving intensity, reported difficulty with providing care, and having unmet needs with care provision. RESULTS: Over 70% of caregivers had no help from formal caregivers, even though over 80% had been providing care for at least 1 year, and 40% had been providing this care for 20 or more hr per week. Compared with White caregivers, Black caregivers were more likely to provide higher intensity care, to report having unmet needs with care provision, and to experience increased religiosity since becoming caregivers, but were less likely to report difficulty with providing care. Hispanic caregivers were more likely than White caregivers to have help from formal caregivers and to experience increased religiosity since becoming caregivers. IMPLICATIONS: Although many similarities exist in the experiences and challenges of informal caregivers, gaining insight from different populations of family caregivers would help program planners, policy makers, and formal caregivers to develop and implement culturally sensitive programs and policies that are supportive of the needs of these caregivers in their ever-expanding roles. Future efforts also should focus on exploring the potentially significant role that community resources, in particular, religious institutions, could play in providing outreach and support to racial/ethnic minority caregivers.

Synthesis of carbocyclic analogs of 2',3'-dideoxysangivamycin, 2',3'-dideoxytoyocamycin, and 2',3'-dideoxytriciribine.

Syntheses and antiviral activity of new carbocyclic analogs of 2', 3'-dideoxysangivamycin, 2',3'-dideoxytoyocamycin and 2',3'-dideoxytriciribine is described. The key intermediate, carbocyclic 4-chloro-5-iodopyrrolopyrimidine. was synthesized in good yield via a novel iodination method using I2 and CF3COOAg. This carbocyclic 4-chloro-5-iodopyrrolopyrimidine then allowed for a concise synthesis of the desired 4,5-disubstituted carbocyclic nucleosides.

A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder.

OBJECTIVE: The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents. METHODS: This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Children's Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale). RESULTS: Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p < 0.001). Using predefined criteria for improvement of > or = 30% decline in the YMRS and a CGI-S Mania score of < or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p < 0.001). CONCLUSIONS: Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.

Neighborhood problems as sources of chronic stress: development of a measure of neighborhood problems, and associations with socioeconomic status and health.

The impact of the residential neighborhood on health and well-being is being increasingly recognized in behavioral medicine, with evidence for neighborhood-level effects that are independent of the individual characteristics of residents. This study addressed the possibility that the effects of neighborhood are due in part to exposure to community-wide stressors rather than variations inprotective factors such as social capital. A questionnaire survey including a 10-item neighborhood problems scale and measures of self-reported health, health behaviors, and social capital was completed by 419 residents of 18 higher socioeconomic status (SES) neighborhoods and 235 residents of 19 lower SES neighborhoods. Data were analyzed using regression and multilevel methods. Neighborhood problem scores were greater in lower than higher SES neighborhoods, positively associated with individual deprivation, and negatively correlated with social capital. Neighborhood problems were not related to smoking, diet, alcohol consumption, or physical activity. However, neighborhood problems were associated with poor self-rated health, psychological distress on the General Health Questionnaire, and impaired physical function, independent of age, sex, neighborhood SES, individual deprivation, and social capital. Adjusted odds ratios for the highest versus lowest neighborhood problem quartiles ranged from 2.05 (confidence interval = 1.15-3.69) for poor self-rated health to 3.07 (1.63-5.79) for impairedphysical function. The results provide preliminary evidence that residential neighborhood problems constitute sources of chronic stress that may increase risk ofpoor health.

Deficiency of molecular hydrogen in the disk of beta Pictoris.

Molecular hydrogen (H2) is by far the most abundant material from which stars, protoplanetary disks and giant planets form, but it is difficult to detect directly. Infrared emission lines from H2 have recently been reported towards beta Pictoris, a star harbouring a young planetary system. This star is surrounded by a dusty 'debris disk' that is continuously replenished either by collisions between asteroidal objects or by evaporation of ices on Chiron-like objects. A gaseous disk has also been inferred from absorption lines in the stellar spectrum. Here we present the far-ultraviolet spectrum of beta Pictoris, in which H2 absorption lines are not seen. This allows us to set a very low upper limit on the column density of H2: N(H2) 6 x 10-4. As CO would be destroyed under ambient conditions in about 200 years (refs 9, 11), our result demonstrates that the CO in the disk arises from evaporation of planetesimals.

Possible medication errors in home healthcare patients.

OBJECTIVE: To determine the frequency of possible medication errors in a population of older home healthcare patients according to expert panel objective criteria. DESIGN: A cross-sectional survey. SETTING: Two of the largest urban home healthcare agencies in the United States. PARTICIPANTS: Home healthcare patients age 65 and older admitted to selected offices of these agencies between October 1996 and September 1998. MEASUREMENTS: We used two sets of consensus-based expert panel criteria to define possible medication errors. The Home Health Criteria identify patients with patterns of medication use and signs and symptoms that indicate sufficient likelihood of a medication-related problem to warrant reevaluating the patient. The Beers criteria identify medications that experts have deemed generally inappropriate for older patients. RESULTS: The 6,718 study subjects took a median of five drugs; 19% were taking nine or more medications. A possible medication error was identified for 19% of patients according to Home Health Criteria, 17% according to the Beers criteria, and 30% according to either. Possible errors increased linearly with number of medications taken. When patients taking one to three medications were compared with those taking nine or more drugs, the percentages with possible errors were, respectively, 10% and 32% for the Home Health Criteria, 8% and 32% for the Beers criteria, and 16% and 50% for both. CONCLUSION: Nearly one-third of the home healthcare patients surveyed had evidence of a potential medication problem or were taking a drug considered inappropriate for older people. More-effective methods are needed to improve medication use in this vulnerable population.

Stereocontrolled synthesis of cis-dibenzoquinolizine chlorofumarates: curare-like agents of ultrashort duration.

The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzo[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzo[a,g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis-selectivity. The cis-dibenzo[a,h]quinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium alpha-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (+/-)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.

HST and VLT investigations of the fragments of comet C/1999 S4 (LINEAR).

At least 16 fragments were detected in images of comet C/1999 S4 (LINEAR) taken on 5 August 2000 with the Hubble Space Telescope (HST) and on 6 August with the Very Large Telescope (VLT). Photometric analysis of the fragments indicates that the largest ones have effective spherical diameters of about 100 meters, which implies that the total mass in the observed fragments was about 2 x 10(9) kilograms. The comet's dust tail, which was the most prominent optical feature in August, was produced during a major fragmentation event, whose activity peaked on UT 22.8 +/- 0.2 July 2000. The mass of small particles (diameters less than about 230 micrometers) in the tail was about 4 x 10(8) kilograms, which is comparable to the mass contained in a large fragment and to the total mass lost from water sublimation after 21 July 2000 (about 3 x 10(8) kilograms). HST spectroscopic observations during 5 and 6 July 2000 demonstrate that the nucleus contained little carbon monoxide ice (ratio of carbon monoxide to water is less than or equal to 0.4%), which suggests that this volatile species did not play a role in the fragmentation of C/1999 S4 (LINEAR).

The effects of olanzapine in reducing the emergence of psychosis among nursing home patients with Alzheimer's disease.

BACKGROUND: Elderly patients with Alzheimer's disease (AD) commonly exhibit psychotic symptoms, prompting clinicians to administer antipsychotics. This article compares the effects of olanzapine and placebo in the emergence of hallucinations or delusions in AD patients with symptoms of agitation/aggression but little or no psychotic symptomatology at baseline. METHOD: A multicenter, double-blind, placebo-controlled study was conducted in nursing home patients with AD according to DSM-IV criteria and symptoms of agitation/aggression and/or psychosis. Patients (N = 206) were randomly assigned to receive either placebo or fixed-dose olanzapine (5, 10, or 15 mg/day) for up to 6 weeks. This article analyzes data from a subgroup of patients (N = 165) with no or minimal delusions and/or hallucinations at baseline as measured by the Neuropsychiatric Inventory-Nursing Home Version (NPI/NH). Three subsets of patients were identified on the basis of their symptoms at baseline: those with no clinically significant hallucinations, those with no clinically significant delusions, and those with no clinically significant delusions or hallucinations. RESULTS: Of the patients without hallucinations or delusions at baseline (N = 75), the placebo-treated patients showed significantly greater development of these symptoms compared with olanzapine-treated patients overall (NPI/NH hallucinations + delusions mean change score, +2.73 vs. +0.27, p = .006). Similarly, of the patients without baseline hallucinations (N = 153), the placebo-treated patients showed greater hallucinations score increases than did olanzapine-treated patients overall (+1.25 vs. +0.33, p = .026), whereas patients without baseline delusions (N = 87) showed no significant treatment effects. Olanzapine had a favorable safety profile in each patient subset. CONCLUSION: These results suggest that, overall, olanzapine effectively attenuated emergence of psychosis in a short-term trial of patients with Alzheimer's disease.

A scintillation proximity assay for rna detection.

A homogeneous scintillation proximity assay (SPA) for detection of RNA transcripts is described. 3H-labeled RNA transcripts are hybridized in solution to biotinylated oligodeoxynucleotides (ODNs), which are then bound by streptavidin-coated, scintillant-embedded beads. Only bound 3H-labeled RNA transcripts are brought in close enough proximity to stimulate light emission from the beads. The results from this novel homogeneous assay correlated well with those obtained using the traditional filter-binding methods to measure RNA polymerase activity. The assay has been miniaturized to a 384-well format compatible with automated high-throughput screening. This SPA method has also been successfully used to probe RNA-accessible sites to hybridization, and thus should provide a useful tool for selecting effective antisense ODNs in antisense research.

A novel augmentation strategy for treating resistant major depression.

OBJECTIVE: Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression. METHOD: An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine. RESULTS: Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions. CONCLUSIONS: Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.

Olanzapine versus haloperidol in schizoaffective disorder, bipolar type.

BACKGROUND: The present analysis was performed on data from a subsample of patients with schizoaffective disorder, bipolar type, who participated in a multicenter, double-blind study comparing olanzapine to haloperidol. METHODS: Patients with schizoaffective disorder bipolar type, characterized as currently manic, mixed, depressed, or euthymic, were assessed weekly for 6 weeks during treatment with either olanzapine or haloperidol. Manic symptoms were measured using the sum of six items of the BPRS, and depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. In addition, cognitive functioning was measured using the sum of seven items from the PANSS. Repeated measures analyses were performed using random coefficients regression of the serial measurement of manic, cognitive, and depressive symptoms. RESULTS: A significant treatment difference was detected overall, indicating that olanzapine was significantly more effective than haloperidol in reducing symptoms of depression and improving patients' cognitive symptoms. The superiority of olanzapine over haloperidol in the reduction of manic symptoms did not reach statistical significance (P=.052). The greatest improvement in both manic and cognitive symptoms was seen in the olanzapine-treated 'currently manic' subgroup, and least improvement in the haloperidol-treated 'euthymic' subgroup. Depressive symptoms were most improved in the olanzapine-treated 'depressed' subgroup, and least improved in the corresponding haloperidol subgroup. CONCLUSIONS: Overall, olanzapine was superior to haloperidol with respect to thymoleptic effects in patients with schizoaffective disorder, bipolar type.