Community-based treatment of late life depression an expert panel-informed literature review

OBJECTIVES: To present findings from an expert panel-informed literature review on community-based treatment of late-life depression. METHODS: A systematic literature review was conducted to appraise publications on community-based interventions for depression in older adults. The search was conducted between March and October 2005. An expert panel of mental health, aging, health services, and epidemiology researchers guided the review and voted on quality and effectiveness of these interventions. RESULTS: A total of 3,543 articles were found with publication dates from 1967 to October 2005; of these, 116 were eligible for inclusion. Adequate data existed to determine effectiveness for the following interventions: depression care management, group and individual psychotherapy for depression, psychotherapy targeting mental health, psychotherapy for caregivers, education and skills training (to manage health problems besides depression; and for caregivers), geriatric health evaluation and management, exercise, and physical rehabilitation and occupational therapy. After reviewing the data, panelists rated the depression care management interventions as effective. Education and skills training, geriatric health evaluation and management, and physical rehabilitation and occupational therapy received ineffective ratings. Other interventions received mixed effectiveness ratings. Insufficient data availability and poor study quality prevented the panelists from rating several reviewed interventions. CONCLUSIONS: While several well-described interventions were found to treat depression effectively in community-dwelling older adults, significant gaps still exist. Interventions that did not target depression specifically may be of benefit to older adults, but they should not be presumed to treat depression by themselves. Treating depressed elders may require a multifaceted approach to ensure effectiveness. More research in this area is needed.     

Preliminary studies of offspring exposure to phenylbutazone and ivermectin during the perinatal period in a Holstein cow-calf model

The pregnant Holstein cow and her newborn calf were evaluated as an animal model to study in utero and for lactational drug transfer and offspring exposure. A nonsteroidal antiinflammatory drug, phenylbutazone, and an antiparasitic drug, ivermectin, were tested in the model. Prior to parturition, pregnant cows were dosed orally to steady state with phenylbutazone at 4 g/day or given a single subcutaneous injection of 200 microg ivermectin/kg body wt. The level of drug transferred to calves exposed in utero, in utero combined with lactational exposure, and via lactational exposure only, was measured from days 1 through 7 postpartum. At birth the plasma level in phenylbutazone-exposed calves was approximately one-half the dam's steady-state level. For ivermectin-exposed calves, plasma levels were at or below the limit of quantitation (0.5 ng/ml) at birth, suggesting that placental transfer of ivermectin is limited in the cow. For both drugs, rapid accumulation of the drug in calf plasma occurred with lactational exposure to a mean daily dose of 2 microg ivermectin/kg body wt or 0.1 mg phenylbutazone/kg body wt/day for the first 7 days of life. The accumulation observed in the newborn calf is attributed to the lipid solubility and long elimination half-lives of these drugs. These results demonstrate that drug transfer and offspring exposure can be studied using the cow-calf model. The data also highlight the importance of considering not only the dose but also physicochemical characteristics and pharmacokinetics of the drug in the offspring when evaluating the safety of a newborn's exposure to a drug in breast milk.     

CYP3A induction by N-hydroxyformamide tumor necrosis factor-alpha converting enzyme/matrix metalloproteinase inhibitors use of a pregname X receptor activation assay and primary hepatocyte culture for assessing induction potential in humans.

A series of N-hydroxyformamide tumor necrosis factor-alpha converting enzyme (TACE)/matrix metalloprotease (MMP) inhibitors were evaluated for their potential to induce human cytochrome P450 3A (CYP3A). Two in vitro assays were used: 1) a cell-based reporter gene assay for activation of the pregnane X receptor (PXR), and 2) a primary "sandwich" culture of human hepatocytes. Approximately 50 TACE/MMP inhibitors were evaluated in the human PXR assay. A range of PXR activation was observed, 0 to 150% of the activation of the known human CYP3A inducer rifampicin. Three TACE/MMP inhibitors were evaluated in rat and human hepatocytes. Significantly higher PXR activation/CYP3A induction was observed in PXR/hepatocyte models, respectively, for (2R,3S) 3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)-4-methylpentanoic acid [(1S,2S)-2-methyl-1-(2-pyridylcarbamoyl)-1-butyl]amide (GW3333) compared with (2R,3S)-6,6,6-trifluoro-3-[formyl(hydroxy)amino]-2-isobutyl-N-[(1S,2R)-2-methoxy-1-[(1,3-thiazol-2-ylamino)carbonyl]propyl]hexanamide (GW6495) and (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]-propyl]-2-[(1S)-1-[formyl(hydroxy)amino]ethyl]-5-phenylpentanamide (GI4023). The CYP3A induction level achieved with GW3333 at a concentration of approximately 10 microM in human hepatocytes was comparable to that achieved with rifampicin at a concentration of 10 microM. The extent of rodent CYP3A induction caused by GW3333 was confirmed in vivo after daily oral administration for 14 days to rats. In conclusion, GW3333 is a potential inducer of CYP3A expression in vivo in humans, but other N-hydroxyformamides are less likely to induce CYP3A.     

Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis

The antiapoptotic proteins Bcl-x(L) and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-x(L) and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-x(L) inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (K(d)) of approximately 300 microM for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-x(L) with an inhibition constant (K(i)) of 36 +/- 2 nM.     

Changes in neurons,neuroendocrine cells and nerve fibres in the lamina propria of irradiated bowel

Summary Damage to bowel often complicates radiotherapy for abdominal and pelvic malignancy. The symptoms of chronic irradiation enteropathy, which often include intractable diarrhoea, are generally attributed to vascular injury. We have examined specimens of bowel resected from patients who had been therapeutically irradiated to assess the extent of injury to the enteric nerve plexuses. To facilitate visualisation of nerve fibres and cells of neural or neuroendocrine origin, sections were immunostained with antibodies to neuronspecific enolase or PGP 9.5, widely used markers of nerves and neurons. Electron microscopy was performed in selected cases. In 27 out of 33 specimens the number of nerve fibres in the lamina propria was obviously increased compared to that in control material. Scattered cells with the histological, immunohistochemical and ultrastructural features of ganglion cells were noted within the lamina propria in 23 of the specimens, and in 18 cases so-called neuroendocrine cells, not normally seen in this location, were also present. These radiation-induced changes in the innervation of the bowel may contribute to the symptoms of chronic radiation enteropathy.     

Off-line motion correction methods for multi-frame PET data

Purpose  

Patient motion during PET acquisition may affect measured time-activity curves, thereby reducing accuracy of tracer kinetic analyses. The aim of the present study was to evaluate different off-line frame-by-frame methods to correct patient motion, which is of particular interest when no optical motion tracking system is available or when older data sets have to be reanalysed.