Drug and Alcohol Rehabilitation: Sustainable Tuberculosis Drug Development.

Sustainable tuberculosis drug development.

Filed under: Drug and Alcohol Rehabilitation

Clin Infect Dis. 2012 Oct 5;
Wallis RS

Six new anti-tuberculosis compounds in 4 classes are presently in clinical trials. Although these show substantial promise for drug-resistant (DR) tuberculosis, the presently planned studies of these compounds will not inform their optimal use, as each will be tested singly vs. placebo with existing drugs, rather than in new regimens. Each successive regulatory approval will increase the size, cost, and complexity of trials for those that follow, causing delays during which suboptimal use will occur and resistance will emerge. This paper proposes the development of a novel regimen with the potential for use in both drug sensitive (DS) and DR-TB. Adaptive licensing for DR-TB based on 2-month sputum culture would shorten time to initial approval by several years. A global outcomes registry would confirm safety and effectiveness in both DS and DR-TB, making possible the second transformation of TB treatment. We should do our utmost to see it succeed.
HubMed – drug

Does accumulating exposure to illicit drugs bring forward the age at onset in schizophrenia?

Filed under: Drug and Alcohol Rehabilitation

Aust N Z J Psychiatry. 2012 Oct 8;
Power BD, Dragovic M, Jablensky A, Stefanis NC

Objective:Whilst cannabis has been associated with an earlier age at onset in schizophrenia, the impact of amphetamine and/or cocaine plus cannabis consumption on age at onset remains unclear. The present study was designed to test the hypothesis that consumption of amphetamine and/or cocaine in addition to cannabis would lead to an earlier age at onset of schizophrenia than that seen for cannabis consumption alone. A secondary objective was to determine what kind of effect additional substance use exerted (e.g. additive, multiplicative).Method:Patients with a diagnosis of schizophrenia were recruited from consecutive admissions to the inpatient and outpatient services of a large psychiatric hospital in Perth, Australia and 167 participants were assessed using the Diagnostic Interview for Psychosis, which included detailed inquiry into illicit drug use in the 12 months prior to the onset of psychiatric symptoms. Participants were categorized into four groups: no illicit substance use (n = 65), cannabis use (n = 68), cannabis plus amphetamine use (n = 25), and cocaine plus cannabis/cocaine plus cannabis plus amphetamine use (n = 9). Analysis of variance was performed to detect trends, and linear regression used to analyze the consumption of each additional substance as a predictor of age at onset.Results:We observed a linear trend for mean age at onset: 23.34 (SD = 6.91) years for no illicit substance use, 22.51 (SD = 5.27) years for cannabis use, 20.84 (SD = 3.48) years for cannabis plus amphetamine use, and 19.56 (SD = 3.54) years for cocaine plus cannabis/cocaine plus cannabis plus amphetamine use; the variation in the means between groups was statistically significant: F(1,163) = 5.66, p = 0.008, Cohen’s d = 0.38. For the consumption of each additional substance, age at onset was earlier by 1.2 years: R(2) = 0.034, F(1,165) = 5.72, p = 0.018.Conclusions:Whilst preliminary, these findings suggest that additional consumption of each substance predicted an earlier age at onset by approximately 1 additional year.
HubMed – drug

Selective Inhibition of HER2-Positive Breast Cancer Cells by the HIV Protease Inhibitor Nelfinavir.

Filed under: Drug and Alcohol Rehabilitation

J Natl Cancer Inst. 2012 Oct 5;
Shim JS, Rao R, Beebe K, Neckers L, Han I, Nahta R, Liu JO

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2-positive breast cancer are needed.MethodsWe conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library. To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xenografts in athymic nude mouse models (n = 4-6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided.ResultsPharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2-positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, difference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations.ConclusionNelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients. HubMed – drug

Automated Segmentation of Hippocampal Subfields in Drug-Naive Patients with Alzheimer Disease.

Filed under: Drug and Alcohol Rehabilitation

AJNR Am J Neuroradiol. 2012 Oct 4;
Lim HK, Hong SC, Jung WS, Ahn KJ, Won WY, Hahn C, Kim IS, Lee CU

BACKGROUND AND PURPOSE:Although a few automated hippocampal subfield segmentation methods have been developed, there is no study on the effects of the diagnosis of Alzheimer disease on the hippocampal subfield volume with in vivo MR imaging. The aim of this study was to investigate hippocampal subfield volume differences between drug-naïve subjects with AD and healthy elderly controls by using an automated hippocampal subfield segmentation technique.MATERIALS AND METHODS:Thirty-one drug-naïve subjects with AD and 33 group-matched healthy control subjects underwent 3T MR imaging, and hippocampal subfield volume was measured and compared between the groups.RESULTS:Subjects with AD had significantly smaller volumes of the presubiculum, subiculum, CA2-3, and CA4 DG compared with healthy subjects (uncorrected, P < .001). In addition, we found significant positive correlations between the presubiculum and the subicular volumes and the MMSE-K and the CERAD-K verbal delayed recall scores in the AD group.CONCLUSIONS:We are unaware of previous imaging studies of automated hippocampal subfield segmentation in AD. These structural changes in the hippocampal presubiculum, subiculum, and CA2-3 might be at the core of underlying neurobiologic mechanisms of hippocampal dysfunction and their relevance to verbal delayed recall impairments in AD. HubMed – drug

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