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John G.K.,University of Oxford | Douglas N.M.,University of Oxford | Douglas N.M.,Charles Darwin University | Von Seidlein L.,Charles Darwin University | And 10 more authors.
Malaria Journal | Year: 2012

Background: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. Methods. Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (2.5 mg/kg), low (>2.5 mg/kg-<5.0 mg/kg) and high ( 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. Results: Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n=44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n=82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR=0.60, 95%CI 0.33-1.09, p=0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR=0.14, 95%CI: 0.06-0.35, p<0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR=0.03 (95%CI: 0.01-0.13); p<0.0001). Conclusions: Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors. © 2012 John et al.; licensee BioMed Central Ltd.

Ehlers C.L.,Scripps Research Institute | Gizer I.R.,University of North Carolina at Chapel Hill | Vieten C.,Pacific Research Group | Gilder A.,Scripps Research Institute | And 4 more authors.
American Journal on Addictions | Year: 2010

We examined gender differences in age of onset, clinical course, and heritability of alcohol dependence in 2,524 adults participating in the University of California San Francisco (UCSF) family study of alcoholism. Men were significantly more likely than women to have initiated regular drinking during adolescence. Onset of regular drinking was not found to be heritable but was found to be significantly associated with a shorter time to onset of alcohol dependence. A high degree of similarity in the sequence of alcohol-related life events was found between men and women, however, men experienced alcohol dependence symptoms at a younger age and women had a more rapid clinical course. Women were found to have a higher heritability estimate for alcohol dependence (h2 =.46) than men (h2 =.32). These findings suggest that environmental factors influencing the initiation of regular drinking rather than genetic factors associated with dependence may in part underlie some of the gender differences seen in the prevalence of alcohol dependence in this population. © American Academy of Addiction Psychiatry.

Allen M.H.,Aurora University | Feifel D.,University of California at San Diego | Lesem M.D.,Claghorn Lesem Research Clinic Ltd | Zimbroff D.L.,Pacific Research Group | And 5 more authors.
Journal of Clinical Psychiatry | Year: 2011

Objective: The objective of this study was to assess the efficacy and safety of inhaled loxapine in the treatment of agitation in patients with psychotic disorders. Method: In this randomized, double-blind, placebocontrolled study, 129 agitated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) were randomized to receive in a clinical or hospital setting a single inhalation of 5 or 10 mg of loxapine or placebo administered using the Staccato loxapine for inhalation device. The inhalation device delivered thermally generated drug aerosol to the deep lung for rapid absorption. The primary efficacy measure was change on the Positive and Negative Syndrome Scale-excited component (PANSS-EC) 2 hours following treatment. Secondary outcomes included the Clinical Global Impressions-Improvement scale (CGI-I), Behavioral Activity Rating Scale (BARS), and time to first rescue medication. The study was conducted between September 2006 and January 2007. Results: Differences were statistically significant (P < .05) between placebo and both 5-mg and 10-mg doses on the CGI-I and the CGI-I responder analyses at 2 hours and in time to first rescue medication, and they were statistically significant (P < .05) between placebo and 10-mg loxapine on the PANSS-EC 20 minutes after administration continuing through 2 hours and in change from baseline BARS. Three serious adverse events occurred at least 6 days after treatment, but none were judged related to study treatment. The most common adverse events were sedation and dysgeusia (22% and 17%, respectively, in the 10-mg group, and 14% and 9%, respectively, in the placebo group). Conclusions: Inhaled loxapine was generally safe and well tolerated and produced rapid improvement in agitated patients with psychotic disorders. Statistically significant differences in efficacy were found for the 10-mg dose compared with placebo, with results suggesting 5 mg may be effective. The delivery of loxapine by inhalation may provide a rapid, well-tolerated option for treating acute psychotic agitation that allows patients to avoid the aversive effects and loss of autonomy often associated with use of intramuscular medications. Further investigation of this new loxapine formulation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT00369577. © Copyright 2011 Physicians Postgraduate Press Inc.

Bullock M.,Pacific Research Group
Endocrine-Related Cancer | Year: 2016

The majority of metastatic breast cancers cannot be cured and present a major public health problem worldwide. Approximately 70% of breast cancers express the estrogen receptor, and endocrine-based therapies have significantly improved patient outcomes. However, the development of endocrine resistance is extremely common. Understanding the molecular pathways that regulate the hormone sensitivity of breast cancer cells is important to improving the efficacy of endocrine therapy. It is becoming clearer that the PI3K-AKT- forkhead box O (FOXO) signaling axis is a key player in the hormone-independent growth of many breast cancers. Constitutive PI3K-AKT pathway activation, a driver of breast cancer growth, causes down-regulation of FOXO tumor suppressor functions. This review will summarize what is currently known about the role of FOXOs in endocrine-resistance mechanisms. It will also suggest potential therapeutic strategies for the restoration of normal FOXO transcriptional activity. © 2016 Society for Endocrinology.

Hsieh P.-C.,National Sun Yat - sen University | Hsu S.-H.,National Sun Yat - sen University | Lee C.-L.,National Sun Yat - sen University | Lee C.-L.,Pacific Research Group | Brimblecombe P.,University of East Anglia
Environmental Toxicology and Chemistry | Year: 2010

The binding constant (KDOC) between humic acid and the nitrogen-containing polycyclic aromatic compound (N-PAC), benzo[h]quinoline, was measured at varying pH levels using fluorescence quenching (FQ). Because fluorescence characteristics of benzo[h]quinoline change with pH, determination required two optimum sets of excitation and emission wavelength pairs. A simple mixing model was used to eliminate the inherent fluorescence interference between benzo[h]quinoline and its protonated form, benzo[h]quinolinium, when estimating binding constants. Hydrophobic interaction is likely to control the binding between humic acid and benzo[h]quinoline and benzo[h]quinolinium, in lower and higher pH ranges (pH <3, pH >6). In contrast, cation exchange seems to control the binding affinity of benzo[h]quinolinium in the middle range of pH. The estimates of KDOC were up to 70% smaller after elimination of interference. This indicates that the contribution of the minor form influences estimates of the KDOC-pH trend for benzo[h]quinoline, and potentially explains the large discrepancy reported in the literature between results based on using FQ and those based on equilibrium dialysis methods. Previous FQ measurements overestimate KDOC at some pH values and lead to an underestimation of bioavailability in an aquatic environment. The application of our models appears to be necessary when using FQ for determining the KDOC-pH trend for organic compounds with acid-base pair analogs. © 2010 SETAC.

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