Intravenous butyrylcholinesterase administration and plasma and brain levels of cocaine and metabolites in rats

Butyrylcholinesterase is a major cocaine-metabolizing enzyme in humans and other primates, catalyzing hydrolysis to ecgonine methylester. Increasing butyrylcholinesterase activity may be a treatment for cocaine addiction. We evaluated the effect of 30-min pretreatment with horse-derived butyrylcholinesterase (5-15,000 U i.v.) or with the selective butyrylcholinesterase inhibitor cymserine (10 mg/kg i.v.) on the metabolism of cocaine (17 mg/kg i.p.) in anesthetized rats. Venous blood samples were collected for two hours after cocaine administration and later assayed for cocaine and metabolites by gas chromatography/mass spectroscopy. Whole brains were collected after the last blood sample and similarly assayed. Butyrylcholinesterase significantly increased plasma and brain ecgonine methylester levels and decreased cocaine plasma half-life from 26.2 min (saline) to 16.4 min (15,000 U). Butyrylcholinesterase had no significant effect on plasma or brain cocaine or benzoylecgonine levels. Cymserine had no effect on any variable. These findings suggest that butyrylcholinesterase treatment may have benefits in enhancing cocaine metabolism and in increasing levels of ecgonine methylester, which may have a protective action against cocaine.     

Pramipexole and levodopa in early Parkinson's disease: dynamic changes in cost effectiveness

BACKGROUND AND OBJECTIVE: In chronic disease, treatment effects and costs accumulate over time; hence, the choice of time horizon in cost-effectiveness analysis can be particularly important. In this article we analyse the dynamic changes in cumulative costs, effects and incremental cost effectiveness of two competing drug strategies in patients with early Parkinson's disease (PD). METHODS: Three hundred and one subjects with PD were randomised to initial pramipexole or levodopa and followed every 3 months over a 4-year period. Healthcare resource use was recorded in patient diaries and valued using a variety of sources at year 2002 US dollar values. Health-related quality of life (HRQoL) was measured using the EuroQoL EQ-5D. The study was conducted from a US societal perspective. Missing data were imputed using a multivariate fixed-effects model. Additional quality adjusted life years (QALY) gained by using pramipexole compared with levodopa were estimated as the area between the normalised treatment HRQoL profiles. The QALYs and costs for each treatment arm were calculated for various study horizons.The incremental cost-effectiveness ratio (ICER) and the net monetary benefit (NB) [using 50,000 US dollars, 100,000 US dollars and 150,000 US dollars as the value of a QALY] were estimated, and were bootstrapped to calculate the standard errors. Cost-effectiveness acceptability curves (CEAC) were built to estimate the probability that pramipexole was cost effective given different societal values of QALY, for various study horizons.We conducted sensitivity analyses on the ICER and the NB to test their robustness to various assumptions about missing data, for various subpopulations and under changes in the drug prices. RESULTS: Under the base-case assumptions, the ICER for pramipexole was 42,989 US dollars per QALY. Using the CEAC approach, the probability that pramipexole was cost effective relative to levodopa over the first 4 years was 0.57, 0.77 and 0.82 when a QALY was valued at 50,000 US dollars, 100,000 US dollars, and 150,000 US dollars, respectively. Over time, the ICER for pramipexole improved and uncertainty around the ICER decreased. If, after treatment withdrawal, HRQoL improved in pramipexole subjects and declined in levodopa subjects (best-case scenario for pramipexole), the probability of pramipexole being cost effective increased to 0.88, 0.96 and 0.98, respectively. Factors that improved the ICER of pramipexole were a decrease in the relative price of pramipexole and having low HRQoL or depression at baseline. CONCLUSIONS: The cost effectiveness of pramipexole compared with levodopa in the treatment of early PD increased as the time horizon of the clinical trial extended from 2 to 4 years. Our results suggest that pramipexole is more cost effective for patients with depression and low baseline HRQoL than in other patient subgroups.     

The inositol monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test

Rationale

Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization.

Objectives

The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST).

Methods

The inhibitor was administered intracerebroventricularly in liposomes.

Results

L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST.

Conclusions

It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor’s effect with intracerebroventricular inositol would be an important further step in proof.     

Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

How Do Students Source and Supply Drugs? Characteristics of the University Illegal Drug Trade

Background: It is widely known that a proportion of university students use drugs. However, much less is known about how they source and supply their drugs. Objectives: In this article, we investigate student drug trading activity, including how they obtained their drugs, whether they sold drugs, and the extent to which their drug trading might be described as a form of “social supply”. Methods: A survey was conducted of all students across seven of the nine universities of Wales. In total, 7855 students submitted a questionnaire and 1877 of these reported drug use in the current academic year. All students who reported using one or more illegal drugs in the current academic year were asked how they obtained their drugs, how they funded their drug use, whether they had sold, traded or given away illegal drugs, along with their motives for drug trading. Results: The results showed that about half of users obtained drugs solely from friends and associates and one-fifth obtained them solely from external dealers. One-quarter used friends and associates as well as external markets. In many cases, supplying drugs amounted to sharing them or giving them away. However, over one-third of students said that they had sold drugs. Conclusions: Overall, the methods of sourcing and supplying drug among university students shares features of both “social supply” and “traditional” drug markets. We conclude that the student drug market investigated is best described as a “hybrid” combination of both.     

Structural Inequities and Social Networks Impact Hormone Use and Misuse Among Transgender Women in Los Angeles County

In order to reduce gender dysphoria and combat stigma, transgender women often affirm their gender through social and medical transition, which may include cross-sex hormone therapy. This study examined associations between medically monitored hormone use and hormone misuse (non-prescribed hormone use including “fillers”), structural inequities (access to housing, health insurance, and income), and social network dynamics among 271 transgender women in Los Angeles. Hormone use status was coded trichotomously (hormone use, hormone misuse, no hormone use), and robust multinomial logistic regression as well as novel social network analysis was conducted to examine associations. Results demonstrated that younger, African-American/Black transgender women were most likely to engage in hormone misuse compared to transgender women who were older or non-African-American/Black. One-third of the sample reported sex work as a main source of income, and this group was more likely to misuse hormones than those with another primary source of income. Transgender women with access to stable housing and health insurance were most likely to engage in medically monitored hormone use. Social network analysis revealed that transgender women with a greater number of hormone-using network alters were most likely to misuse hormones, but that using the Internet to find transgender friends mitigated this association. Results demonstrate the multifaceted risk profile of transgender women who use and misuse hormones, including that social networks play an important role in hormone usage among transgender women.     

Cell Phone Internet Access,Online Sexual Solicitation,Partner Seeking,and Sexual Risk Behavior Among Adolescents

Archives of Sexual Behavior - Online partner seeking is associated with sexual risk behavior among young adults (specifically men who have sex with men), but this association has yet to be explored...     

Antismoking Ads at the Point of Sale: The Influence of Ad Type and Context on Ad Reactions

Efforts are underway to educate consumers about the dangers of smoking at the point of sale (POS). Research is limited about the efficacy of POS antismoking ads to guide campaign development. This study experimentally tests whether the type of antismoking ad and the context in which ads are viewed influence people’s reactions to the ads. A national convenience sample of 7,812 adult current smokers and recent quitters was randomized to 1 of 39 conditions. Participants viewed one of the four types of antismoking ads (negative health consequences—graphic, negative social consequences—intended emotive, benefits of quitting—informational, benefits of quitting—graphic) in one of the three contexts (alone, next to a cigarette ad, POS tobacco display). We assessed participants’ reactions to the ads, including perceived effectiveness, negative emotion, affective dissonance, and motivational reaction. Graphic ads elicited more negative emotion and affective dissonance than benefits of quitting ads. Graphic ads elicited higher perceived effectiveness and more affective dissonance than intended emotive ads. Antismoking ads fared best when viewed alone, and graphic ads were least influenced by the context in which they were viewed. These results suggest that in developing POS campaigns, it is important to consider the competitive pro-tobacco context in which antismoking ads will be viewed.     

Experiences and career intentions of general practice registrars from The Netherlands

For some years prospective general practitioners (GPs) from the Netherlands have come to Britain to complete their training. Not all report enjoying their time here, and many leave this country after training. The aim of this study was to examine reasons for coming to Britain, experiences, perceptions and career intentions. The sample consisted of 14 general practice registrars working in their practice year in Southern England. Data were collected through in-depth semistructured interviews and analysed by thematic qualitative analysis. The main reasons for training in this country were easier access, a quicker route to specialization and the quality of training provided. Most had positive professional and personal experiences and saw the British system of training GPs as up to date and supportive of their educational and professional needs. They highlighted some of the positive aspects of the British system, such as the emphasis on teamwork and collaboration with other primary care professionals. They did, however, point out problems and conflicts; for instance, they saw the health care system in Britain as more bureaucratic and as providing unequal access for different groups of the population. Despite their fear of litigation, which they saw as one of the drawbacks for British general practitioners, most looked favourably on the option of staying in or returning to this country if possible. All registrars valued their stay in Britain; however, personal circumstances often dictated a return to Holland. Our findings have implications for manpower planning and recruitment for general practice in both Britain and Holland.