Intervening early to reduce developmentally harmful substance use among youth populations

Early-onset or frequent substance use during adolescence increases the risk of developing mental health problems, as well as a range of other adverse outcomes (eg, alcohol or drug dependence, educational underachievement, health problems, social difficulties) during late adolescence and early adulthood.

Increases in rates of risky drinking among young people are particularly concerning, suggesting that an effective, evidence-based alcohol policy and preventive framework needs to be developed.

Restricting the supply of licit and illicit substances to adolescents, delaying the age that licit substances can be legally purchased, reducing positive media portrayals of substance use, and banning targeted promotions, should be universal, public prevention priorities.

Mass-media campaigns need to deliver coherent and credible evidence-based messages to young people, utilising a broad array of dissemination strategies.

Clear policy and guidelines for parents regarding appropriate alcohol use for adolescents also need to be developed.

Prevention programs should target children and adolescents in families with parents who use drugs, young people who have been suspended from school, or those with mental health problems.

Preventive screening and targeted brief interventions can be effectively delivered in a variety of settings by a range of health professionals.

Properties of an in vitro selected Pb2+ cleavage motif

The addition of Pb 2+ to a small RNA molecule consisting of an asymmetric internal loop of six nucleotides results in site-specific cleavage followed by hydrolysis of the 2′,3′-cyclic phosphate intermediate [Pan, T., & Uhlenbeck, O. C. (1992) Nature 358, 560-563]. Here we show that the reaction is highly specific for Pb 2+ and the cleavage rate increases exponentially with pH from 5.5 to 7.0, both in the presence and in the absence of Mg 2+. This suggests that the reaction mechanism involves Pb 2+ hydroxide acting as a base. Several sequence variants of the RNA are found to be equally active in both steps of the reaction, suggesting that they fold into a similar structure.

Effect of dietary fatty acids on the intestinal permeability of marker drug compounds in excised rat jejunum

The aim of this study was to explore the effects of diets containing saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and ω-3 and ω-6 polyunsaturated fatty acids (ω-3 and ω-6 PUFA, respectively) on the passive and active transport properties of rat jejunum using marker compounds. Rats were fed diets supplemented with 18.4% (w/w) lipid (4 groups) or standard rat chow (1 group) for a period of 30 days. At the end of the dietary period, mucosal scrapings were taken for the determination of membrane phospholipids, and the apparent jejunal permeability of radiolabelled marker compounds was determined using modified Ussing chambers. Changes in the phospholipid content of the brush border membrane reflected the different lipid content of the diets. The passive paracellular permeability of mannitol was not significantly affected by the fatty acid composition of the diet, although there was a trend toward decreased mannitol permeability in the rats fed both the ω-3 and ω-6 PUFA diets. In comparison, the transcellular diffusion of diazepam was reduced by 20% (P < 0.05) in rats fed diets supplemented with ω-3 and ω-6 PUFA. In the lipid-fed rats, the serosal to mucosal flux of digoxin, an intestinal P-glycoprotein substrate, was reduced by 20% (P < 0.05) relative to the chow-fed group, however there were no significant differences between the different lipid groups. The active absorption of D-glucose via the Na+-dependent transport pathway was highest in the SFA, MUFA and PUFA ω-3 dietary groups, intermediate in the low-fat chow group and lowest in the PUFA ω-6 group, and was positively correlated with short-circuit current. These studies indicate that dietary fatty acid changes can result in moderate changes to the active and passive transport properties of excised rat jejunum.

Drug release rate and anti-microbial effect of controlled-diffusion biopolymer membranes

In this study, a series of fibrous membranes made from cellulose acetate (CA) and polyester urethane (PEU) by co-electrospining or blend-electrospining were evaluated for drug release kinetics, in vitro anti-microbial activity and in vivo would healing performance when used as wound dressings. To stop common clinical infections, an antibacterial agent, Polyhexamethylene Biguanide (PHMB) was incorporated into e-spun fibres. The presence of CA in the wound healing membrane was found to improve hydrophilicity and permeability to air and moisture. The in vivo tests indicated that the addition of PHMB and CA considerably improved the wound healing efficiency. CA fibres became slightly swollen upon contacting with the wound exudates. It can not only speed up the liquid evaporation but also create a moisture environment for wound recovery. The drug release dynamics of membranes was controlled by the structure of membranes and component rations within membranes. The lower ration of CA:PEU retained the sound mechanical properties of membranes, and also reduced the boost release effectively and slowed down diffusion of antibacterial agent during in vitro tests. The controlled-diffusion membranes exert long-term anti-infective effect.

School, parent, and student perspectives of school drug policies

Background: Schools use a number of measures to reduce harmful tobacco, alcohol, and drug use by students. One important component is the school's drug policy, which serves to set normative values and expectations for student behavior as well as to document procedures for dealing with drug-related incidents. There is little empirical evidence of how policy directly or indirectly influence students' drug taking. This study compares how effectively schools communicate school drug policies to parents and students, how they are implemented, and what policy variables impact students' drug use at school and their perceptions of other students' drug use at school.

Methods: Data were obtained from 3876 students attending 205 schools from 2 states in the United States and Australia, countries with contrasting national drug policy frameworks. School policy data were collected from school personnel, parents, and students.

Results: Schools' policies and enforcement procedures reflected national policy approaches. Parents and students were knowledgeable of their school's policy orientation.

Conclusions: When delivered effectively, policy messages are associated with reduced student drug use at school. Abstinence messages and harsh penalties convey a coherent message to students. Strong harm-minimization messages are also associated with reduced drug use at school, but effects are weaker than those for abstinence messages. This smaller effect may be acceptable if, in the longer term, it leads to a reduction in harmful use and school dropout within the student population.

Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.
Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.
Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).
In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Assessing cost-effectiveness of drug interventions for schizophrenia

Objective: To assess from a health sector perspective the incremental cost-effectiveness of eight drug treatment scenarios for established schizophrenia.

Method: Using a standardized methodology, costs and outcomes are modelled over the lifetime of prevalent cases of schizophrenia in Australia in 2000. A two-stage approach to assessment of health benefit is used. The first stage involves a quantitative analysis based on disability-adjusted life years (DALYs) averted, using best available evidence. The robustness of results is tested using probabilistic uncertainty analysis. The second stage involves application of 'second filter' criteria (equity, strength of evidence, feasibility and acceptability) to allow broader concepts of benefit to be considered.

Results: Replacing oral typicals with risperidone or olanzapine has an incremental costeffectiveness ratio (ICER) of A$48 000 and A$92 000/DALY respectively. Switching from low-dose typicals to risperidone has an ICER of A$80 000. Giving risperidone to people experiencing side-effects on typicals is more cost-effective at A$20 000. Giving clozapine to people taking typicals, with the worst course of the disorder and either little or clear deterioration, is cost-effective at A$42 000 or A$23 000/DALY respectively. The least costeffective intervention is to replace risperidone with olanzapine at A$160 000/DALY.

Conclusions: Based on an A$50 000/DALY threshold, low-dose typical neuroleptics are indicated as the treatment of choice for established schizophrenia, with risperidone being reserved for those experiencing moderate to severe side-effects on typicals. The more expensive olanzapine should only be prescribed when risperidone is not clinically indicated. The high cost of risperidone and olanzapine relative to modest health gains underlie this conclusion. Earlier introduction of clozapine however, would be cost-effective. This work is limited by weaknesses in trials (lack of long-term efficacy data, quality of life and consumer satisfaction evidence) and the translation of effect size into a DALY change. Some stakeholders, including SANE Australia, argue the modest health gains reported in the literature do not adequately reflect perceptions by patients, clinicians and carers, of improved quality of life with these atypicals.

Thermodynamics of lipophilic drug binding to intestinal fatty acid binding protein and permeation across membranes

Intestinal fatty acid binding protein (I-FABP) is present at high levels in the absorptive cells of the intestine (enterocytes), where it plays a role in the intracellular solubilization of fatty acids (FA). However, I-FABP has also been shown to bind to a range of non-FA ligands, including some lipophilic drug molecules. Thus, in addition to its central role in FA trafficking, I-FABP potentially serves as an important intracellular carrier of lipophilic drugs. In this study we provide a detailed thermodynamic analysis of the binding and stability properties of I-FABP in complex with a series of fibrate and fenamate drugs to provide an insight into the forces driving drug binding to I-FABP. Drug binding and selectivity for I-FABP are driven by the interplay of protein−ligand interactions and solvent processes. The Gibbs free energies (ΔG°) determined from dissociation constants at 25 °C ranged from −6.2 to −10 kcal/mol. The reaction energetics indicate that drug binding to I-FABP is an enthalpy−entropy driven process. The relationship between I-FABP stability and drug binding affinity was examined by pulse proteolysis. There is a strong coupling between drug binding and I-FABP stability. The effect of an I-FABP protein sink on the kinetics and thermodynamics of tolfenamic acid permeation across an artificial phospholipid membrane were investigated. I-FABP significantly decreased the energy barrier for desorption of tolfenamic acid from the membrane into the acceptor compartment. Taken together, these data suggest that the formation of stable drug−I-FABP complexes is thermodynamically viable under conditions simulating the reactant concentrations likely observed in vivo and maybe a significant biochemical process that serves as a driving force for passive intestinal absorption of lipophilic drugs.

Common structural basis for central nervous system drug design

The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.

Effect of erectile dysfunction medications on coexsisting dysfunctions in couples : Partner's Preference Study

There is sparse information on how treatments for erectile dysfunction (ED) affects couples. This study investigated the effects of ED treatments on 100 heterosexual couples' sexual functioning and whether function achieved using a short-acting versus a long-acting ED medication differed significantly. Couples were randomized to use tadalafil or sildenafil for each of two 12-week study phases; they completed questionnaires (International Index of Sexual Function and Female Sexual Function Index) and kept sexual event diaries. All participants experienced significant improvements over baseline sexual functioning, while the men used short- or long-acting ED medications with no significant differences related to the duration of drug action recorded for either the men or women. Despite this lack of difference in efficacy there was a strong preference by women (79%) and their partners (16%) for the longer-acting medication. The reasons for this warrant further investigation. Understanding the effects on couples of the use of ED medications is a necessary aspect of ensuring ongoing sexual satisfaction in couples treated for ED.

Boron nitride nanotubes : a novel vector for targeted magnetic drug delivery

Whereas several biomedical applications of carbon nanotubes have been proposed, the use of boron nitride nanotubes (BNNTs) in this field has been largely unexplored despite their unique and potentially useful properties. Our group has recently initiated an experimental program aimed at the exploration of the interactions between BNNTs and living cells. In the present paper, we report on the magnetic properties of BNNTs containing Fe catalysts which confirm the feasibility for their use as nanovectors for targeted drug delivery. The magnetisation curves of BNNTs characterised by the present study are typical of superparamagnetic materials with important parameters, including magnetic permeability and magnetic momentum, derived by employing Langevin theory. In-vitro tests have demonstrated the feasibility for influencing the uptake of BNNTs by living cells by exposure to an external magnetic source. A finite element method analysis devised to predict this effect produced predictive data with close agreement with the experimental observations.

Rural adolescent alcohol, tobacco, and illicit drug use: a comparison of students in Victoria, Australia, and Washington State, United States

Purpose: There are inconsistent research findings regarding the impact of rurality on adolescent alcohol, tobacco, and illicit substance use. Therefore, the current study reports on the effect of rurality on alcohol, tobacco, and illicit
drug use among adolescents in 2 state representative samples in 2 countries, Washington State (WA) in the United States and Victoria (VIC) in Australia.
Participants: The International Youth Development Study (IYDS) recruited representative samples of students from Grade 7 (aged 12 to 13 years) and Grade 9 (aged 14 to 15) in both states. A total of 3,729 students responded to questions about alcohol, tobacco, cannabis, and other illicit substance use (n_VIC = 1,852; n_WA = 1,877). In each state, males and females were equally represented and ages ranged from 12 to 15 years.
Methods: Data were analyzed to compare lifetime and current (past 30 days) substance use for students located in census areas classified as urban, large or small town, and rural. Findings were adjusted for school clustering and
weighted to compare prevalence at median age 14 years.
Findings: Rates of lifetime and current alcohol, tobacco, and cannabis use were significantly higher in rural compared to urban students in both states (odds ratio for current substance use = 1.31).
Conclusions: In both Washington State and Victoria, early adolescent rural students use substances more frequently than their urban counterparts. Future studies should examine factors that place rural adolescents at risk for alcohol, tobacco, and illicit drug use.

The use of drug detection dogs in Sydney, Australia

Introduction and Aims. At present there is little research into the use of drug detection dogs. The present study sought to explore the use of detection dogs in Sydney, Australia, utilising multiple data sources.

Design and Methods. Data were taken from interviews with 100 regular ecstasy users and 20 key experts as part of the 2006 New South Wales arm of the Ecstasy and Related Drugs Reporting System, and secondary data sources.

Results. The majority of regular ecstasy users reported taking some form of precaution if made aware that dogs would be at an event they were attending. A small proportion of the sample reported consuming their drugs when coming into contact with detection dogs. One group of key experts viewed the use of detection dogs as useful; one group disliked the use of detection dogs though cooperated with law enforcement when dogs were used; and one group considered that detection dogs contribute to greater harm. Secondary data sources further suggested that the use of detection dogs do not significantly assist police in identifying and apprehending drug suppliers.

Discussion and Conclusions. The present study suggests that regular ecstasy users do not see detection dogs as an obstacle to their drug use. Future research is necessary to explore in greater depth the experiences that drug users have with detection dogs; the effect detection dogs may have on deterring drug consumption; whether encounters with detection dogs contribute to drug-related harm; and the cost–benefit analysis of this law enforcement exercise.