Are normal healthy research volunteers psychologically healthy? A pilot investigation

Most new drug development in Phase I clinical trials relies on the use of "normal healthy research volunteers" (NHRVs); however, little is known about the personality functioning of these volunteers. Determining whether NHRVs are similar to or different from individuals with "normal" personalities can impact participant recruitment, group assignment, and statistical interpretation of study results. This pilot study was undertaken to gain insight into the demographics, personality functioning, and potential psychopathology of the volunteers who participated in a Phase I confinement clinical drug trial. NHRVs (N=28) in an all-male, Phase I clinical trial completed a battery of questions, including the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and a sociodemographic questionnaire. Fifty percent of the sample showed clinically significant elevations on at least one of the scales. Current findings need to be replicated and expanded through future research. Results must be interpreted with caution because of the small, all-male sample. This preliminary study suggests that there is a difference in personality functioning between NHRVs and the general population. In addition, NHRVs may purposefully distort or conceal self-report information when participating in studies.     

Are drugs really toxic for older people?

Many diseases are now treatable with modern drugs. Elderly people, because they suffer from age-related illnesses, stand to gain the most, but they are also at risk from adverse drug reactions (ADRs). There are complex reasons for the increased frequency of ADRs, including poor prescribing, polypharmacy, altered drug handling and response, and poor compliance. Difficulties with interpretation of apparent ADR data include uncertainties about exposure and various confounding factors, for example, confounding by indication. Some simple prescribing guidelines can significantly help to minimise the extent of the clinical problem. These include:     

Are drugs really toxic for older people?

Many diseases are now treatable with modern drugs. Elderly people, because they suffer from age-related illnesses, stand to gain the most, but they are also at risk from adverse drug reactions (ADRs). There are complex reasons for the increased frequency of ADRs, including poor prescribing, polypharmacy, altered drug handling and response, and poor compliance. Difficulties with interpretation of apparent ADR data include uncertainties about exposure and various confounding factors, for example, confounding by indication. Some simple prescribing guidelines can significantly help to minimise the extent of the clinical problem. These include:     

Are occupational exposure limits becoming more alike within the European Union?

The occupational exposure limits (OELs) established by seven different national regulatory agencies of EU member states are compared with those of the European Commission (EC). The comparison concerned: (1) what chemicals have been selected, (2) the average level of exposure limits for all chemicals, and (3) the similarity between the OELs of different EU member states and the OELs recommended by the European Commission. The average level of the exposure limits has declined during the past 10 years in four of the five countries in our study for which historical data were available to us. Poland has not changed its level noticeably and Germany has increased it. Since the first list of indicative OELs was established by the EC, a few of the EU exposure limits have been lowered. The similarity index indicates that the exposure limits of EU member states are converging towards the European Commission's recommended OELs. Still, the average level of OELs differs between organizations--the Estonian OELs are on average 35% higher than the Polish OELs.     

Eradicating hepatitis C: Are novel screening strategies for people who inject drugs cost-effective?

Background: In developed countries, people who inject drugs (PWID) have a high prevalence of hepatitis C virus (HCV), yet they are often under-diagnosed. The World Health Organization has set 2030 as a target year for HCV elimination. To meet this target, improving screening in convenient community settings in order to reach infected undiagnosed individuals is a priority. This study assesses the cost-effectiveness of alternative novel strategies for diagnosing HCV infection in PWID. Methods: A cost-effectiveness analysis was undertaken to compare HCV screening at needle exchange centres, substance misuse services and at community pharmacies, with the standard practice of detection during general practitioners’ consultations. A decision tree model was developed to assess the incremental cost per positive diagnosis, and a Markov model explored the net monetary benefit (NMB) and the cost per Quality Adjusted Life Years (QALYs) gained over a lifetime horizon. Results: Needle exchange services provided a 7.45-fold increase in detecting positive individuals and an incremental cost of £12,336 per QALY gained against current practice (NMB £163,827), making this the most cost-effective strategy over a lifetime horizon. Screening at substance misuse services and pharmacies was cost-effective only at a £30,000/QALY threshold. With a 24% discount to HCV treatment list prices, all three screening strategies become cost-effective at £20,000/QALY. Conclusions: Targeting PWID populations with screening at needle exchange services is a highly cost-effective strategy for reaching undiagnosed HCV patients. When applying realistic discounts to list prices of drug treatments, all three strategies were highly cost-effective from a UK NHS perspective. All of these strategies have the potential to make a cost-effective contribution to the eradication of HCV by 2030.     

GPCR expression in tissues and cells: Are the optimal receptors being used as drug targets?

G-protein-coupled receptors [GPCRs, also known as 7-transmembrane (7-TM) receptors] comprise the largest family of membrane receptors in humans and other species and, in addition, represent the greatest number of current drug targets. In this article, we review methods to define GPCR expression and data indicating that individual cells express >100 different GPCRs. Results from studies that have quantified expression of these receptors lead us to conclude that the optimal GPCRs may not be currently used as therapeutic targets. We propose that studies of GPCR expression in individual cells will likely reveal new insights regarding cellular physiology and therapeutic approaches. Findings that define and characterize the most highly expressed GPCRs thus have important potential in terms of identifying new drug targets and novel therapies directed at a wide range of clinical disorders.     

Are Societal Judgments Being Incorporated into the Uncertainty Factors Used in Toxicological Risk Assessment?

The aim of this paper is to show that the uncertainty factors used in toxic risk assessment to develop exposure standards do contain societal judgments as well as technical judgments. The process generally used today originated in the 1950s, when a deterministic approach to risk was the norm. Technical judgments are required concerning the nature and the quality of the evidence used in the risk assessment. Judgments taken are essentially cautious. This caution may not matter when measured exposure is significantly below the standard and may be accepted when exposure occurs only following an approval process based on "gate keeping." More sophisticated judgments are required when actual exposure may exceed this type of standard or when risk needs to be compared with benefit. These circumstances can occur with patient exposure to human medicines and with occupational exposure to chemicals. Under these circumstances more explicitly considered societal judgments concerning what constitute "broadly acceptable" and "tolerable" risk criteria, and hence what are appropriate uncertainty factors, are required. The outcomes of those societal judgments are likely to vary according to the circumstances surrounding the exposure and have led to smaller uncertainty factors being considered appropriate for occupational exposure, when compared with widespread public exposure.     

Nutritional status and well being. Is there a relationship between body mass index and the well-being of older people?

Poor nutritional status may impair well being indirectly as a consequence of increased morbidity and decline in functional status. The aim of this study was to examine the independent effect of body mass index on the well being of older people. Thirty one hospital-based patients over 65 years of age were studied. Well being was assessed using the Philadelphia Geriatric Center Morale Scale (PGCMS)--anglicised version. Body mass index and well being were assessed on admission to hospital and at three months. At follow-up, a significant correlation was observed between body mass index and PGCMS values. Further analysis showed that this relationship was linear, with poor nutritional status being associated with low levels of well being and good nutritional status being associated with the highest levels of well being. High or low body mass index was able to predict the PGCMS score with a poor sensitivity of 44% and specificity of 96%. When the contribution of potential confounding variables was analysed, body mass was found to have no significant independent effect on well being. Instead, the presence of depression was the most powerful predictor of levels of well being. In conclusion, this study has demonstrated that nutritional status, as indicated by body mass index, has no detectable independent effect on well being. However, measurement of nutritional status may still have a role in the assessment of well being, in that, while the finding of a low body mass index cannot be taken as indicative of low levels of well being, the finding of a high body mass index is likely to indicate adequate well being. Further studies, however, are required in this area that would involve larger numbers of subjects and alternative measures of nutritional status and well being.     

Ginkgo biloba: a smart drug? A systematic review of controlled trials of the cognitive effects of ginkgo biloba extracts in healthy people

Extracts of Ginkgo biloba are widely used to alleviate or delay the progress of age-related cognitive impairment. Its use as a "smart" drug by healthy individuals has also been commercially promoted. The aim of this study was to systematically review and critically evaluate the trial data to test whether Ginkgo biloba enhances cognitive function in healthy subjects. Literatures searches of 6 computerised databases were made for placebo-controlled, double-blind trials of the effect of standardized Ginkgo biloba extracts on cognitive function in healthy subjects. Trials published in any language were included and data were extracted independently by the authors following a standardized protocol. Nine trials were identified, and these were mainly short term. The longest had a treatment period of 30 days. Trials were mostly of good intrinsic methodological quality, but certain aspects of methodology were inadequately reported by all trials. Taken together, these studies indicate no marked or consistent positive effects of Ginkgo biloba on any particular objective measure of cognitive function. A positive subjective effect was reported only in the longest trial. It is concluded that a positive effect of Ginkgo biloba on cognitive function is not proven by data from rigorous clinical trials. The use of Ginkgo biloba as a "smart" drug cannot be recommended on the basis of the evidence available to date, and there is a particular need for further long-term trials with healthy subjects.     

Are primary health care centres that target injecting drug users attracting and serving the clients they are designed for? A case study from Sydney,Australia

BackgroundLow-threshold primary healthcare (PHC) centres targeting injecting drug users (IDUs) are increasingly being created to offer preventative and opportunistic services. However, no data are available on the characteristics of clients who utilise such services, or the effectiveness of these services in facilitating prevention or treatment.MethodA retrospective clinical record audit examined the characteristics, service utilisation patterns and referral uptake of 384 clients presenting to a low-threshold PHC service in Sydney, Australia.ResultsOf the 384 clients, 85% were IDUs. Sixty-two percent reported also having access to a general medical practitioner (GP), with this group more likely to report taking benzodiazepines or other psychoactive medication. Despite this relatively high level of GP access, only 50% were fully vaccinated against hepatitis B virus (HBV). Testing for blood-borne viral and sexually transmitted infections were the most common reasons for presentation to the PHC. Most (82%) clients made at least one return visit, with an average of 3.5 presentations per client. All clients were offered HBV vaccination where indicated (n = 145); and more than half (55%) of referrals to external services were attended. Clients accessing this PHC were younger, more likely to be male and born outside Australia than IDUs attending needle syringe programs (NSPs) in Australia's most populous state, New South Wales.ConclusionResults suggest that this low-threshold PHC service was underutilised and its role as a low-threshold healthcare outlet remains limited. Further research is needed to more clearly delineate the health and economic benefits of this model.     

Are they being used safely? A retrospective cross‐sectional tertiary health care survey of selective serotonin reuptake inhibitors prescribing practice in Singapore

OBJECTIVES: To determine the prescribing pattern of the SSRIs and to evaluate the safety of current utilization of SSRIs associated with concomitant psychotropic medications in Singapore. METHODS: The average prescribed daily dose (PDD) for each SSRI was calculated and compared with the defined daily dose (DDD). Pearson's chi2 test, one-way analysis of covariance (ANCOVA) and multinomial logistic regression were performed to examine the impacts of variables such as age, gender, patient type and concomitant psychotropic medications on the utilization of SSRIs. Safety issues were discussed by examining the potential metabolic drug interactions between the SSRIs and concomitant psychotropic medications. RESULTS: The most frequently prescribed SSRI was fluoxetine and the PDDs were slightly more than the DDDs for all these SSRIs except fluvoxamine. The SSRIs were mainly prescribed to the patients who were younger, female and outpatients. Psychotropics were more likely concomitantly used with fluvoxamine, sertraline and paroxetine, relative to fluoxetine. CONCLUSION: The prescribing pattern of SSRIs in a tertiary health center in Singapore is generally consistent with the accepted practices, although some safety concerns in terms of metabolic drug interactions were raised. This study provides useful baseline information for further in-depth studies for SSRIs usage both locally and for international comparison.     

Circumstances of initiation into new-type drug use among adults in Shanghai: Are there differences by types of first new-type drug used?

Background

This study investigated circumstances of initiating new-type drug use among adult new-type drug users and differences among those who first used methamphetamine, ecstasy and ketamine.

Methods

A total of 276 participants were recruited, using respondent-driven sampling (RDS) from nine seeds recruited through NGOs, social workers and outreach workers in Shanghai, China.

Results

Methamphetamine was the most frequently reported first new-type drug used (37.1%), followed by ecstasy (35.6%) and ketamine (20.0%). 38.7% of participants initiated new-type drug use before the age of 21 years. 47.8% knew at initiation that club drugs can be harmful. Most were introduced to new-type drug use by friends, spouses or boy/girlfriends. The three most common reasons for initiation were curiosity, peer influence, and wishing to dull one's emotions. Those first using methamphetamine were more likely to be female, have a monthly individual income less than 3000 Yuan (approx. $476), initiate use at 21 years or older and at private setting than those first using ecstasy and ketamine.

Conclusions

There is an urgent need for drug education efforts in China to raise awareness of the harms of new-type drugs, as well as to increase knowledge about the paradox of new-type drug effects. Drug prevention and intervention programs should be tailore to target populations and their social context.     

Are major reductions in new HIV infections possible with people who inject drugs? The case for low dead-space syringes in highly affected countries

Circumstantial evidence from laboratory studies, mathematical models, ecological studies and bio behavioural surveys, suggests that injection-related HIV epidemics may be averted or reversed if people who inject drugs (PWID) switch from using high dead-space to using low dead-space syringes. In laboratory experiments that simulated the injection process and rinsing with water, low dead space syringes retained 1000 times less blood than high dead space syringes. In mathematical models, switching PWID from high dead space to low dead space syringes prevents or reverses injection-related HIV epidemics. No one knows if such an intervention is feasible or what effect it would have on HIV transmission among PWID. Feasibility studies and randomized controlled trials (RCTs) will be needed to answer these questions definitively, but these studies will be very expensive and take years to complete. Rather than waiting for them to be completed, we argue for an approach similar to that used with needle and syringe programs (NSP), which were promoted and implemented before being tested more rigorously. Before implementation, rapid assessments that involve PWID will need to be conducted to ensure buy-in from PWID and other local stakeholders. This commentary summarizes the existing evidence regarding the protective effects of low dead space syringes and estimates potential impacts on HIV transmission; it describes potential barriers to transitioning PWID from high dead space to low dead space needles and syringes; and it presents strategies for overcoming these barriers.     

Are we becoming more alike? Comparison of substance use in Australia and the United States as seen in the 1995, 1998, 2001 and 2004 national household surveys

Introduction . This paper reports the results of the 1995, 1998, 2001 and 2004 Australian and US household surveys, with emphasis on changes since 2001. Design and Methods . The US survey data were recalculated to match age groups in the Australian data. Statistically significant changes are reported. Differences in prevalence of use by gender within age group were tested for significance. Results . The past‐year use of ‘any illicit drug’, cannabis, cocaine, tranquillisers and injecting drugs decreased between 2001 and 2004 in Australia, but remained stable for all these drugs except ecstasy between 2002 and 2004 in the United States. The use of hallucinogens decreased in both countries. Alcohol and use of many illicit drugs by teenage girls in both countries increased to rates similar to or higher than boys, and teens in both countries reported binge and heavy drinking in the past month. Australians in their 20s had the highest rates of use, but in the United States, past‐year use of many drugs was highest among teenagers. Discussion . More treatment services are needed, particularly for people dependent upon non‐opiate drugs. The changes in acceptability of use of different drugs and their perceived availability are related to changes in prevalence rates. Even with the similarities in levels of use, there are differences in patterns of use and preferences for certain drugs in each country, and geographic proximity to drug sources is a factor.     

Are there differences in the catalytic activity per unit enzyme of recombinantly expressed and human liver microsomal cytochrome P450 2C9? A systematic investigation into inter‐system extrapolation factors

The ‘relative activity factor’ (RAF) compares the activity per unit of microsomal protein in recombinantly expressed cytochrome P450 enzymes (rhCYP) and human liver without separating the potential sources of variation (i.e. abundance of enzyme per mg of protein or variation of activity per unit enzyme). The dimensionless ‘inter‐system extrapolation factor’ (ISEF) dissects differences in activity from those in CYP abundance. Detailed protocols for the determination of this scalar, which is used in population in vitro–in vivo extrapolation (IVIVE), are currently lacking. The present study determined an ISEF for CYP2C9 and, for the first time, systematically evaluated the effects of probe substrate, cytochrome b5 and methods for assessing the intrinsic clearance (CL_int). Values of ISEF for S‐warfarin, tolbutamide and diclofenac were 0.75 ± 0.18, 0.57 ± 0.07 and 0.37 ± 0.07, respectively, using CL_int values derived from the kinetic values V_max and K_m of metabolite formation in rhCYP2C9 + reductase + b5 BD Supersomes?. The ISEF values obtained using rhCYP2C9 + reductase BD Supersomes? were more variable, with values of 7.16 ± 1.25, 0.89 ± 0.52 and 0.50 ± 0.05 for S‐warfarin, tolbutamide and diclofenac, respectively. Although the ISEF values obtained from rhCYP2C9 + reductase + b5 for the three probe substrates were statistically different (p < 0.001), the use of the mean value of 0.54 resulted in predicted oral clearance values for all three substrates within 1.4 fold of the observed literature values. For consistency in the relative activity across substrates, use of a b5 expressing recombinant system, with the intrinsic clearance calculated from full kinetic data is recommended for generation of the CYP2C9 ISEF. Furthermore, as ISEFs have been found to be sensitive to differences in accessory proteins, rhCYP system specific ISEFs are recommended. Copyright © 2011 John Wiley & Sons, Ltd.