The Valley of Death in anticancer drug development: a reassessment

The past decade has seen an explosion in our understanding of cancer biology and with it many new potential disease targets. Nonetheless, our ability to translate these advances into therapies is poor, with a failure rate approaching 90%. Much discussion has been devoted to this so-called 'Valley of Death' in anticancer drug development, but the problem persists. Could we have overlooked some straightforward explanations to this highly complex problem? Important aspects of tumor physiology, drug pharmacokinetics, preclinical models, drug delivery, and clinical translation are not often emphasized, but could be crucial. This perspective summarizes current views on the problem and suggests feasible alternatives.     

Epidemiology Abuse: Epidemiologic and Psychosocial Perspectives on Heroin Maintenance

Two perspectives on drug abuse have evolved. Epidemiologic approaches treat drug abuse as if it were an infectious disease and deal with it within the framework of host, agent, and environment. Epidemiologists, approaching drug abuse from a public health standpoint, tend to think in terms of supply reduction. Psychosocial approaches focus on the demand aspect of drug abuse. Interest centers on psychological/sociological explanations of drug-taking behavior, such as psychopathology and alienation, and on unintended consequences of supply-reduction strategies.

The author proposes that the two models complement each other and need to be integrated. A policy of strict supply reduction for nonaddicts coupled with heroin maintenance for addicts is suggested. Such a policy combines epidemiologic emphasis on supply reduction with psychosocial stress on the     

Variations in drug users' accounts of the connection between drug misuse and crime

A great deal of progress has been made in identifying explanations for the links between drug use and crime. However, less progress has been made in the application of these explanations. In particular, less is known about whether some explanations are more common than others, whether some are linked to certain conditions, whether some apply only to certain individuals, and whether some apply only to certain kinds of drug use and crime. In this article, we investigate the extent to which explanations for the connection between drug misuse and crime vary by type of drug user, type of drug use and type of crime by looking at users' own accounts of the connection. The research is based on data collected as part of the New English and Welsh Arrestee Drug Abuse Monitoring (NEW-ADAM) program conducted in 16 custody suites in England and Wales. The analysis investigates the proportion of drug users who believe that there is a connection and looks at variations in accounts of the connection by individual and behavioral factors. The implications for government policy designed to reduce drug-related crime are discussed.     

Rapid identification of P-glycoprotein substrates and inhibitors.

Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on time-consuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed their affinity as inhibitors in vitro. Seven molecules (acitretin, cholecalciferol, misoprostol, nafcillin, repaglinide, salmeterol, and telmisartan) with no published details for P-gp affinity, one positive control inhibitor (miconazole), and two negative control molecules (phenelzine and zonisamide) were selected for testing. The MDCK-MDR1 in vitro cell model was used to confirm their inhibitory effect on [3H]digoxin transport, and the ATPase assay was used as an additional in vitro tool to indicate P-gp activation. All seven test drugs were confirmed to have P-gp affinity. Additionally, our experimental results provided plausible explanations for the published pharmacokinetic profiles of the tested drugs and their classification according to the biopharmaceutics and drug disposition classification system. In this study, we showed the successful application of pharmacophore models to accurately predict P-gp binding, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P-gp inhibitors or substrates.     

Pharmacokinetic models for the saturable distribution of paclitaxel.

Paclitaxel pharmacokinetics are nonlinear with saturable metabolism and saturable distribution to the tissues. The saturable distribution has in previous pharmacokinetic modeling been described as a saturable transport process, whereas the present study was undertaken to investigate alternative explanations. Using a sparse sampling scheme (on average 3.3 samples per profile), 101 plasma concentration-time profiles in 22 female patients with metastatic cancer of the breast or ovary were monitored. It was found that the observed data could be equally well described by saturable tissue binding as well as by capacity-limited tissue transport. The data were better described by a model where equilibrium was achieved with drug in the central rather than in the peripheral compartment. Models where the binding was assumed to be an instantaneous or a noninstantaneous process were tried, but the data did not allow resolution between these two possibilities. The value at which the saturable transport was half-maximal was 0.55 microM. The K(d) values of the binding models were 0.06 to 0.12 microM. These are close to the values reported as a threshold for drug toxicity of paclitaxel, suggesting a possible connection between the binding sites involved in the pharmacokinetics and the mechanism responsible for the toxicity. For all models, a saturable elimination of paclitaxel was included using the Michaelis-Menten model. K(m) for the elimination ranged in the different models from 2.5 to 5.6 microM.     

Transient response to amoxapine in depressed patients

Amoxapine is an antidepressant drug with a fast onset of action. We report two cases of transient response to amoxapine and discuss possible explanations.     

The psychobiology of comfort eating: implications for neuropharmacological interventions

Comfort eating, that is eating induced by negative affect, has been a core theme of explanations for overeating and obesity. Psychobiological explanations and processes underlying comfort eating are examined, as well as its prevalence in clinical and nonclinical populations, to consider who may be susceptible, whether certain foods are comforting, and what the implications for treatment may be. Comfort eating may occur in a substantial minority, particularly in women and the obese. Human and animal theories and models of emotional or stress-induced eating show some convergence, and may incorporate genetic predispositions such as impulsivity and reward sensitivity, associated with dopamine dysregulation underlying incentive salience. Comfort eaters show vulnerability to depression, emotional dysregulation and a need to escape negative affect and rumination. During negative affect, they preferentially consume sweet, fatty, energy-dense food, which may confer protection against stress, evidenced by suppression of the hypothalamic-pituitary-adrenal axis response, although activation of the hypothalamic-pituitary-adrenal axis may itself drive appetite for these palatable foods, and the risk of weight gain is increased. Benefits to mood may be transient, but perhaps sufficient to encourage repeated attempts to prolong mood improvement or distract from negative rumination. Cognitive behavioural treatments may be useful, but reliable drug therapy awaits further pharmacogenomic developments.     

Differential effects of MDMA, cocaine, and cannabis use severity on distinctive components of the executive functions in polysubstance users: a multiple regression analysis

Executive functioning impairments have been demonstrated following consumption of drugs of abuse. These executive impairments could play an important role on the development of the addictive process and rehabilitation of substance abusers. Recent neuropsychological models of executive functioning assume a multicomponent organization of these processes, suggesting different functions could contribute differentially to performance on executive tasks. The aim of this study was to analyze the relationship between severity of consumption of different drugs and neuropsychological performance on tasks sensitive to impairment in the executive subprocesses of working memory, response inhibition, cognitive flexibility, and abstract reasoning. Instruments sensitive to impairment in these four components were administered to 38 polysubstance abusers along with a severity of drug consumption interview. Multiple regression analyses were used. Results showed a differential impact of severity of MDMA abuse on working memory and abstract reasoning indices, of cocaine severity on an inhibitory control index and of cannabis on a cognitive flexibility index. Metabolic reorganization of monoamine frontal-subcortical pathways after drug exposure are proposed as possible explanations for these impairments.     

Drug treatment outcomes in the criminal justice system: What non-self-report measures of outcome can tell us

Coerced drug treatment has become a common route for drug users to enter drug treatment in the UK and has been shown to be effective in reducing drug use and offending. This article presents the non-self-report measures of offending and drug use for one such treatment. The results support the findings of other studies in that those with lower offending rates prior to starting treatment and lower drug use during treatment show reduced offending following treatment commencement. More serious drug-using offenders showed limited changes in their offending following drug treatment. Possible explanations for this are discussed.     

Substance Use and Delinquency During Adolescence: A Prospective Look at an At-Risk Sample

This paper focuses on the relationship between adolescent substance use and delinquent behavior in a sample of homeless young people. Confirmatory factor analyses indicated that delinquency and substance use are best described as discrete factors, and competing theoretical models of the longitudinal association between these two factors were examined using structural equations modeling techniques. The results suggest that delinquent behavior is associated with changes in alcohol, marijuana, and drug use across time. This effect was statistically significant over relatively brief lags in time of six months or less. Combined with previous results, these findings challenge the utility of single-factor explanations of adolescent deviance for at-risk populations and suggest that the relationship between substance use and externalizing across time may be more dynamic than previously thought. Implications for intervention are also discussed.     

Substance use and delinquency during adolescence: a prospective look at an at-risk sample

This paper focuses on the relationship between adolescent substance use and delinquent behavior in a sample of homeless young people. Confirmatory factor analyses indicated that delinquency and substance use are best described as discrete factors, and competing theoretical models of the longitudinal association between these two factors were examined using structural equations modeling techniques. The results suggest that delinquent behavior is associated with changes in alcohol, marijuana, and drug use across time. This effect was statistically significant over relatively brief lags in time of six months or less. Combined with previous results, these findings challenge the utility of single-factor explanations of adolescent deviance for at-risk populations and suggest that the relationship between substance use and externalizing across time may be more dynamic than previously thought. Implications for intervention are also discussed.     

Beyond 'peer pressure': rethinking drug use and 'youth culture'

The study of drug use by young people in the West has been transformed over the last decade by the development of sociological approaches to drug use which take serious account of the cultural context in which young people encounter drugs. One consequence is that the notion of 'peer pressure', as the primary articulation of the engagement between youth culture and drug use, has been displaced by that of 'normalisation', which envisages 'recreational' drug use as one expression of consumer-based youth cultural lifestyles. In stark contrast, academic discussion of drug use in Russia remains primarily concerned with the prevalence and health consequences of (intravenous) drug use while explanations of rising rates of drug use focus on structural factors related to the expansion of drugs supply and, to a lesser extent, post-Soviet social and economic dislocation. In this article, original empirical research in Russia is used to develop an understanding of young people's drug use that synthesises structural and cultural explanations of it. It does this by situating young people's narratives of their drugs choices in the context of local drugs markets and broader socio-economic processes. However, it attempts to go beyond seeing structural location as simply a 'constraint' on individual choice by adopting an understanding of 'youth culture' as a range of youth cultural practices and formations that simultaneously embody, reproduce and negotiate the structural locations of their subjects.     

Ockham's Razor Applied on Pharmaceutical Powder Compaction Models

This investigation contains a critical survey of a collection of five well-known and often used standard models in pharmaceutical technology. The basic idea is to use the recognised Ockham's razor as a tool in search for simpler methods or explanations for these models. The study includes the indirect tensile strength of tablets, Pitt's equation for tensile strength of biconvex tablets, Adams' model for strength of agglomerates, Weibull's distribution for variability of strength measurements and Heckel's equation for compressibility. In all these cases simpler and equally valid solutions and explanations are presented and subsequently preferred rather than the original.     

Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents

The exposure-response relationship of anti-infective agents at the site of infection is currently being re-examined. Epithelial lining fluid (ELF) has been suggested as the site (compartment) of antimicrobial activity against lung infections caused by extracellular pathogens. There have been an extensive number of studies conducted during the past 20 years to determine drug penetration into ELF and to compare plasma and ELF concentrations of anti-infective agents. The majority of these studies estimated ELF drug concentrations by the method of urea dilution and involved either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Antibacterial agents such as macrolides, ketolides, newer fluoroquinolones and oxazolidinones have ELF to plasma concentration ratios of >1. In comparison, β-lactams, aminoglycosides and glycopeptides have ELF to plasma concentration ratios of ≤1. Potential explanations (e.g. drug transporters, overestimation of the ELF volume, lysis of cells) for why these differences in ELF penetration occur among antibacterial classes need further investigation. The relationship between ELF concentrations and clinical outcomes has been under-studied. In vitro pharmacodynamic models, using simulated ELF and plasma concentrations, have been used to examine the eradication rates of resistant and susceptible pathogens and to explain why selected anti-infective agents (e.g. those with ELF to plasma concentration ratios of >1) are less likely to be associated with clinical treatment failures. Population pharmacokinetic modelling and Monte Carlo simulations have recently been used and permit ELF and plasma concentrations to be evaluated with regard to achievement of target attainment rates. These mathematical modelling techniques have also allowed further examination of drug doses and differences in the time courses of ELF and plasma concentrations as potential explanations for clinical and microbiological effects seen in clinical trials. Further studies are warranted in patients with lower respiratory tract infections to confirm and explore the relationships between ELF concentrations, clinical and microbiological outcomes, and pharmacodynamic parameters.     

Police drug crackdowns and hospitalisation rates for illicit-injection-related infections in New York City

Using longitudinal data, this analysis tests the hypothesis that eight police drug crackdowns implemented in 27 New York City police precincts between 1995 and 1999 were associated with subsequent increases in monthly precinct-specific hospitalisation rates for illicit-injection-related abscesses, cellulitis, and endocarditis. Crackdowns are sustained police initiatives designed to reduce the possession and sale of illicit drugs through heightened surveillance and arrests of drug users and street-level dealers. We linked hospitalisation data (48,986 illicit-injection-related abscess or cellulitis cases and 5452 illicit-injection-related endocarditis cases) and arrest and United States Census data to police precincts to calculate hospitalisation and arrest rates. Analyses indicate that drug-related arrest rates climbed 39% in the crackdowns’ first year compared with the previous year. Contrary to our hypothesis, we found evidence of a stasis or decline in hospitalisation rates in the crackdowns’ first year, based on multivariate Poisson regression models that included sensitivity analyses that accounted for the increased incarceration of injectors after each crackdown's onset. We discuss several possible explanations for these findings and conclude that future research is warranted regarding the relationship between police strategies and drug users’ health that incorporates inmate health data and both individual-level and precinct-level data.     

Disentangling the sources of opioid withdrawal responses: comment on McDonald and Siegel (2004)

R. V. McDonald and S. Siegel (see record 2004-10475-001) present new evidence for the idea that opioid drug-opposite responses can become conditioned to cues of initial drug onset and that they could, therefore, play a role in the development of tolerance of some drug effects and a role in the elicitation of withdrawal-like symptoms in cases in which addicted individuals are exposed to small doses of the drug they normally consume. In this comment, some puzzling features of the data are discussed, and alternative explanations are suggested.     

Comparison of drug treatment histories of single and multiple drug abusers in detox

This study was undertaken to determine differences in previous treatment patterns in individuals currently using different numbers of substances. Medical records of 1198 inpatient detoxification (detox) admissions were analyzed. Numbers of past admissions to completed detox, methadone, or other types of drug abuse treatment were totaled and ranked to determine most frequent type. Within gender, treatment histories of single and multiple drug abusers usually do not differ. The one exception is male multiple drug abusers ages 26-30, who show increased admissions. Possible explanations are that men do not seek treatment before developing medical complications of addiction or until external factors influence admission. There were differences in treatment histories between genders in multiple drug abusers only. Before age 30, women reported increased treatment of certain types. Possible explanations are that treatment priority is given to women who are, or may be, pregnant. Also, younger men may not enter or complete treatment. Previous treatment history may influence many behaviors. The results of this study delineate several valuable indicators for assessing past history.     

Integrating Mainstream and Subcultural Explanations of Drug Use Among Puerto Rican Youth

The broad question of how to integrate mainstream and subcultural explanations of drug use and other problem behaviors is addressed. An integrated social control model was examined with inner-city Puerto Rican youth. The model did apply to drug use and delinquency. Adherence to traditional Hispanic culture provides some protection against dysfunctional behavior.     

Nanodiamonds as vehicles for systemic and localized drug delivery

Owing to their exceptional biocompatibility and unique surface properties, nanodiamonds (NDs) are shown to be a progressively promising nanomaterial for drug delivery. In this article, NDs as a platform for a host of biomedical applications are described, with an emphasis on cancer therapy, ranging from systemic modalities to primary constituents within polymer hybrid microfilms. Experimental results and theoretical explanations of ND–drug dynamics are compared. Water-dispersion of previously insoluble therapeutics when complexed with NDs demonstrates great promise in expanding current drug delivery options. Various forms of incorporating NDs within microfilms as a localized drug release coating and implant are also discussed.