Impact of a Large-Scale Narcotics Treatment Program: A Six Month Experience

Economics is the study of choice among alternatives under conditions of scarcity. Drug policy is manifestly an “economic” problem in the sense that these policies are developed under conditions of scarcity: there are not enough police, treatment facilities, and social services to solve the drug problem, however it is defined. This paper argues that a harms reduction approach to drug policy can be characterized as pragmatic cost-effective drug control which attempts to achieve efficient drug policy. Economic aspects of drug enforcement are discussed which reveal that these policies do not necessarily reduce drug problems and can generate unintended consequences. Enforcement remains the dominant drug policy in the United States despite evidence that it is overused, in part because both federal and state asset forfeiture laws and budget processes offer police agencies incentives to focus on enforcement rather than other policy alternatives. An efficiency-based harms reduction approach may be one way to effectively advocate a rational approach to drug issues in the often strident and ideological drug policy debates. [Translations are provided in the International Abstracts Section of this issue.]     

Reducing the harms of drug policy: an economic perspective

Economics is the study of choice among alternatives under conditions of scarcity. Drug policy is manifestly an "economic" problem in the sense that these policies are developed under conditions of scarcity: there are not enough police, treatment facilities, and social services to solve the drug problem, however it is defined. This paper argues that a harms reduction approach to drug policy can be characterized as pragmatic cost-effective drug control which attempts to achieve efficient drug policy. Economic aspects of drug enforcement are discussed which reveal that these policies do not necessarily reduce drug problems and can generate unintended consequences. Enforcement remains the dominant drug policy in the United States despite evidence that it is overused, in part because both federal and state asset forfeiture laws and budget processes offer police agencies incentives to focus on enforcement rather than other policy alternatives. An efficiency-based harms reduction approach may be one way to effectively advocate a rational approach to drug issues in the often strident and ideological drug policy debates. [Translations are provided in the International Abstracts Section of this issue.]     

Non-invasive drug delivery to the human brain using endogenous blood-brain barrier transport systems

Brain drug development is limited by the blood-brain barrier (BBB), which restricts the passage into the brain of >95% of all drug candidates intended for the CNS. The growth of future CNS drug development can be accelerated by fostering parallel growth in both CNS drug discovery and CNS drug delivery. One approach to solving the BBB problem is to target endogenous BBB transport systems, and to develop CNS drug delivery strategies that take advantage of these natural portals of entry into the brain.     

Michaelis-Menten metabolite formation kinetics: equations relating area under the curve and metabolite recovery to the administered dose

A computational approach which concomitantly determines the capacity-limited rate constants of parent drug elimination and metabolite formation is presented. The approach applies both the presently derived total excretory recovery versus dose relationships of the metabolite and the AUC versus dose relationships of the parent drug to identify the parameters. Three parent drug elimination conditions were assessed: pooled first-order, pooled Michaelis-Menten, and parallel first-order and pooled Michaelis-Menten kinetics. Model and parameter identification criteria are discussed. Literature data for theophylline and two of its metabolites in rats were examined to reveal pooled Michaelis-Menten elimination kinetics of theophylline and capacity-limited formation of the metabolites. The proposed technique is useful for quantitating commonly obtained nonlinear drug disposition data such as AUC and amount of metabolites excreted.     

药物研究技术指导原则的体系设计及探讨

通过对指导原则体系构建的方式和内容的分析,为建立既符合我国国情又符合监管国际化发展趋势的技术指导原则体系提供了新思路.     

Current progress in identifying endogenous biomarker candidates for drug transporter phenotyping and their potential application to drug development

Drug transporters play important roles in the elimination of various compounds from the blood. Genetic variation and drug–drug interactions underlie the pharmacokinetic differences for the substrates of drug transporters. Some endogenous substrates of drug transporters have emerged as biomarkers to assess differences in drug transporter activity—not only in animals, but also in humans. Metabolomic analysis is a promising approach for identifying such endogenous substrates through their metabolites. The appropriateness of metabolites is supported by studies in vitro and in vivo, both in animals and through pharmacogenomic or drug–drug interaction studies in humans. This review summarizes current progress in identifying such endogenous biomarkers and applying them to drug transporter phenotyping.     

Unfinished business: target-based drug discovery

The switch in the mid-1980s/early 1990s from a phenotypic approach to a target-based approach to drug discovery has been followed by low productivity of new drugs entering the market. Reasons for the (necessary) switch and unsolved problems with both approaches to drug discovery are discussed. The S-curve theory of new technology development and introduction can act as guide as to when an upturn in productivity can be expected; this should occur during the next decade leading possibly to a new golden age of drug discovery.     

Resistant TB: Newer Drugs and Community Approach

Drug resistance in tuberculosis (TB) is a serious problem compromising both the treatment and control programs. Poor usage of the available anti TB drugs has led to progressive drug resistance-multi drug resistance (MDR), extensively drug-resistance (XDR) and even total drug resistance (TDR). While drug sensitive TB is completely curable, MDR-TB is difficult to treat, XDR and TDR are often fatal. Non availability of new drugs to treat drug resistant cases further complicates the problem. The Global Alliance for Tuberculosis Drug Developments, a non-profit organization with the World Health Organization (WHO) as a partner was formed in February 2000 for the development of new drugs. In the last decade this venture has resulted in several promising new antituberculosis drugs like TMC207 (diaryquinoline), PA-824 (nitroimidazo-oxazine), OPC-67683 (nitroimidazo-oxazole) and SQ 109 (diamine compound). Drug resistance in TB is a man made problem. Therefore, while global efforts towards new drug development must continue it is equally important to have a well defined community approach to prevent the emergence of drug resistance to the existing and newer drugs. The present review article discusses some recent drug patents for the treatment of tuberculosis and the appropriate community approach to prevent and treat drug resistant TB.     

Allosteric approaches to the targeting of G-protein-coupled receptors for novel drug discovery: a critical assessment

In recent years, the concept of allosteric modulation of G-protein-coupled receptors (GPCRs) has matured and now represents an increasingly viable approach to drug discovery. This is evident in the fact that allosteric modulators have been reported for every class of GPCR, and several are currently in clinical trials with one drug example approved and launched. The allosteric approach has been highlighted for the potential of identifying highly selective compounds with a minimal propensity to produce adverse effect. While much has been written regarding the promises of this approach, important challenges, caveats, and pitfalls exist that are often overlooked. Therefore, a balanced overview of the field that describes both the promises and the challenges of discovering allosteric modulators of GPCRs as novel drugs is presented.     

Target selection and pharma industry productivity: what can we learn from technology S-curve theory?

The number of new drug approvals per annum has been decreasing regularly over the past decade, and changes made 12 to 15 years ago to the research and development approach of the pharmaceutical industry may have contributed to this fall in productivity. In particular, the rapid switch at that time away from an 'observation-led' approach toward a 'hypothesis-led' approach to target selection may be a key contributing factor to this issue. The strengths and weaknesses of both approaches are analyzed herein, and it is suggested that unsolved weaknesses in both approaches are holding back the productivity of the pharmaceutical/biotechnology industry.     

Modeling of tumor growth and anticancer effects of combination therapy

Combination therapies are widely used in the treatment of patients with cancer. Selecting synergistic combination strategies is a great challenge during early drug development. Here, we present a pharmacokinetic/pharmacodynamic (PK/PD) model with a smooth nonlinear growth function to characterize and quantify anticancer effect of combination therapies using time-dependent data. To describe the pharmacological effect of combination therapy, an interaction term was introduced into a semi-mechanistic anticancer PK/PD model. This approach enables testing of a pharmacological hypothesis with respect to an anticipated pharmacological synergy of drug combinations, such as an assumed pharmacological synergy of complementary inhibition of a particular signaling pathway. The model was applied to three real data sets derived from preclinical screening experiments using xenograft mice. The suggested model fitted well the observed data from mono- to combination-therapy and allowed physiologically meaningful interpretation of the experiments. The tested drug combinations were assessed for their ability to act as synergistic modulators of tumor growth inhibition by the interaction parameter ψ. The presented approach has practical implications because it can be applied to standard xenograft experiments and may assist in the selection of both optimal drug combinations and administration schedules. The unique feature of the presented approach is the ability to characterize the nature of combined drug interaction as well as to quantify the intensity of such interactions by assessing the time course of combined drug effect.     

Modelling partitioning of sparingly soluble drugs in a two-phase liquid system

The aim of this work was to develop a proper mathematical model able to describe the kinetics partitioning of a drug between a polar (water buffer) and an apolar (n-octanol) liquid phase. In particular, attention is focussed on sparingly soluble drugs in one or both environments. Basically, we suppose that drug fluxes occurring between the polar and apolar phase depend also on drug solubility, and not only on both the kinetics constants and the instantaneous drug concentration in the two phases. The proposed model adequately describes the drug partitioning of sparingly water soluble drugs (piroxicam and nimesulide) as proven by the comparison of the predicted and experimental data. Moreover, it indicates the unsuitability of a previous approach (Chem. Pharm. Bull. 29 (1961) 2718) in describing the partitioning kinetics unless sink conditions in both phases are attained, this being difficult to achieve when working with sparingly soluble drugs. Consequently, the model represents a simple and reliable tool to study the drug partitioning kinetics.     

Microdialysis and drug delivery to the eye

The eye presents unique challenges in both the development of tools for elucidating drug disposition as well as for the development of modes of drug delivery for treatment of ocular diseases. In this paper, we present a discussion of the anatomical and physiological characteristics and limitations present in the eye for microdialysis sampling of endogenous substrates and xenobiotics. To date, over twenty papers describing microdialysis approaches for assessment of ocular drug delivery and endogenous substrate characterization have been published. Although the majority of papers describe sampling of vitreous humor, recent efforts have been directed towards ocular anterior segment sampling using microdialysis. With this approach, an appreciable reduction in animal use has been realized. In addition, simultaneous examination of administered drug and endogenous substrates modulated by the drug is possible with this approach, facilitating construction of ocular pharmacokinetic/pharmacodynamic relationships through use of relevant surrogate markers.     

Estimating the willingness to pay for drug abuse treatment: a pilot study

Previous economic studies of the benefits of drug treatment have limited their estimation to tangible benefits, and thus have underestimated the benefits of drug treatment. The willingness-to-pay (WTP) approach is a more encompassing benefit valuation method that captures both tangible and intangible benefits and accords with valuation concepts used by economists. In this study, we report the results of a pilot study in which we used the contingent valuation (CV) method to value drug treatment. We conducted mall intercept surveys in two communities: the Triad area in North Carolina and Brooklyn, New York. We estimated WTP models for two different drug treatment programs: a program for all drug users and a program specifically targeted to women drug users. We modeled respondents' WTP for drug treatment as a function of their demographics and to responses from attitudinal/experience questions. The mean WTP for both types of drug treatment programs was estimated to be approximately $37 per respondent. Finally, we demonstrated how the results of the CV method may be used in a benefit-cost analysis of drug treatment.     

Do the affective properties of smoking-related cues influence attentional and approach biases in cigarette smokers?

Research indicates that drug-related cues elicit attention and approach biases in drug users. However, attentional biases are not unique to addiction (e.g., they are also found for emotional information). This study examined whether attentional and approach biases in cigarette smokers are mediated by the motivational salience of cues (relevance to drug-taking), rather than by their affective properties (subjective liking of the cues). Cues included pleasant and unpleasant smoking-related pictures. Attentional biases, approach tendencies and subjective evaluation of the cues were assessed on visual probe, stimulus-response compatibility and rating tasks, respectively. Compared with non-smokers, smokers showed a greater attentional bias for both pleasant and unpleasant smoking-related cues presented for 2000 ms, but not for 200 ms. Smokers showed a greater approach bias for unpleasant cues, although the groups did not differ significantly in approach bias for pleasant smoking-related cues. Smokers rated both pleasant and unpleasant smoking pictures more positively than did non-smokers. Results suggest that a bias to maintain attention on smoking-related cues in young adult smokers is primarily a function of drug-relevance, rather than affective properties, of the cues. In contrast, approach tendencies and pleasantness judgements were influenced by drug use, drug-relevance and the affective properties of the cues.     

Calculating the Charcoal Blockade Efficiency for Bioequivalence Study of Inhaled Ipratropium Bromide Using A Model Method

Charcoal blockade is a useful approach to block gastrointestinal (GI) absorption of orally inhaled drug products (OIDPs) and therefore can be used effectively to determine drug absorption exclusively via the pulmonary route. Charcoal blockade efficiency (CBE) should be measured to show whether adequate blockade of GI exposure is achieved in bioequivalence (BE) study. The purpose of this study is to employ a model method to calculate the CBE for a pilot pharmacokinetic (PK) BE study of inhaled ipratropium bromide. This model method, based on a convolution integral, is built in-house using MATLAB package. The results demonstrated a full blockade of GI absorption of ipratropium bromide for both test and reference drug products. This study has shown that the model method may provide a useful approach for validation of charcoal blockade method used in PK BE study for OIDPs. The ability to use modeling may simplify human PK studies in general, and is particularly valuable when for ethical, technical or regulatory reasons administration of an orally swallowed form of the drug is not possible.     

Economic and developmental considerations for pharmacogenomic technology

The pharmaceutical industry's core business is the innovation, development and marketing of new drugs. Pharmacogenetic (PG) testing and technology has the potential to increase a drug's value in many ways. A critical issue for the industry is whether products in development should be teamed with genetic tests that could segment the total population into responders and non-responders. In this paper we use a cost-effectiveness framework to model the strategic decision-making considerations by pharmaceutical manufacturers as they relate to drug development and the new technology of PG (the science of using genetic markers to predict drug response). In a simple, static, one-period model we consider three drug development strategies: a drug is exclusively developed and marketed to patients with a particular genetic marker; no distinguishing among patients based on the expression of a genetic marker is made (traditional approach); and a strategy whereby a drug is marketed to patients both with and without the genetic marker but there is price discrimination between the two subpopulations. We developed three main principles: revenues under a strategy targeting only the responder subpopulation will never generate more revenue than that which could have been obtained under a traditional approach; total revenues under a targeted PG strategy will be less than that under a traditional approach but higher than a naive [corrected] view would believe them to be; and a traditional [corrected] approach will earn the same total revenues as a price discrimination strategy, assuming no intermarket arbitrage. While these principles relate to the singular (and quite narrow) consideration of drug revenues, they may nevertheless partially explain why PG is not being used as widely as was predicted several years ago when the technology first became available, especially in terms of pharmaceutical manufacturer-developed tests.     

Integrating systemic cue exposure with standard treatment in recovering drug dependent patients

Repeated drug administration readily produces classically conditioned responses in animal and human experimental studies. The majority of patients applying for treatment of drug dependence show both autonomic and subjective responses when exposed to drug-related stimuli. These responses are presumed to have been conditioned during a period of active drug use, persist after traditional treatment for drug dependence, and may constitute one of several factors which predispose to relapse. Preliminary data are presented from a novel treatment approach which is designed to test whether drug-conditioned responses can be reduced or extinguished by systematic exposure to drug-related cues and whether such extinction improves the overall results of treatment.