Decision-theoretic designs for phase II clinical trials allowing for competing studies

This article describes an approach to optimal design of phase II clinical trials using Bayesian decision theory. The method proposed extends that suggested by Stallard (1998, Biometrics54, 279–294) in which designs were obtained to maximize a gain function including the cost of drug development and the benefit from a successful therapy. Here, the approach is extended by the consideration of other potential therapies, the development of which is competing for the same limited resources. The resulting optimal designs are shown to have frequentist properties much more similar to those traditionally used in phase II trials.

Incorporating data received after a sequential trial has stopped into the final analysis: implementation and comparison of methods

In a sequential clinical trial, accrual of data on patients often continues after the stopping criterion for the study has been met. This is termed “overrunning.” Overrunning occurs mainly when the primary response from each patient is measured after some extended observation period. The objective of this article is to compare two methods of allowing for overrunning. In particular, simulation studies are reported that assess the two procedures in terms of how well they maintain the intended type I error rate. The effect on power resulting from the incorporation of “overrunning data” using the two procedures is evaluated.

Variance estimation for systematic sampling from deliberately ordered populations

The systematic sampling (SYS) design (Madow and Madow, 1944) is widely used by statistical offices due to its simplicity and efficiency (e.g., Iachan, 1982). But it suffers from a serious defect, namely, that it is impossible to unbiasedly estimate the sampling variance (Iachan, 1982) and usual variance estimators (Yates and Grundy, 1953) are inadequate and can overestimate the variance significantly (Särndal et al., 1992). We propose a novel variance estimator which is less biased and that can be implemented with any given population order. We will justify this estimator theoretically and with a Monte Carlo simulation study.

Implementation of a Bayesian design in a dose-escalation study of an experimental agent in healthy volunteers

Bayesian decision procedures have recently been developed for dose escalation in phase I clinical trials concerning pharmacokinetic responses observed in healthy volunteers. This article describes how that general methodology was extended and evaluated for implementation in a specific phase I trial of a novel compound. At the time of writing, the study is ongoing, and it will be some time before the sponsor will wish to put the results into the public domain. This article is an account of how the study was designed in a way that should prove to be safe, accurate, and efficient whatever the true nature of the compound. The study involves the observation of two pharmacokinetic endpoints relating to the plasma concentration of the compound itself and of a metabolite as well as a safety endpoint relating to the occurrence of adverse events. Construction of the design and its evaluation via simulation are presented.

Equivalence of truncated count mixture distributions and mixtures of truncated count distributions

This article is about modeling count data with zero truncation. A parametric count density family is considered. The truncated mixture of densities from this family is different from the mixture of truncated densities from the same family. Whereas the former model is more natural to formulate and to interpret, the latter model is theoretically easier to treat. It is shown that for any mixing distribution leading to a truncated mixture, a (usually different) mixing distribution can be found so. that the associated mixture of truncated densities equals the truncated mixture, and vice versa. This implies that the likelihood surfaces for both situations agree, and in this sense both models are equivalent. Zero-truncated count data models are used frequently in the capture-recapture setting to estimate population size, and it can be shown that the two Horvitz-Thompson estimators, associated with the two models, agree. In particular, it is possible to achieve strong results for mixtures of truncated Poisson densities, including reliable, global construction of the unique NPMLE (nonparametric maximum likelihood estimator) of the mixing distribution, implying a unique estimator for the population size. The benefit of these results lies in the fact that it is valid to work with the mixture of truncated count densities, which is less appealing for the practitioner but theoretically easier. Mixtures of truncated count densities form a convex linear model, for which a developed theory exists, including global maximum likelihood theory as well as algorithmic approaches. Once the problem has been solved in this class, it might readily be transformed back to the original problem by means of an explicitly given mapping. Applications of these ideas are given, particularly in the case of the truncated Poisson family.

Investigating the mechanism of enhanced cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells

Recently we have described an HPMA copolymer conjugate carrying both the aromatase inhibitor aminoglutethimide (AGM) and doxorubicin (Dox) as combination therapy. This showed markedly enhanced in vitro cytotoxicity compared to the HPMA copolymer-Dox (FCE28068), a conjugate that demonstrated activity in chemotherapy refractory breast cancer patients during early clinical trials. To better understand the superior activity of HPMA copolymer-Dox-AGM, here experiments were undertaken using MCF-7 and MCF-7ca (aromatase-transfected) breast cancer cell lines to: further probe the synergistic cytotoxic effects of AGM and Dox in free and conjugated form; to compare the endocytic properties of HPMA copolymer-Dox-AGM and HPMA copolymer-Dox (binding, rate and mechanism of cellular uptake); the rate of drug liberation by lysosomal thiol-dependant proteases (i.e. conjugate activation), and also, using immunocytochemistry, to compare their molecular mechanism of action. It was clearly shown that attachment of both drugs to the same polymer backbone was a requirement for enhanced cytotoxicity. FACS studies indicated both conjugates have a similar pattern of cell binding and endocytic uptake (at least partially via a cholesterol-dependent pathway), however, the pattern of enzyme-mediated drug liberation was distinctly different. Dox release from PK1 was linear with time, whereas the release of both Dox and AGM from HPMA copolymer-Dox-AGM was not, and the initial rate of AGM release was much faster than that seen for the anthracycline. Immunocytochemistry showed that both conjugates decreased the expression of ki67. However, this effect was more marked for HPMA copolymer-Dox-AGM and, moreover, only this conjugate decreased the expression of the anti-apoptotic protein bcl-2. In conclusion, the superior in vitro activity of HPMA copolymer-Dox-AGM cannot be attributed to differences in endocytic uptake, and it seems likely that the synergistic effect of Dox and AGM is due to the kinetics of intracellular drug liberation which leads to enhanced activity. (c) 2006 Elsevier B.V All rights reserved.

Polymer-drug conjugates: current status and future trends

Polymer conjugates are nano-sized, multicomponent constructs already in the clinic as anticancer compounds, both as single agents or as elements of combinations. They have the potential to improve pharmacological therapy of a variety of solid tumors. Polymer-drug conjugation promotes passive tumor targeting by the enhanced permeability and retention (EPR) effect and allows for lysosomotropic drug delivery following endocytic capture. In the first part of this review, we analyze the promising results arising from clinical trials of polymer-bound chemotherapy. The experience gained on these studies provides the basis for the development of a more sophisticated second-generation of polymer conjugates. However, many challenges still lay ahead providing scope to develop and refine this field. The "technology platform'' of polymer therapeutics allows the development of both new and exciting polymeric materials, the incorporation of novel bioactive agents and combinations thereof to address recent advances in drug therapy. The rational design of polymer drug conjugates is expected to realize the true potential of these "nanomedicines".

Synthesis and biological in vitro evaluation of novel PEG-psoralen conjugates

Psoralens are well-known photosensitizers, and 8- methoxypsoralen and 4,5',8-trimethylpsoralen are widely used in photomedicine as "psoralens plus UVA therapy" (PUVA), in photopheresis, and in sterilization of blood preparations. In an attempt to improve the therapeutic efficiency of PUVA therapy and photopheresis, four poly(ethylene glycol) (PEG)-psoralen conjugates were synthesized to promote tumor targeting by the enhanced permeability and retention (EPR) effect. Peptide linkers were used to exploit specific enzymatic cleavage by lysosomal proteases. A new psoralen, 4-hydroxymethyl-4', 8-dimethylpsoralen (6), suitable for polymer conjugation was synthesized. The hydroxy group allowed exploring different strategies for PEG conjugation, and linkages with different stability such ester or urethanes were obtained. PEG (5 kDa) was covalently conjugated to the new psoralen derivative using four different linkages, namely, (i) direct ester bond (7), (ii) ester linkage with a peptide spacer (8), (iii) a carbamic linker (9), and (iv) a carbamic linker with a peptide spacer (12). The stability of these new conjugates was assessed at different pHs, in plasma and following incubation with cathepsin B. Conjugates 7 and 8 were rapidly hydrolyzed in plasma, while 9 was stable in buffer and in the presence of cathepsin B. As expected, only the conjugates containing the peptide linker released the drug in presence of cathepsin B. In vitro evaluation of the cytotoxic activity in the presence and absence of light was carried out in two cell lines (MCF-7 and A375 cells). Conjugates 7 and 8 displayed a similar activity to the free drug (probably due to the low stability of the ester linkage). Interestingly, the conjugates containing the carbamate linkage (9 and 12) were completely inactive in the dark (IC50 > 100 mu M in both cell lines). However, antiproliferative activity become apparent after UV irradiation. Conjugate 12 appears to be the most promising for future in vivo evaluation, since it was relatively stable in plasma, which should allow tumor targeting and drug release to occur by cathepsin B-mediated hydrolysis.

The influence of changing nicotine to tar ratios on human puffing behaviour and perceived sensory response

Rationale. Smokers modify their smoking behaviour when switching from their usual product to higher or lower tar and nicotine-yield cigarettes. Objective. The aims of the current study were to assess the influence of varying nicotine yields at constant tar yield on human puffing measures, nicotine deliveries under human smoking conditions and the sensory response to mainstream cigarette smoke. These assessments would allow an evaluation of the degree of compensation and the various possible causes of changes, if any. Methods. The participants were 13 regular smokers of commercial or hand-rolled cigarettes. They were tested with four cigarettes, which exhibited a wide range of nicotine to 'tar' ratios at a relatively constant 'tar' yield. Their smoking behaviour was monitored by placing the test cigarettes into an orifice-type holder/flowmeter attached to a custom-built smoker behaviour analyser. In addition, a comprehensive sensory evaluation of the products was carried out. Results. The differences in the nicotine to tar ratios of the samples did not significantly influence the puffing behaviour patterns, i.e. puff number and interval, total and average puff volume, integrated pressure and puff duration. Additionally the pre- to post-exhaled CO boosts were not significantly influenced by the experimental samples used in the study. However, the nicotine yields obtained by the smokers were significantly influenced by the machine-smoked nicotine yields or the nicotine to tar ratios of the samples. The machine-smoked nicotine yields were highly correlated with the nicotine yields obtained under human smoking conditions. For the sensory evaluation, there was only a significant difference between the samples in the intensity of the impact. Conclusion. These observations imply that these puffing variables are not controlled by the nicotine yield of the cigarette.

The ethical challenges of ubiquitous healthcare

Ubiquitous healthcare is an emerging area of technology that uses a large number of environmental and patient sensors and actuators to monitor and improve patients’ physical and mental condition. Tiny sensors gather data on almost any physiological characteristic that can be used to diagnose health problems. This technology faces some challenging ethical questions, ranging from the small-scale individual issues of trust and efficacy to the societal issues of health and longevity gaps related to economic status. It presents particular problems in combining developing computer/information/media ethics with established medical ethics. This article describes a practice-based ethics approach, considering in particular the areas of privacy, agency, equity and liability. It raises questions that ubiquitous healthcare will force practitioners to face as they develop ubiquitous healthcare systems. Medicine is a controlled profession whose practise is commonly restricted by government-appointed authorities, whereas computer software and hardware development is notoriously lacking in such regimes.

Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults.

The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, and MetS risk and whether plasma fatty acids, a biomarker of dietary fatty acids, modulate this. LEPR polymorphisms (rs10493380, rs1137100, rs1137101, rs12067936, rs1805096, rs2025805, rs3790419, rs3790433, rs6673324, and rs8179183), biochemical measurements, and plasma fatty acid profiles were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). LEPR rs3790433 GG homozygotes had increased MetS risk compared with the minor A allele carriers [odds ratio (OR) = 1.65; 95% CI: 1.05–2.57; P = 0.028], which may be accounted for by their increased risk of elevated insulin concentrations (OR 2.40; 95% CI: 1.28–4.50; P = 0.006) and insulin resistance (OR = 2.15; 95% CI: 1.18–3.90; P = 0.012). Low (less than median) plasma (n-3) and high (n-6) PUFA status exacerbated the genetic risk conferred by GG homozygosity to hyperinsulinemia (OR 2.92–2.94) and insulin resistance (OR 3.40–3.47). Interestingly, these associations were abolished against a high (n-3) or low (n-6) PUFA background. Importantly, we replicated some of these findings in an independent cohort. Homozygosity for the LEPR rs3790433 G allele was associated with insulin resistance, which may predispose to increased MetS risk. Novel gene-nutrient interactions between LEPR rs3790433 and PUFA suggest that these genetic influences were more evident in individuals with low plasma (n-3) or high plasma (n-6) PUFA.

Self-immolative linkers in polymeric delivery systems

There has been significant interest in the methodologies of controlled release for a diverse range of applications spanning drug delivery, biological and chemical sensors, and diagnostics. The advancement in novel substrate-polymer coupling moieties has led to the discovery of self-immolative linkers. This new class of linker has gained popularity in recent years in polymeric release technology as a result of stable bond formation between protecting and leaving groups, which becomes labile upon activation, leading to the rapid disassembly of the parent polymer. This ability has prompted numerous studies into the design and development of self-immolative linkers and the kinetics surrounding their disassembly. This review details the main concepts that underpin self-immolative linker technologies that feature in polymeric or dendritic conjugate systems and outlines the chemistries of amplified self-immolative elimination.

Metabolism of tea flavonoids in the gastrointestinal tract

There is considerable interest in the bioavailability of flavan-3-ols such as tea catechins and their bioactivity in vivo. Although flavanols such as catechin and epicatechin have long been characterized as powerful antioxidants in vitro, evidence suggests that these compounds undergo significant metabolism and conjugation during absorption in the small intestine and in the colon. In the small intestine these modifications lead primarily to the formation of glucuronide conjugates that are more polar than the parent flavanol and are marked for renal excretion. Other phase II processes lead to the production of O-methylated forms that have reduced antioxidant potential via the methylation of the B-ring catechol. Significant modification of flavanols also occurs in the colon where the resident microflora degrade them to smaller phenolic acids, some of which may be absorbed. Cell, animal and human studies have confirmed such metabolism by the detection of flavanol metabolites in the circulation and tissues. This review will highlight the major sites of flavanol metabolism in the gastrointestinal tract and the processes that give rise to potential bioactive forms of flavan-3-ols in vivo.

Enhancing model predictive control using dynamic data reconciliation

The use of data reconciliation techniques can considerably reduce the inaccuracy of process data due to measurement errors. This in turn results in improved control system performance and process knowledge. Dynamic data reconciliation techniques are applied to a model-based predictive control scheme. It is shown through simulations on a chemical reactor system that the overall performance of the model-based predictive controller is enhanced considerably when data reconciliation is applied. The dynamic data reconciliation techniques used include a combined strategy for the simultaneous identification of outliers and systematic bias.