Amine Containing Analogs of Sulindac for Cancer Prevention

Background: Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity. Objective: Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities. Method: A series of sulindac amine analogs were designed and synthesized and then further modified in a “libraries from libraries” approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast). Results: Several active compounds were identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range. Conclusion: Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds

An introduction to the application of system identification techniques to elements of the neuromuscular system

A simplified account of the organisation of the neuromuscular system is presented. An important component of this system, the "muscle spindle", is a complex sensor that responds to imposed length changes and is thought to provide information which is important in the control of movement and in the maintenance of posture. The structure of the muscle spindle and its response to various inputs are described. The multi-input and multi-output nature and nonlinear behaviour of the muscle spindle are emphasised, both in terms of continuous and pulse-coded quantities. The methods of pre-processing of pulse-coded signals from nerves, and the identification techniques currently applied by neurophysiologists for the estimation of of the parameters of linearised models of the muscle spindle, are presented and assessed. New developments in the identification of point-process systems are shown to be applicable to some aspects of muscle-spindle behaviour. This approach, based upon point-process parameters, is applied to the analysis of the output signal of a muscle spindle under a variety of input conditions and to the estimation of a transfer function of the muscle spindle subjected to a point process input. A description of one non-linearity and the effects ofan additional input are also presented

Muscle spindle modelling and identification

Muscles concerned with movement and the maintenance of posture contain large numbers of sensory receptors called muscle spindles which respond to changes in load imposed on the parent muscle. These receptors play an important role in neuromuscular control systems. This article presents a simplified description of muscle spindles, summarizes the methods used to describe the signals which they generate and outlines the modelling and identification procedures used to investigate their behaviour

A periodogram-based test for weak stationarity and consistency between sections in time series

In one approach to spectral estimation, a sample record is broken into a number of disjoint sections, or data is collected over a number of discrete trials. Spectral parameters are formed by averaging periodograms across these discrete sections or trials. A key assumption in this approach is that of weak stationarity. This paper describes a simple test that checks if periodogram ordinates are consistent across sections as a means of assessing weak stationarity. The test is called the Periodogram Coefficient of Variation (PCOV) test, and is a frequency domain test based on a technique of spectral analysis. Application of the test is illustrated to both simulated and experimental data (EMG, physiological tremor, EEG). An additional role for the test as a useful tool in exploratory analysis of time series is highlighted

The identification of a complex biological receptor

Muscle spindles are complex biological receptors involved in the maintenance of posture. Such receptors have several inputs, some of which are point-process like (neural signals), whereas others are continuous (e.g. muscle length). These inputs combine to produce a neural output which is also a point-process. Frequency-domain analysis of the point process signals has revealed features not apparent by other methods of investigation. Processes occurring within the muscle spindle which may not be directly accessible experimentally have been studied successfully using a combination of simulation and identification techniques

A frequency-domain identification approach to the study of neuromuscular systems - a combined experimental and modelling study

Experimental investigation of the neuromuscular system involves not only analysis of continuous signals but also necessitates the study of sequences of action potentials recorded from individual neurones together with the interactions between several sequences. Trains of action potentials may be regarded as realisations of stochastic point processes and techniques for the identification of point process systems can provide valuable experimental tools for the investigation of neuromuscular systems. Computational methods are presented for estimating the finite Fourier transform of a point process, and the associated spectral estimation procedures are described. An example is presented to illustrate the application of linear point process model identification techniques to the muscle spindle receptor. Using this example, simulation techniques are applied to demonstrate that spectral estimates can provide valuable physiological insight

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer

PURPOSE The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P &lt; .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P &lt; .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings. </jats:sec