Partition coefficients for a set of drug compounds have been measured in four solvent-water systems, with octanol, chloroform, cyclohexane and toluene as solvents. The data have been used to test four different methods for the calculation of the three Abraham descriptors, dipolarity/polarizability S, hydrogen bond acidity A, and hydrogen bond basicity B. The methods involved (i) the use of Microsoft 'Solver', (ii) use of a series of regression equations developed from compounds with known descriptors, and use of two further methods that have been developed, (iii) a program similar to Solver that we denote as 'Descfit', and (iv) a program that uses a set of three simultaneous equations, and which we denote as 'TripleX'. We show that partition coefficients for a given drug in only four solvent-water systems can be used to calculate the three Abraham descriptors reliably, and we test all four methods of calculation for reproducibility and ease of use. We finally test the applicability of descriptors calculated for the set of drug compounds, to predict properties of biological importance such as human intestinal absorption and blood/ brain distribution.

No abstract

Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired resistance inevitably occurs after long-term exposure. More recently, combination therapy has emerged as a promising strategy to overcome this issue. Several experiments have been carried out to evaluate the synergism of combination therapy both in vitro and in vivo. Additionally, many clinical studies have been carried out to investigate the feasibility of treatment with EGFR-tyrosine kinase inhibitors (TKi) combined with other NSCLC treatments, including radiotherapy, cytotoxic chemotherapies, targeted therapies, and emerging immunotherapies. However, a significant gap still exists when applying pre-clinical results to clinical scenarios, which hinders the development and use of these strategies. This article is a literature review analysing the rationalities and controversies in the transition from pre-clinical investigation to clinical practice associated with various combination strategies. It also highlights clues and challenges regarding future combination therapeutic options in NSCLC treatment.

No abstract

In this paper, outage performance of hybrid automatic repeat request with incremental redundancy (HARQ-IR) is analyzed. Unlike prior analyses, time-correlated Nakagami-m fading channel is considered. The outage analysis thus involves the probability distribution analysis of a product of multiple correlated shifted Gamma random variables and is more challenging than prior analyses. Based on the finding of the conditional independence of the received signal-to-noise ratios (SNRs), the outage probability is exactly derived by using conditional Mellin transform. Specifically, the outage probability of HARQ-IR under time-correlated Nakagami-m fading channels can be written as a weighted sum of outage probabilities of HARQ-IR over independent Nakagami fading channels, where the weightings are determined by a negative multinomial distribution. This result enables not only an efficient truncation approximation of the outage probability with uniform convergence but also asymptotic outage analysis to further extract clear insights which have never been discovered for HARQ-IR even under fast fading channels. The asymptotic outage probability is then derived in a simple form which clearly quantifies the impacts of transmit powers, channel time correlation and information transmission rate. It is proved that the asymptotic outage probability is an inverse power function of the product of transmission powers in all HARQ rounds, an increasing function of the channel time correlation coefficients, and a monotonically increasing and convex function of information transmission rate. The simple expression of the asymptotic result enables optimal power allocation and optimal rate selection of HARQ-IR with low complexity. Finally, numerical results are provided to verify our analytical results and justify the application of the asymptotic result for optimal system design. Hybrid automatic repeat request with incremental redundancy, time correlation, Nakagami-m fading, asymptotic outage analysis, product of multiple random variables. Index Terms

No abstract

No abstract

No abstract