Optimum test planning for heterogeneous inverse Gaussian processes.

The heterogeneous inverse Gaussian (IG) process is one of the most popular and most considered degradation models for highly reliable products. One difficulty with heterogeneous IG processes is the lack of analytic expressions for the Fisher information matrix (FIM). Thus, it is a challenge to find an optimum test plan using any information-based criteria with decision variables such as the termination time, the number of measurements and sample size. In this article, the FIM of an IG process with random slopes can be derived explicitly in an algebraic expression to reduce uncertainty caused by the numerical approximation. The D- and V-optimum test plans with/without a cost constraint can be obtained by using a profile optimum plan. Sensitivity analysis is studied to elucidate how optimum planning is influenced by the experimental costs and planning values of the model parameters. The theoretical results are illustrated by numerical simulation and case studies. Simulations, technical derivations and auxiliary formulae are available online as supplementary materials.

Dry heat forced degradation of buserelin peptide: kinetics and degradant profiling.

Buserelin is a GnRH agonist peptide drug, comprising a nine amino acid sequence (pGlu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-Et) and most commonly known for its application in hormone dependent cancer therapy, e.g. prostate cancer. In order to evaluate its hot-melt extrusion (HME) capabilities, buserelin powder in its solid state was exposed to elevated temperatures for prolonged time periods. A stability indicating UPLC-PDA method was used for quantification of buserelin and the formed degradants. Different solid state kinetic models were statistically evaluated of which the Ginstling-Brounshtein model fitted the data best. Extrapolation to and experimental verification of typical HME-related conditions, i.e. 5 min at 100°C and 125°C, showed no significant degradation, thus demonstrating the HME capabilities of buserelin. Mass spectrometric identification of the buserelin-related degradants formed under solid state heat stress was performed. Based upon the identity of these degradants, different degradation hypotheses were raised. First, direct ß-elimination of the hydroxyl moiety at the serine residue, followed by fragmentation into an amide (pGlu-His-Trp-NH2) and pyruvoyl (pyruvoyl-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-Et) peptide fragments, was postulated. Alternatively, internal esterification due to nucleophilic attack of the unprotected serine residue, followed by ß-elimination or hydrolysis would yield pGlu-His-Trp, pGlu-His-Trp-NH2 and the pyruvoyl peptide fragment. Degradant pGlu-His-Trp-Ser-Tyr-NH2 is believed to be formed in a similar way. Secondly, direct backbone hydrolysis would yield pGlu-His-Trp and Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-Et peptide fragments. Moreover, the presence of Ala-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-Et can be explained by hydrolysis of the Trp-Ser peptide bond and conversion of the serine moiety to an alanine moiety. Third and finally, isomerisation of aforementioned peptide fragments and buserelin itself was also observed.

Surface anthropometric indices in obesity-related metabolic diseases and cancers.

Metabolic syndrome (MetS), cardiovascular diseases (CVD) and cancers such as colon cancer (CCa), prostate cancer (PCa) and breast cancer (BCa) have been recognized as obesity-initiated diseases. The development of obesity can cause changes in metabolic and hormonal conditions, which can result in the storage of excess energy in different forms in the human body. Existing anthropometric data are useful in the prognosis of these diseases. Although frequently studied, there is disagreement on the applicability, reliability and trends of weight, height, waist circumference (WC) and relevant indices. WC is generally accepted as a key marker in CVD and CCa risk assessment whereas more evidence of the usefulness of WC-CVD, WC-PCa and WC-BCa correlations is needed. The body mass index, which has been widely used as a determinant of obesity, has a strong connection with CCa risk in men and young women, but an inconsistent connection with BCa. Cross-referencing measurements, with indices such as the waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR), enhances the association with diseases, e.g. WHtR-CVD and WHR-CCa, and connections are strong. This idea is further applied to multiple referencing. For example, the WHtR/WHR has been studied and found highly correlated with the MetS risk in Asia. In addition, latent issues (such as tools or techniques for surface anthropometric measurement), which could affect the prognosis of diseases, have been discussed. To this end, three-dimensional technology is suggested as a reliable tool for various anthropometric data collection and analysis in preventive medicine.