Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments.

Compartmental models which yield linear ordinary differential equations (ODEs) provide common tools for pharmacokinetics (PK) analysis, with exact solutions for drug levels or concentrations readily obtainable for low-dimensional compartment models. Exact solutions enable valuable insights and further analysis of these systems. Transit compartment models are a popular semi-mechanistic approach for generalising simple PK models to allow for delayed kinetics, but computing exact solutions for multi-dosing inputs to transit compartment systems leading to different final compartments is nontrivial. Here, we find exact solutions for drug levels as functions of time throughout a linear transit compartment cascade followed by an absorption compartment and a central blood compartment, for the general case of n transit compartments and M equi-bolus doses to the first compartment. We further show the utility of exact solutions to PK ODE models in finding constraints on equi-dosing regimen parameters imposed by a prescribed therapeutic range. This leads to the construction of equi-dosing regimen regions (EDRRs), providing new, novel visualisations which summarise the safe and effective dosing parameter space. EDRRs are computed for classical and transit compartment models with two- and three-dimensional parameter spaces, and are proposed as useful graphical tools for informing drug dosing regimen design.

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.

Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.

North Atlantic storm track changes during the Last Glacial Maximum recorded by Alpine speleothems.

The European Alps are an effective barrier for meridional moisture transport and are thus uniquely placed to record shifts in the North Atlantic storm track pattern associated with the waxing and waning of Late-Pleistocene Northern Hemisphere ice sheets. The lack of well-dated terrestrial proxy records spanning this time period, however, renders the reconstruction of past atmospheric patterns difficult. Here we present a precisely dated, continuous terrestrial record of meteoric precipitation in Europe between 30 and 14.7 ka. In contrast to present-day conditions, our speleothem data provide strong evidence for preferential advection of moisture from the South across the Alps supporting a southward shift of the storm track during the local Last Glacial Maximum (that is, 26.5-23.5 ka). Moreover, our age control indicates that this circulation pattern preceded the Northern Hemisphere precession maximum by ~3 ka, suggesting that obliquity may have played a considerable role in the Alpine ice aggradation.

Interleukin-6 receptor pathways in abdominal aortic aneurysm.

METHODS: We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. RESULTS: Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers. CONCLUSIONS: A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.

The mechanism of sevoflurane-induced cardioprotection is independent of the applied ischaemic stimulus in rat trabeculae.

BACKGROUND: Sevoflurane protects the myocardium against ischaemic injury through protein kinase C (PKC) activation, mitochondrial K+ATP-channel (mitoK+ATP) opening and production of reactive oxygen species (ROS). However, it is unclear whether the type of ischaemia determines the involvement of these signalling molecules. We therefore investigated whether hypoxia (HYP) or metabolic inhibition (MI), which differentially inhibit the mitochondrial electron transport chain (ETC), are comparable concerning the relative contribution of PKC, mitoK+ATP and ROS in sevoflurane-induced cardioprotection. METHODS: Rat right ventricular trabeculae were isolated and isometric contractile force (Fdev) was measured. Trabeculae were subjected to HYP (hypoxic glucose-free buffer; 40 min) or MI (glucose-free buffer, 2 mM cyanide; 30 min), followed by 60 min recovery (60 min). Contractile recovery (Fdev,rec) was determined at the end of the recovery period and expressed as a percentage of Fdev before hypoxia or MI, respectively. Chelerythrine (CHEL; 6 microM), 5-hydroxydecanoic acid sodium (100 microM) and n-(2-mercaptopropionyl)-glycine (MGP; 300 microM) were used to inhibit PKC, mitoK+ATP and ROS, respectively. RESULTS: Fdev,rec after HYP was reduced to 47 (3)% (P<0.001 vs control; n=5) whereas MI reduced Fdev,rec to 28 (5)% (P<0.001 vs control; n=5). A 15 min period of preconditioning with sevoflurane (3.8%) equally increased contractile recovery after HYP [76 (9)%; P<0.05 vs HYP] and MI [67 (8)%; P<0.01 vs MI]. Chelerythrine, 5-hydroxydecanoate and n-(2-mercaptopropionyl)-glycine abolished the protective effect of sevoflurane in both ischaemic models. Trabeculae subjected to HYP or MI did not demonstrate any increased apoptotic or necrotic markers. CONCLUSIONS: PKC, mitoK+ATP and ROS are involved in sevoflurane-induced cardioprotection after HYP or MI, suggesting that the means of mitochondrial ETC inhibition does not determine the signal transduction pathway for cardioprotection by anaesthetics.

Highly selective synthesis of heterosubstituted aromatic sulfamides.

The sulfamide functional group is increasingly relevant in both medicinal and supramolecular chemistry, yet few selective synthetic steps are available for its elaboration. We report here a mild, general, and efficient method for the selective differentiation of N-atom substituents of aromatic sulfamides. [reaction: see text]

Endogenous growth of population and income depending on resource and knowledge.

PIP: This study focuses on the dynamic, endogenous, nonlinear interactions between the economy, population growth and the environment. Literature on endogenous growth theory was reviewed and the 3-sector demoeconomic model was provided as the analytical framework for the study of sustainable development through the integration of population growth, resource use and economic growth. The model is described in such a way that the labor force is considered as a free migrating variable among three different kinds of employment: the primary sector, which harvests a renewable resource, the secondary or industrial sector, and the tertiary sector, which is responsible for the accumulation of the stock that represents a public good for all three sectors. Presented in this paper is a nontechnical outline of the model that describes the economic, demographic, and environmental interactions considered. Also given are dynamics, market equilibrium and dynamic feedback rules. Furthermore, numerical analysis of the model quantifying the resulting time paths of the variables involved is included. The dynamics are simply the outcome of the nonlinear interactions of the demographic, economic and environmental modules. Numerical studies have also shown that the system variables move with different velocity. Technology and population can generally be regarded as slow moving variables by comparison with resources.^ieng