Half-Life 2 CODEX: The Best Mods and Add-ons to Enhance Your Gameplay

The original code name for Half-Life was Quiver, after the Arrowhead military base from Stephen King's novella The Mist, which served as an early inspiration for the game. Gabe Newell explained in an interview that the name Half-Life was chosen because it was evocative of the theme, not clichéd, and had a corresponding visual symbol: the Greek letter lambda, which represents the decay constant in the half-life equation.

Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration (Cmax) to half of Cmax in the blood plasma,[1][2][3][4][5] and is denoted by the abbreviation t 1 2 \displaystyle t_\frac 12 . [2][4]

Half-Life 2 CODEX

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This is used to measure the removal of things such as metabolites, drugs, and signalling molecules from the body. Typically, the biological half-life refers to the body's natural cleansing through the function of the liver and through the excretion of the measured substance through the kidneys and intestines. This concept is used when the rate of removal is roughly exponential.[clarification needed][6]

In a medical context, half-life explicitly describes the time it takes for the blood plasma concentration of a substance to halve (plasma half-life) its steady-state when circulating in the full blood of an organism. This measurement is useful in medicine, pharmacology and pharmacokinetics because it helps determine how much of a drug needs to be taken and how frequently it needs to be taken if a certain average amount is needed constantly. By contrast, the stability of a substance in plasma is described as plasma stability. This is essential to ensure accurate analysis of drugs in plasma and for drug discovery.

The biological half-life of water in a human is about 7 to 14 days. It can be altered by behavior. Drinking large amounts of alcohol will reduce the biological half-life of water in the body.[8][9] This has been used to decontaminate humans who are internally contaminated with tritiated water. The basis of this decontamination method is to increase the rate at which the water in the body is replaced with new water.

The biological half-life of caesium in humans is between one and four months. This can be shortened by feeding the person prussian blue. The prussian blue in the digestive system acts as a solid ion exchanger which absorbs the caesium while releasing potassium ions.

For some substances, it is important to think of the human or animal body as being made up of several parts, each with their own affinity for the substance, and each part with a different biological half-life (physiologically-based pharmacokinetic modelling). Attempts to remove a substance from the whole organism may have the effect of increasing the burden present in one part of the organism. For instance, if a person who is contaminated with lead is given EDTA in a chelation therapy, then while the rate at which lead is lost from the body will be increased, the lead within the body tends to relocate into the brain where it can do the most harm.[28]

The longer half-life is called the terminal half-life and the half-life of the largest component is called the dominant half-life.[39] For a more detailed description see Pharmacokinetics Multi-compartmental models.

Once dioxins enter the body, they last a long time because of their chemical stability and their ability to be absorbed by fat tissue, where they are then stored in the body. Their half-life in the body is estimated to be 7 to 11 years. In the environment, dioxins tend to accumulate in the food chain. The higher an animal is in the food chain, the higher the concentration of dioxins.

Peptides are notoriously known to display very short in vivo half-lives often measured in minutes which in many cases greatly reduces or eliminates sufficient in vivo efficacy. To obtain long half-lives allowing for up to once-weekly dosing regimen, fatty acid acylation (lipidation) have been used to non-covalently associate the peptide to serum albumin thus serving as a circulating depot. This approach is generally considered in the scientific and patent community as a standard approach to protract almost any given peptide. However, it is not trivial to prolong the half-life of peptides by lipidation and still maintain high potency and good formulation properties. Here we show that attaching a fatty acid to the obesity-drug relevant peptide PYY3-36 is not sufficient for long pharmacokinetics (PK), since the position in the backbone, but also type of fatty acid and linker strongly influences PK and potency. Furthermore, understanding the proteolytic stability of the backbone is key to obtain long half-lives by lipidation, since backbone cleavage still occurs while associated to albumin. Having identified a PYY analogue with a sufficient half-life, we show that in combination with a GLP-1 analogue, liraglutide, additional weight loss can be achieved in the obese minipig model.

PYY3-36 has been extensively characterized with respect to promotion of satiety and regulation of energy balance either as standalone treatment or in combination with GLP-11,11,12,13,14,15. Consequently, PYY3-36 administration has attracted attention as a novel anti-obesity treatment. The half-life of PYY3-36 is very short below 10 minutes in plasma, due to rapid renal clearance and enzymatic degradation8,16. As a result, continuous administration, e.g. by pumps, has been used to report satiety effects in humans. More attractive from a pharmaceutical point of view, however, is the design of a PYY3-36 analogue displaying a much-prolonged half-life after administration by s.c. injection.

In order to avoid renal clearance of PYY3-36, approaches have been reported that increase the hydrodynamic volume of PYY3-36 by conjugation of polyethylene glycol (PEG) to PYY3-36 and analogues thereof17,18, conjugation to serum albumin19,20 or immunoglobulin Fc domain21. These methods have been shown to prolong the half-life while maintaining the pharmacological activity. Also sustained release of a PYY analogue has been reported and shown effect in a human trial study22. Serum albumin and the Fc domain of antibodies display a very long half-life of approximately 19 days in humans due to recycling via the neonatal Fc receptor (FcRn)23. Albumin is also known as a transporter and binder of fatty acids and other hydrophobic small molecule drugs. Consequently, prolonged half-lives can be achieved by attaching a fatty acid to a target protein or peptide, which, due to the binding of the fatty acid to albumin, then serves as a circulating depot of the target protein or peptide. This has been shown to be an attractive way of prolonging the in vivo effect of the insulin analogues determir and degludec24,25,26, as well as GLP-1 analogues27,28. In the once-daily dosed GLP-1 analogue, liraglutide, a palmitic acid (C16) is connected to a l-γ-glutamyl (γGlu) residue on Lys26, whereas in the once-weekly dosed GLP-1 analogue, semaglutide28, it is an octadecanedioic acid (C18 diacid) linked to a γGlu moiety and connected to a spacer, consisting of two 8-amino-3,6-dioxaoctanoic acid (Ado) units attached to the side chain of Lys26 (Fig. 1a). The C18 diacid has also been attached to PYY3-36 as a stabling moiety between positions 10 and 17 or 23 and 30, showing extended half-life in a rodent model29. In the once-weekly dosed GLP-1/GIP dual acting analogue, tirzepatide, the protraction is mediated by eicosanedioic acid (C20 diacid) linked to γGlu and a 2xAdo unit, which is then attached to the side chain of a lysine residue30. For liraglutide and the insulin analogue degludec, the prolonged half-life is also achieved by self-association at the site of injection in addition to albumin binding26,31, whereas in semaglutide and tirzepatide much stronger albumin binding is the main driver of protraction. A tight association to albumin has been considered essential to obtain very long half-lives, necessary for obtaining a once-weekly dosing profile.

We synthesized a large series of PYY3-36 analogues (Table 1) in which we studied the half-life in minipigs, the NPY receptor potencies and binding properties for both human and porcine albumin as a function of fatty diacid derivatization. This was achieved by synthesizing a series of analogues of PYY3-36 where the fatty diacid side chain from semaglutide (C18 diacid-γGlu-2xAdo) was positioned on the side chain of a lysine residue throughout the backbone of PYY3-36. The in vitro potency on Y1R, Y2R and Y4R as a function of fatty diacid position was also determined, as well as binding to the Y2R in the absence and presence of albumin for a selected set of analogues. Analogues with the fatty diacid protractor in position 30 were also studied with respect to length of fatty diacid and linker type, as well as backbone modifications and the impact these modifications may have on the half-life and potency. Finally, we performed an in vivo metabolism study in the obese minipig model with one of the optimized analogues in combination with the once-daily GLP-1 analogue, liraglutide.

Plasma half-life in minipigs as a function of the position and type of fatty acid protractor. (a) Half-life in minipig using protractor C18diacid-γGlu-2xAdo as a function of position in PYY3-36. (b) Half-life as a function of fatty acid length and presence or absence of linker γGlu with all analogues having the protractor moieties placed in position 30. Half-lives are also listed in Table 1. 2ff7e9595c