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Using a novel method the force between two charged surfaces with an intervening electrolyte solution has been determined from Monte Carlo simulations. We find large deviations from the standard Poisson–Boltzmann treatment of the so called double layer force for divalent counterions at high surface charge densities and at short separations. The deviations have two causes: (i) Due to the inclusion of the effect of ion–ion correlations the counterions concentrate more towards the charged wall reducing the overlap between the double layers; and (ii) correlated fluctuations in the ion clouds of the two surfaces lead to an attractive interaction of a van der Waals type. For some realistic values of the parameters the attraction overcomes the repulsive part and there is a net attractive force between similarly charged surfaces. This finding leads to a modification of our conceptual understanding of the interaction between charged particles and it shows that the DLVO theory is qualitatively deficient under some, realistic, conditions.

Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV 1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase. AM404 also inhibits purified cyclooxygenase (COX)-1 and COX-2 and prostaglandin synthesis in lipopolysaccharide-stimulated RAW264.7 macrophages. This novel metabolite of acetaminophen also acts on the endogenous cannabinoid system, which, together with TRPV 1 and COX, is present in the pain and thermoregulatory pathways. These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen.Acetaminophen was introduced into clinical medicine more than a century ago, but its mechanism of action is still a matter of debate. The analgesic, antipyretic, and anti-inflammatory effects of non-steroidal anti-inflammatory drugs are believed to depend on their ability to inhibit COX 1 (1, 2). However, acetaminophen differs from most non-steroidal anti-inflammatory drugs in that it is a weak anti-inflammatory agent with a low incidence of COX-related adverse effects (2-4).Although this may seem incompatible with an action on COX, studies in vitro clearly show that acetaminophen is able to inhibit both COX-1 and COX-2, provided that the ambient concentration of peroxides is kept low (5-7). Such a peroxidedependent inhibition of COX could explain why acetaminophen does not suppress inflammation and platelet activity (5-7). However, final proof that the analgesic and antipyretic effects of acetaminophen are dependent on COX is still lacking. There are also indications that the analgesic effect of acetaminophen is mediated by molecular targets distinct from COX (8 -10).In this study we have explored the possibility that acetaminophen undergoes a two-step metabolic transformation to form the bioactive N-acylphenolamine AM404. AM404 is a potent activator of TRPV 1 , a ligand at cannabinoid CB 1 receptors and an inhibitor of cellular anandamide uptake, the inhibition of which leads to increased levels of endogenous cannabinoids (11-15). TRPV 1 and cannabinoid CB 1 receptors are both present in the pain and thermoregulatory pathways, and much interest has been focused on these receptors as potential drug targets for the treatment of pain and inflammation (11, 14, 16 -19).AM404 belongs to a group of bioactive N-acylamines that also includes the endogenous lipids anandamide (20), N-arachidonoyldopamine (21), and N-arachidonoylglycine (22) and the synthetic compounds olvanil (23) and arvanil (24). These drugs all display analgesic activity in a ...

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Abstract:The self-diffusion of small molecules in colloidal systems is calculated using the cell model to describe the effect of varying concentration of colloidal particles. The relevant boundary conditions are found using arguments from the thermodynamics of irreversible processes. From a general description of the self-diffusion in systems with spherically symmetrical particles we derive expressions for the concentration dependence of the effective self-diffusion coefficient De~t for several cases of practical importance. It is shown that when the molecule studied is strongly attracted to the particle a minimum in D ~ff is expected around volume fraction 4~ = 0.35. It is also shown that the often made distinction between free and bound molecules is often problematic and a more general description is proposed. The obstruction effect generated by the excluded volume is discussed both for spherical and spheroidal systems. It is pointed out that the often used formula due to Wang ((1954) J Amer Chem Soc 76:4755) is incorrect for self-diffusion and for the obstruction factor for spheres we obtain (1 + 0.5 ~)-1. This expresion is tested both by experiments on water diffusion in systems containing latex particles and through computer simulations and it is found valid over a wide concentration range. For prolate ellipsoids the obstruction factor is not greatly different from that for spheres, while for oblate aggregates the limking obstruction factor of 2/3 can be obtained at low concentrations. It is demonstrated that this effect can be used to distinguish between different aggregate shapes. It is also shown that the disorder present in a solution of colloidal particles leads to a decrease in the obstruction effect.

Some exact statistical mechanical relations have been derived for polyelectrolyte systems within the primitive model. Using the cell model, the osmotic pressure is determined through an explicit evaluation of the derivative of the partition function. Planar, cylindrical, and spherical systems are considered and for a planar charged wall the contact value theorem [Henderson and Blum, J. Chem. Phys. 69, 5441 (1978)] is obtained as a special case. Analogous relations are derived for the cylindrical and spherical geometries. It is argued that the exact relations can be used as consistency tests for analytical approximations. It is pointed out that one merit of the Poisson–Boltzmann approximation is that the validity of the exact equations is retained. Finally, a simple method is devised for determining the osmotic pressure from Monte Carlo simulations. Results from such simulations are used to assess the accuracy of the osmotic pressure calculated using the Poisson–Boltzmann equation. For monovalent ions, the pressure is overestimated by 10%–50% in the cases studied, while with divalent counterions the error is substantially larger and a discrepancy of one order of magnitude is found.

It is known that the overall charge of a protein can change as the molecule approaches a charged object like another protein or a cell membrane. We have formalized this mechanism using a statistical mechanical framework and show how this rather overlooked interaction increases the attraction between protein molecules. From the theory, we can identify a unique property, the protein charge capacitance, that contains all information needed to describe the charge regulation mechanism. The capacitance can be obtained from experiment or theory and is a function of pH, salt concentration, and the number of titrating residues. For a range of different protein molecules, we calculate the capacitance and demonstrate how it can be used to quantify the charge regulation interaction. With minimal effort, the derived formulas can be used to improve existing models by including a charge regulation term. Good agreement is found between theory, simulations, and experimental data.