3,947 research outputs found

    Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action

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    Paracetamol (acetaminophen) is undoubtedly one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that \u1d62a\u1d62f \u1d637\u1d62a\u1d635\u1d633\u1d630 screens demonstrate low potency on the inhibition of COX-1 and COX-2. \u1d610\u1d62f \u1d637\u1d62a\u1d637\u1d630 data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol

    Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes

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    Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin Eâ‚‚ (PGEâ‚‚) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGEâ‚‚-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGEâ‚‚ biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme

    Improved Bond Stress-Slip Relationships for CFRP-Strengthened Masonry Triplets

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    Carbon fibre-reinforced polymer (CFRP) emerges as a viable solution for reinforcing unreinforced masonry (URM) walls subjected to shear loads. While masonry structures are straightforward to construct, the complexity of the construction materials, especially in terms of their mechanical properties, poses challenges for numerical studies of their structural behaviour. Walls, being fundamental components in masonry construction, play a crucial role in transferring both horizontal and vertical lateral forces. This study investigates the enhancement of masonry wall behaviour through the reinforcement of CFRP. CFRP reinforcement increases ductility and strength, reducing the risk of failure under shear conditions. Additionally, CFRP composites present a practical solution to strengthening masonry structures compared to traditional reinforcement. However, brick, mortar, and CFRP have not been thoroughly investigated. Experimental tests on the bond behaviour of different configurations of CFRP-retrofitted masonry triplets have not been performed before and are therefore presented in this paper. Triplet specimens, comprising three bricks and two mortar joints, both with and without CFRP strengthening, were subjected to bond testing. The study affirms that masonry triplets strengthened with CFRP under shear loads exhibit strength levels at least four to six times greater than those without CFRP. The experimental work was carried out with eight different CFRP configurations on triplet masonry, and each test was repeated four times. Further, the bond stress-slip relationship in the case of masonry triplets with and without CFRP was predicted with new mathematical equations based on the conducted test results. These equations were included in the commercial finite element software ANSYS and used to conduct simulations of CFRP-reinforced masonry triplets. The numerical results indicate good agreement between the finite element model and the test results. The outcome of this research improves the current knowledge on the use of CFRP to reinforce masonry walls with brick and mortar, which will contribute to the understanding of the effect of CFRP on masonry structures.The outcome of this research improves the current knowledge on the use of CFRP to reinforce masonry walls with brick and mortar, which will contribute to the understanding of the effect of CFRP on masonry structures

    Assessing the outcome of orthognathic surgery by three-dimensional soft tissue analysis

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    Studies of orthognathic surgery often focus on pre-surgical versus post-surgical changes in facial shape. In contrast, this study provides an innovative comparison between post-surgical and control shape. Forty orthognathic surgery patients were included, who underwent three different types of surgical correction: Le Fort I maxillary advancement, bilateral sagittal split mandibular advancement, and bimaxillary advancement surgery. Control facial images were captured from volunteers from local communities in Glasgow, with patterns of age, sex, and ethnic background that matched those of the surgical patients. Facial models were fitted and Procrustes registration and principal components analysis used to allow quantitative analysis, including the comparison of group mean shape and mean asymmetry. The primary characteristic of the difference in shape was found to be residual mandibular prognathism in the group of female patients who underwent Le Fort I maxillary advancement. Individual cases were assessed against this type of shape difference, using a quantitative scale to aid clinical audit. Analysis of the combined surgical groups provided strong evidence that surgery reduces asymmetry in some parts of the face such as the upper lip region. No evidence was found that mean asymmetry in post-surgical patients is greater than that in controls

    Earth-like sand fluxes on Mars

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    Strong and sustained winds on Mars have been considered rare, on the basis of surface meteorology measurements and global circulation models, raising the question of whether the abundant dunes and evidence for wind erosion seen on the planet are a current process. Recent studies showed sand activity, but could not determine whether entire dunes were moving—implying large sand fluxes—or whether more localized and surficial changes had occurred. Here we present measurements of the migration rate of sand ripples and dune lee fronts at the Nili Patera dune field. We show that the dunes are near steady state, with their entire volumes composed of mobile sand. The dunes have unexpectedly high sand fluxes, similar, for example, to those in Victoria Valley, Antarctica, implying that rates of landscape modification on Mars and Earth are similar

    New and novel uses for paracetamol

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    Paracetamol is used clinically for the treatment of pain and fever. Recent investigations in experimental animals confirmed paracetamol is able to induce potent hypothermia, which is self-reversible and does not lead to any long term toxicities. In this investigation, the authors sought to investigate the mechanism through which paracetamol induces hypothermia in experimental animals. The authors present strong scientific evidence, which demonstrate that the paracetamol-induced hypothermia is mediated through inhibition of the activity of the novel cyclooxygenase (COX) enzyme, COX-3. Further investigations confirm that the paracetamol induced hypothermia is not dependent on interactions with the endocannabinoid or transient receptor potential vanillid-1 (TRPV-1). In addition, co-administration of paracetamol with a cannabinoid agonist resulted in synergistic hypothermia. These data provide a strong rationale for the use of paracetamol along with a cannabinoid agonist for the induction of therapeutic hypothermia in the clinic. Hypothermia is induced for therapeutic purposes in critically ill patients presenting to the clinic with stroke, cardiac arrest or neurotrauma. However, the current approaches used for the induction of therapeutic hypothermia are inefficient, slow and can only be performed in the hospital setting. Most of the neuronal damage takes place during the first hour following the development of critical illness. Having provided evidence on the mechanism of paracetamol-induced hypothermia and the fact that paracetamol and cannabinoid agonists induced synergistic hypothermia, we propose that combination therapy can be translated to the clinic for the induction of therapeutic hypothermia. The advantages that drug-induced therapeutic hypothermia offer over the currently used methods for the induction of therapeutic hypothermia include fact onset of hypothermia; within a few minutes as opposed to 30-60 minutes. This approach offers a cheap and readily available method for the induction of therapeutic hypothermia that has the potential of saving thousands of lives

    Effects of Women's Schooling on Contraceptive Use and Fertility in Tanzania

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    This study explores the economic relationships between women's schooling, fertility rates, and contraceptive use in Tanzania where population growth and fertility rates are among the highest in the world and aggravate the already ailing economy. Two models are used: fertility and contraceptive use. This study covers women ages 15 to 49. Drawing on 1996 data from the Demographic and Health Surveys (DHS), the study finds that women's schooling and other socioeconomic variables are important in explaining reproductive behavior. The fertility model indicates that higher education levels are consistently associated with lower fertility rates. Likewise, the contraceptive use model indicates that more education is positively associated with contraceptive use. Both models show that the relations become stronger with higher levels of schooling. The findings indicate that raising women's education levels improves their economic opportunities, increasing the value of their time and, in turn reducing their desire for large families
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