Nonsteroidal Drugs Research Articles

Adrenocorticotropic hormone: Therapeutic use and effects in nephrotic syndrome

Background: NS is defined by the presence of significant proteinuria, which leads to low levels of albumin in the blood and the development of edema. This occurs as a result of damage to the glomerular filtration barrier. Corticosteroids are the main therapeutic approach for NS. Prolonged usage of steroids can result in numerous side effects, including steroid resistant NS, which poses a difficult challenge for treatment and can cause substantial morbidity and mortality. Although efforts have been made to decrease the use of steroids by employing non-steroidal immunosuppressive drugs for rapid recovery, these treatments have also exhibited adverse consequences. These difficulties have prompted the notion of utilizing ACTH in these situations. Objective: This study seeks to analyze the efficacy of ACTH by thoroughly examining its mechanism and comparing it to conventional treatment for NS. Summary and important messages: The study demonstrates that ACTH has the potential to not only decrease protein loss but also reduce the occurrence of relapses and the amount of glucosteroids required. This suggests that ACTH could be a viable treatment alternative. The exact mechanism is currently unidentified, while the MCR1 agonism linked to ACTH suggest a renoprotective mechanism that is beneficial in NS. A comprehensive analysis using a large-scale randomized controlled trial is necessary to fully comprehend the effectiveness and safety profile of ACTH in improving the quality of care for patients.

Effect of Clomiphene Citrate on Fertility Hormones in Women with Polycystic Ovarian Syndrome

This study aims to investigate the positive effect of Clomiphene Citrate (CC) in inducing ovulation in women with PCOS. Clomiphene Citrate is a non-steroidal drug that primarily affects estrogen production. CC also has pronounced effects on balancing of the female hormones, normal ovulation process, and overcoming the PCOS-based infertility issues. Hormonal profile evaluation including follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, and estrogen was performed at Clinical Laboratory, Services Hospital, Lahore. Serum volume of the aforementioned hormones were determined in PCOS-suffering infertile women (n=50) and healthy fertile women (n=50) by using a commercially available ELISA kit manufactured by Calbotech lnc. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone, and estrogen mean values in PCOS patients before the use of CC were evaluated as 5.74±0.939 (IU/L), 3.804±1.163 (IU/L), 2.098±1.233 (ng/ml), and (51.458±7.091 pg/ml respectively, while after management with CC the mean value of serum LH, FSH, Progesterone, and Estrogen were 3.716±0.513 (IU/L), 5.644±1.130 (IU/L), 10.704±2.313 ng/ml and 37.72±4.969 pg/ml respectively, which indicated a significant differences in hormonal pattern . The current study demonstrates that Clomiphene Citrate (CC) has positive effects in ovulation process in females with polycystic ovarian syndrome (PCOS), within the local population.

Exploring novel Apalutamide analogues as potential therapeutics for prostate cancer: design, molecular docking investigations and molecular dynamics simulation.

Introduction: Prostate cancer (PC) ranks as the second most frequent type of cancer in men and is the fourth largest cause of mortality worldwide. Androgenic hormones such as testosterone and dihydrotestosterone are crucial for the development and progression of the prostate gland. Androgenic hormones bind to androgen receptors (AR) and trigger the synthesis of many genes that stimulate the growth of prostate cells, initiating PC growth. Apalutamide (APL) is a non-steroidal antiandrogen drug used to treat PC; however, it also causes a variety of toxicities and resistance during the treatment. Methods: The purpose of this study was to computationally identify new and safer analogues of APL, focusing on improved pharmacokinetic properties and reduced toxicity. Drug likeness (DL) and drug score (DS) were also calculated. Docking studies on the designed analogues were conducted to predict their binding affinities and compare their orientations with the ligands in the original crystal structure. Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite. Results: We generated a total of 1,415 analogues for different groups of APL using the bioisosteric approach. We selected 80 bioisosteres based on pharmacokinetic profiles, DL and DS score predictions, and found that the designed APL bioisosteres were optimal to good compared to APL. Analogues APL19, APL35, APL43, APL76, and APL80, formed hydrogen bonds with protein (PDB ID: 5T8E) which is similar hydrogen bonding to the standard (APL). The MD simulation result confirmed that APL43 and APL80 complexes were stable during the 100nS run. Discussion: The results suggest that the APL analogues, particularly APL43 and APL80, are predicted to be potential antiandrogen drugs for the treatment of prostate cancer.

Recording of hippocampal activity on the effect of convulsant doses of caffeine

Seizures occur when there is a hyper-excitation of the outer layer of the brain, with subsequent excessive synchrony in a group of neurons. According to the World Health Organization (WHO), an estimated 50 million people are affected by this disease, a third of whom are resistant to the treatments available on the market. Caffeine (1,3,7-trimethylxanthine), which belongs to the purine alkaloid family, is the most widely consumed psychoactive drug in the world. It is ingested by people through drinks containing this substance, such as coffee, and as an adjuvant in analgesic therapy with non-steroidal antiflammatory drugs. The present study evaluated the electrocorticographic changes observed in the hippocampus of Wistar rats subjected to acute doses of caffeine (150 mg/kg i.p), which represents a toxic dose of caffeine corresponding to an estimated acute intake of more than 12 cups of coffee to record its convulsant activity. Our results showed, for the first time, that the administration of high doses of caffeine (150 mg/kg i.p.) in rats caused an increase in the spectral distribution of power in all frequency bands and suggested the appearance of periods of ictal and interictal peaks in the electrocorticogram (ECog). We have also shown that the anticonvulsants phenytoin, diazepam and phenobarbital have a satisfactory response when associated with caffeine.

Therapeutic challenges and unmet needs in the management of myasthenia gravis: an Italian expert opinion.

Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs.

Innovative approach for trace level detection of mefenamic acid by ferrite nanocomposite-based electrochemical sensor

In the present work, the rapid and highly efficient catalyst has been designed for the electrochemical sensing of the non-steroidal drug Mefenamic acid (MFA) for quality control and clinical assessment. Ferrite nanocomposite (SFBF-NC) has been synthesized by sol-gel method from the precursor sodium ferrite and barium ferrite and applied for the electrochemical sensing of MFA. The SFBF-NC was examined by various analytical methods to confirm its coral-like shape with a highly rough and porous structure, cubic/spinal phase crystallinity, and average crystalline size < 60 nm with good stable electronic properties. Due to the large electroactive surface area, fast electron transfer rate, and potent electrocatalytic activity of SFBF-NC, the fabricated SFBF-NC/GCE showed good sensitivity for the quantitative determination of MFA. The proposed sensor showed the limit of detection (LOD) of 2.12 nM with a linear range of 0.01–450 μM for MFA detection. Additionally, the proposed sensor demonstrated excellent catalytic activity, stability, repeatability, and selectivity for MFA sensing and was utilized for the routine analysis of MFA in biological and pharmaceutical samples.

Nefopam as a multimodal analgesia in thoracoscopic surgery: a randomized controlled trial.

Video-assisted thoracoscopic surgery (VATS) is a minimally invasive procedure. However, some patients still experience severe pain after VATS. Pain after VATS can disturb deep breathing and coughing, and can increase postoperative pulmonary complications. Therefore, multidisciplinary pain management is emphasized for enhanced recovery after VATS. Nefopam is a centrally-acting, non-opioid, non-steroidal analgesic drug, and its pain reduction effect in many surgeries has been reported. We sought to determine whether administration of nefopam is effective as multimodal analgesia in VATS. This study enrolled patients aged 19 years or older, and scheduled for elective VATS lobectomy with American Society of Anesthesiologists (ASA) physical class I-III. Forty-six participants were randomly divided into a group receiving nefopam (group N), and a control group (group O) in a 1:1 ratio. The study participants, and the researcher collecting the data were blinded to the group allocation. For the group N, nefopam 20 mg was administered before surgical incision and also at the end of surgery while chest tube was inserted. For the group O, normal saline 100 mL was administered. The primary outcome of this study was the pain score, by verbal numerical rating scale, at rest and upon coughing. Forty-five participants (group N =22, group O =23) were involved in the statistical analysis. Nefopam reduced pain at rest at 0 h [8 (IQR, 5-10) vs. 4 (IQR, 2-7), P=0.01], and at 0-1 h [5 (IQR, 5-8) vs. 3 (IQR, 2-5), P=0.001]. Pain upon coughing decreased with nefopam at 0 h [9 (IQR, 6-10) vs. 6 (IQR, 2-8), P=0.009], 0-1 h [6 (IQR, 5-8) vs. 5 (IQR, 2-6), P=0.001], and at 12-24 h [4 (IQR, 3-7) vs. 3 (IQR, 1-4), P=0.03]. Injection of 20 mg of nefopam before incision and at the end of surgery relieved postoperative pain at 0 h, 1 h at rest and at 0 h, 1 h, 12-24 h with coughing after VATS. Therefore, nefopam can serve as a useful component of multimodal analgesia for pain management after VATS. ClinicalTrials.gov (NCT05173337).

Biotransformation of anabolic drug Dianabol with Rizhopus oryzae

Microbial biotransformation technique is an excellent approach for the synthesis of stereo-, enantio-, chemo-, and regio-selective/specific analogues of existing steroidal and non-steroidal drugs by using bacteria, fungi, algae, actinomycetes, yeast, and plants and animals cell cultures. This technique is effectively used to synthesize compounds whose structures resemble to the substrates (parent drugs) without using protecting/deprotecting steps. In the current study, an anabolic-androgenic steroid (AAS) based drug, methandienone (dianabol) (1) was incubated with the filamentous fungi Rhizopus oryzae ATCC 11145 for twelve days under ambient reaction conditions (at room temperature and neutral pH) by using aqueous media. Therefore, the present study has successfully helped to produce the structural analogues of inert steroidal anabolic drug dianabol (1) without using expensive and toxic chemicals. This yielded five known structural analogues of dianabol (1), i.e., 17β,11β-dihydroxy,17α-methyl-androsta-1,4-diene-3-one (2), 17β-hydroxy,17α-methyl-androsta-1,4-diene-3,11-dione (3), 17β,6β-dihydroxy,17α-methyl-androsta-1,4-diene-3-one (4), 17β,6β-dihydroxy,17α-methyl-androsta-4-ene-3-one (5), and 17β-hydroxy,17α-methyl-androsta-4,6-diene-3-one (6). Structures of transformed products 2-6 were determined through 1H-NMR, and FAB-MS spectroscopic techniques.

Harnessing immunity: Immunomodulatory therapies in COVID-19.

An overly exuberant immune response, characterized by a cytokine storm and uncontrolled inflammation, has been identified as a significant driver of severe coronavirus disease 2019 (COVID-19) cases. Consequently, deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation. With these delicate dynamics in mind, immunomodulatory therapies have emerged as a promising avenue for mitigating the challenges posed by COVID-19. Precision in manipulating immune pathways presents an opportunity to alter the host response, optimizing antiviral defenses while curbing deleterious inflammation. This review article comprehensively analyzes immunomodulatory interventions in managing COVID-19. We explore diverse approaches to mitigating the hyperactive immune response and its impact, from corticosteroids and non-steroidal drugs to targeted biologics, including anti-viral drugs, cytokine inhibitors, JAK inhibitors, convalescent plasma, monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2, cell-based therapies (i.e., CAR T, etc.). By summarizing the current evidence, we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.

CO44 Exploring the Impact of Non-Steroidal Immunosuppressive Drugs and Steroids on the Development of Comorbidities in Patients With Myasthenia Gravis in the National Veterans Affairs Health Network

CO44 Exploring the Impact of Non-Steroidal Immunosuppressive Drugs and Steroids on the Development of Comorbidities in Patients With Myasthenia Gravis in the National Veterans Affairs Health Network

Ag/Fe3O4 bifunctional nanocomposite for SERS detection of non-steroidal anti-inflammation drug diclofenac

In this work, a bifunctional nanocomposite based on silver and iron oxide nanoparticles (AgNPs/Fe3O4) was prepared and then used as SERS substrate (surface-enhanced Raman spectroscopy) for sensing diclofenac which is one of the most widely used non-steroid anti-inflammation drugs. AgNPs/Fe3O4 nanocomposite was synthesized by combining co-precipitation of iron oxide and in-situ reduction of silver nanoparticles. Morphology and structural studies revealed a conjugated structure in which silver nanoparticles (80 nm in diameter) were surrounded by iron oxide nanoparticles (18 nm in diameter). There is a slight blue-shift in position of plasmon peak from 405 nm for silver nanoparticles to 375 nm for AgNPs/Fe3O4 nanocomposite. Even the saturation magnetization (Ms) of the Ag/Fe3O4 nanocomposite only reached 28 emu.g-1 but still good enough for immobilizing nanocomposite structures onto the substrate. The use of AgNPs/Fe3O4 nanocomposite as SERS substrate for sensing application was demonstrated with using diclofenac as a model. The detection limit and enhancement factor of the SERS-based diclofenac sensor were found to be 10-12 M and 2.6×1010, respectively. Such kind of bifunctional nanocomposite will probably help us to avoid time-consuming process to immobilize metal nanoparticles onto the surface, and also allow us to regenerate the substrate for multiple uses.

Head-to-head studies on radiographic progression in axial spondyloarthritis

In this review article four clinical comparative studies in axial spondylarthritis (axSpA) are presented and discussed. SURPASS as the only head-to-head study investigated the effect of adalimumab biosimilar disease-modifying antirheumatic drug (bsDMARD) or secukinumab on radiographic progression over a time period of 2 years. Overall, the radiographic progression of the spine was low and no significant difference between adalimumab bsDMARD or secukinumab was noted. The three other studies were not constructed as direct head-to-head studies but compared the efficacy of non-steroidal antirheumatic drugs (NSARD) with and without simultaneous treatment with biological DMARDs (bDMARD). The CONSUL study showed no statistically significant difference in the delay of radiographic progression of the spine over 2 years in radiographic axSpA (r-axSpA) patients, who underwent either combined treatment with golimumab and celecoxib or treatment with golimumab alone over 2 years. The ESTHER study showed that patients with early axSpA active inflammatory lesions, which were detected by whole-body magnetic resonance imaging (MRI), showed a significantly greater improvement under treatment with etanercept than those treated with sulfasalazine. The INFAST study showed that patients with early active axSpA who received a combined treatment of infliximab and naproxen, achieved a clinical remission twice as frequently as those who only received naproxen. Therefore, for the endpoint of radiological progression no difference could be shown in the inhibition of radiological progression between the mechanisms of action investigated. The comparative data for the endpoint of clinical efficacy showed that patients with bDMARDs showed a clearly better response to treatment than patients with NSAR or conventional synthetic DMARDs (csDMARD).

Estimating physico-chemical properties of drugs for prostate cancer using degree-based and neighbourhood degree-based topological descriptors

Prostate cancer is one of the most alarming diseases among men and leads to various illnesses. The main flaw in this disease is that there is not a single test that can find it. Prostate-specific antigens and prostate biopsies are used to identify this type of cancer. Many pharmaceutical industries do active research to identify non-steroidal drugs that can be used to treat prostate cancer effectively. QSPR analysis is one of the best practices that aid scientists in getting a deep insight into the physico-chemical properties of drugs without actually performing experiments in a wet lab, thereby cutting down on the cost of manufacturing such drugs. In this article, we perform a QSPR analysis of nineteen drugs primarily used to treat prostate cancer by using a set of ten degree-based indices and another set of ten novel neighbourhood-degree-based indices. In addition, we have done a comparative study of the findings obtained through these two different sets of indices over thirteen physico-chemical properties of prostate cancer drugs.

Drug-Related Problems and Recommendations Made during Home Medicines Reviews for Sick Day Medication Management in Australia.

Backgrounds and Objectives: Using certain medications during an intercurrent illness can increase the risk of drug related problems (DRP) occurring such as acute kidney injury (AKI). Medications that increase this risk include sulfonylureas, angiotensin converting enzyme inhibitors, diuretics, metformin, angiotensin receptor blockers, non-steroidal anti-inflammatories drugs, and sodium glucose co-transporter 2 inhibitors (SADMANS). Sick day medication guidance (SDMG) recommends withholding SADMANS medications during an intercurrent illness where adequate fluid intake cannot be maintained. But uptake of these recommendations is poor, and it is not known whether Australian pharmacists currently provide these recommendations during home medicine reviews (HMR) as per SDMG. We aimed to gain an understanding of the characteristics of DRP identified by pharmacists during HMR, especially those relating to SADMANS medications. Materials and Methods: We conducted a retrospective audit of 201 randomly selected HMR reports, conducted by accredited pharmacists from 2020 to 2022, that were analysed in 2023. All DRP and recommendations were categorised using a modified DOCUMENT system. Results: Overall, over 98% of participants experienced a DRP and a total of 710 DRP were found, where participants experienced an average of 4.0 ± 2.0 DRP each. Non-SADMANS medications accounted for 83.1% of all DRPs, with nervous system medications contributing the most. Common problems seen in non-SADMANS medications were related to toxicity, over/underdosing and undertreating. Diuretics contributed most to DRP in SADMANS medications. Problems with SADMANS were mainly related to toxicity and contraindications. No pharmacists provided SDMG despite 71.1% of participants using at least one SADMANS medication. Conclusions: We conclude that DRP remain prevalent in community pharmacy settings. Sick day recommendations were not provided in the HMRs included in our study, possibly due to lack of pharmacist knowledge and awareness. To ensure best practice, more research should be conducted to determine pharmacists' knowledge of and barriers to provision of sick day recommendations.

Sophorin mitigates flutamide-induced hepatotoxicity in wistar rats

Flutamide is frequently used in the management of prostate cancer, hirsutism, and acne. It is a non-steroidal anti-androgenic drug and causes hepatotoxicity. The current study's objective is to evaluate sophorin's hepatoprotective effectiveness against flutamide-induced hepatotoxicity in Wistar rats. Sophorin is a citrus flavonoid glycoside, also known as rutin, which is a low molecular weight polyphenolic compound with natural antioxidant properties and reported to have promising hepatoprotective efficacy. In this study, sophorin was used at a dose of 100 mg/kg body weight in purified water via oral route for 4 week daily whereas, flutamide was used at a dose of 100 mg kg/b.wt for 4 weeks daily in 0.5% carboxy methyl cellulose (CMC) through the oral route for the induction of hepatotoxicity. Flutamide administration leads to enhanced reactive oxygen species (ROS) generation, an imbalance in redox homeostasis and peroxidation of lipid resulted in reduced natural antioxidant level in liver tissue. Our result demonstrated that sophorin significantly abrogate flutamide induced lipid peroxidation, protein carbonyl (PC), and also significantly increasesed in enzymatic activity/level of tissue natural antioxidant such as reduced glutathione(GSH), glutathione reductase(GR), catalase, and superoxide dismutase(SOD). Additionally, sophorin reduced the activity of cytochrome P450 3A1 in liver tissue which was elevated due to flutamide treatment. Furthermore, sophorin treatment significantly decreased the pro-inflammatory cytokines (TNF-α and IL-6) level. Immunohistochemical analysis for the expression of inflammatory proteins (iNOS and COX-2) in hepatic tissue was decreased after sophorin treatment against flutamide-induced hepatotoxicity. Moreover, sophorin suppressed the infiltration of mast cells in liver tissue which further showed anti-inflammatory potential of sophorin. Our histological investigation further demonstrated sophorin's hepatoprotective function by restoring the typical histology of the liver. Based on the aforementioned information, we are able to come to the conclusion that sophorin supplementation might benefit wistar rats with flutamide-induced hepatic damage by reducing oxidative stress and hepatocellular inflammation.

Prevalence of geriatric impairments and frailty categorization among real-world patients with multiple myeloma: a prospective cohort study (MFRAIL)

There is limited knowledge regarding the prevalence of geriatric impairments and frailty among patients with multiple myeloma (MM) in a real-world setting. This study evaluated the distribution of frailty profiles among 116 patients with newly diagnosed or relapsed MM, using four common frailty scales. The proportion of patients classified as frail varied significantly, ranging from 15.5% to 56.9%, due to differences in how frailty was operationalized between each frailty measure. Functional, cognitive, and mobility impairments were common overall and irrespective of performance status. Analyses between frailty and treatment selection (dose reduction and doublet vs. triplet therapy) demonstrated significant differences in non-steroid MM drug dose reductions between frail vs. non-frail patients, as scored by the International Myeloma Working Group (IMWG) Frailty Index and Simplified Frailty Score (p < .05). A standardized approach to frailty assessment that is practical in application, and beneficial in guiding treatment selection and minimizing treatment related toxicity is necessary to provide optimal tailored care.

Analysis of Diclofenac Sodium in Traditional Medicine (Jamu) for Rheumatism in Banjarmasin using TLC-UV-Vis Spectrophotometric Method

Jamu is one of Indonesia's most consumed traditional medicines. The government has clearly stated that traditional medicines are strictly prohibited from containing chemicals, both isolated and synthetic. Diclofenac sodium is one of the Non-Steroid Anti Inflammation Drug (NSAID) class drugs that have an effect as a pain reliever and anti-inflammatory, which is also often misused in traditional medicine preparations. The purpose of this study is to determine whether there is a chemical content of diclofenac sodium contained in the preparation of jamu pegal linu circulating in Banjarmasin using thin-layer chromatography (TLC) and to determine whether the validation of the method using a UV-Vis spectrophotometer meets the established requirements. The results of qualitative analysis using thin-layer chromatography showed that 4 out of 7 samples identified positively contained diclofenac sodium with an Rf value of 0.825. The results of quantitative testing using a UV-Vis spectrophotometer showed the acquisition of an r-value of 0.9996, %RSD of 0.97%, % recovery of 95.28%, 92.82%, and 95.48% for the addition of standard solutions of 10 ppm, 15 ppm, and 20 ppm, as well as LOD &amp; LOQ values of 1.1625 ppm and 3.8750 ppm. Based on the analysis results, it can be stated that 4 out of 7 samples of jamu pegal linu circulating in the Banjarmasin area are positive for diclofenac sodium with levels ranging from 10.257 - 18.465 mg/g (1.026% - 1.846%).

The peri / postoperative analgesic effect of intravenous paracetamol in dogs

PICO Question In healthy dogs undergoing a surgical procedure, is there improved pain control in dogs receiving intravenous paracetamol in the peri / postoperative period compared to dogs not receiving intravenous paracetamol? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed Three randomised, controlled, and blinded studies. Two studies directly address the PICO question whereby postoperative pain assessment was clinically evaluated following intravenous (IV) paracetamol. The third study addressed the question to a lesser extent, whereby the impact on the sevoflurane minimum alveolar concentration (MAC) reduction in response to noxious stimuli was assessed following the administration of IV paracetamol. Strength of evidence Weak. Outcomes reported The findings of the first two studies presented appear to directly contradict each other. The first study demonstrated a reduction in pain in all groups and found no differences in analgesia between IV paracetamol and other non-steroidal anti-inflammatories drugs (NSAIDs), while the second study reported no analgesia effects from IV paracetamol and was terminated prematurely because a high number of dogs required rescue analgesia. The first study reported sufficient analgesic effects of IV paracetamol and the second study reported no analgesia effects of IV paracetamol. Both were blinded, randomised, controlled studies and directly addressed the PICO question in relation to the peri / postoperative analgesic effects of IV paracetamol. However, their methods and sample sizes were very different. The third study did not demonstrate a clinically relevant sevoflurane MAC reduction after IV paracetamol in dogs. Conclusion At present, there is limited and weak evidence to suggest that IV paracetamol provides peri / postoperative analgesia in dogs. However, further studies are required to better assess its efficacy, its duration of action, and the appropriate doses that are necessary to reach therapeutic plasma levels. The reduced incidence of side effects at the currently recommended doses could support its peri / postoperative use, where NSAIDs use is contraindicated. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Early versus late caffeine and/or non-steroidal anti-inflammatory drugs (NSAIDS) for prevention of intermittent hypoxia-induced neuroinflammation in the neonatal rat.

Preterm infants often experience frequent intermittent hypoxia (IH) episodes which are associated with neuroinflammation. We tested the hypotheses that early caffeine and/or non-steroidal inflammatory drugs (NSAIDs) confer superior therapeutic benefits for protection against IH-induced neuroinflammation than late treatment. Newborn rats were exposed to IH or hyperoxia (50% O2) from birth (P0) to P14. For early treatment, the pups were administered: 1) daily caffeine (Caff) citrate (Cafcit, 20 mg/kg IP loading on P0, followed by 5mg/kg from P1-P14); 2) ketorolac (Keto) topical ocular solution in both eyes from P0 to P14; 3) ibuprofen (Ibu, Neoprofen, 10mg/kg loading dose on P0 followed by 5mg/kg/day on P1 and P2); 4) Caff+Keto co-treatment; 5) Caff+Ibu co-treatment; or 6) equivalent volume saline (Sal). On P14, animals were placed in room air (RA) with no further treatment until P21. For late treatment, pups were exposed from P0 to P14, then placed in RA during which they received similar treatments from P15-P21 (Sal, Caff, and/or Keto), or P15-P17 (Ibu). RA controls were similarly treated. At P21, whole brains were assessed for histopathology, apoptosis, myelination, and biomarkers of inflammation. IH caused significant brain injury and hemorrhage, inflammation, reduced myelination, and apoptosis. Early treatment with Caff alone or in combination with NSAIDs conferred better neuroprotection against IH-induced damage than late treatment. Early postnatal treatment during a critical time of brain development, may be preferable for the prevention of IH-induced brain injury in preterm infants.

Abstract TP312: Pharmacologically Reducing Acetylated Tau Prevents Traumatic Brain Injury-Induced Acceleration of Alzheimer’s Disease

Traumatic brain injury (TBI) afflicts 70 million people worldwide annually and is the 3rd overall risk factor for developing Alzheimer's disease (AD), behind genetics and aging. In patients with AD, a history of TBI is associated with a 3-4 year earlier onset of cognitive impairment. TBI and AD share many pathologies, including blood brain barrier dysfunction, neuroinflammation, and protein aggregation. Yet, the underlying mechanism of this relationship is not understood, and there are no treatments that protect patients from accelerated AD after TBI. We recently reported that tau, a microtubule binding protein essential for neuronal health, is acetylated after TBI. Acetylation impairs tau binding to microtubules, leading to its mis-localization into the cell soma and pathological aggregation. Acetylated tau is also elevated early in AD, and acetylated tau was significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesize that TBI-induced tau acetylation drives the acceleration of AD. To study this phenomenon, we developed a mouse model of TBI that accelerates AD-like pathology and cognitive impairment in 5xFAD mice, and amyloid-driven AD model. Our unique model of multimodal TBI produces a complex and reproducible brain injury with neurodegeneration and neurobehavioral impairment, beginning with acute axonal degeneration and persisting chronically with blood-brain barrier degradation and nerve cell death. This model of TBI also produces the same systemic metabolic alterations that are reported in TBI patients. TBI causes learning deficits in young 5xFAD mice that are not seen in either sham-injured 5xFAD mice or in wild type littermates subjected to TBI. TBI also accelerates amyloid deposition in 5xFAD mice. We hypothesize that TBI will also worsen blood brain barrier function in 5xFAD mice. Importantly, 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Preliminary data suggests that treatment with the FDA-approved non-steroidal inflammatory drug diflunisal, which inhibits the enzyme that acetylates tau, reduces acetylated tau and rescues behavior deficits after TBI in 5xFAD mice.