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1.
Toxicon X ; 23: 100204, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39280983

RESUMEN

Snakebite is a major global health concern, for which antivenom remains the only approved treatment to neutralise the harmful effects of the toxins. However, some medically important toxins are poorly immunogenic, resulting in reduced efficacy of the final product. Boosting the immunogenicity of these toxins in the commercial antivenom immunising mixtures could be an effective strategy to improve the final dose efficacy, and displaying snake antigens on Virus-like particles (VLPs) is one method for this. However, despite some applications in the field of snakebite, VLPs have yet to be explored in methods that could be practical at an antivenom manufacturing scale. Here we describe the utilisation of a "plug and play" VLP system to display immunogenic linear peptide epitopes from three finger toxins (3FTxs) and generate anti-toxin antibodies. Rabbits were immunised with VLPs displaying individual consensus linear epitopes and their antibody responses were characterised by immunoassay. Of the three experimental consensus sequences, two produced antibodies capable of recognising the consensus peptides, whilst only one of these could also recognise native whole toxins. Further characterisation of antibodies raised against this peptide demonstrated a sub-class specific response, and that these were able to elicit partially neutralising antibody responses, resulting in increased survival times in a murine snakebite envenoming model.

2.
Arch Microbiol ; 206(9): 366, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39098983

RESUMEN

Kombucha, a fermented tea beverage, has seen a significant rise in global popularity. This increase is attributed to its reported health benefits and extensive cultural heritage. The comprehensive review examines kombucha through microbiology, biochemistry, and health sciences, highlighting its therapeutic potential and commercial viability. Central to kombucha production is the symbiotic culture of bacteria and yeasts (SCOBY), which regulates a complex fermentation process, resulting in a bioactive-rich elixir. The study examines the microbial dynamics of SCOBY, emphasizing the roles of various microorganisms. It focuses the contributions of acetic acid bacteria, lactic acid bacteria, and osmophilic yeasts, including genera such as Saccharomyces, Schizosaccharomyces, Zygosaccharomyces, Brettanomyces/Dekkera, and Pichia. These microorganisms play crucial roles in producing bioactive compounds, including organic acids, polyphenols, and vitamins. These bioactive compounds confer therapeutic properties to kombucha. These properties include antioxidant, antimicrobial, anti-inflammatory, antidiabetic, antihypertensive, cancer prevention, hepatoprotective, and detoxifying effects. The review also explores the growing market for kombucha, driven by consumer demand for functional beverages and opportunities for innovative product development. It emphasizes the necessity of standardized production to ensure safety and validate health claims. Identifying research gaps, the review highlights the importance of clinical trials to verify therapeutic benefits. Ultimately, this study integrates traditional knowledge with scientific research, providing directions for future studies and commercial expansion, emphasizing the role of kombucha in health and wellness.


Asunto(s)
Fermentación , Té de Kombucha , Humanos , Té de Kombucha/microbiología , Levaduras/metabolismo , Levaduras/genética , Bacterias/metabolismo , Bacterias/genética
3.
Mol Divers ; 2024 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-38796796

RESUMEN

In the realm of synthetic organic chemistry, by using a one-pot sequential combination of MCR, it is possible to manufacture chemical commodities (fine chemicals, agrochemicals, and pharmaceutical substances) that enhance our quality of life while generating less waste materials and increasing economic advantages. With this motivation, using a "one-pot" method with multiple components, we present a relatively simple way to make stereoselective substitute 2H-indazole analogues for this study. Firstly, functionalised 3-bromo-4-((methylthio)methyl) derivatives were produced using DMSO as both a carbon source and a solvent, in conjunction with TMSOTf as the Lewis acid promoter. These derivatives were then utilised in the synthesis of 2-H-indazole derivatives with an up to 80% yield using t-Bu3PHBF4 as the ligand and Cs2CO3 as the base, in the presence of a Pd catalyst at 100°C in an airtight tube. The phenyl ring is endowed with an electron-releasing group situated at position C-6, which efficiently synthesises several 2-H-indazol derivatives with cost-efficient and noteworthy yields by using this method. A comparative analysis of a number of halogen derivatives was also undertaken, using a variety of solvents that were classified according to their halogen group. To confirm the structures of the synthesised target compounds, spectrometric analysis (1H NMR, 13C NMR, and LCMS) was performed.

5.
Nat Cell Biol ; 26(4): 613-627, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38429478

RESUMEN

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.


Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Pancreáticas , Animales , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Línea Celular Tumoral , Acetatos/farmacología , Acetatos/metabolismo , Neoplasias Pancreáticas/genética , Poliaminas , Microambiente Tumoral
6.
Microvasc Res ; 153: 104667, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38307406

RESUMEN

Extracellular signal-regulated kinase (Erk)-5 is a key mediator of endothelial cell homeostasis, and its inhibition causes loss of critical endothelial markers leading to endothelial dysfunction (ED). Circulating oxidized low-density lipoprotein (oxLDL) has been identified as an underlying cause of ED and atherosclerosis in metabolic disorders. Silymarin (Sym), a flavonolignan, possesses various pharmacological activities however its preventive mechanism in ED warrants further investigation. Here, we have examined the effects of Sym in regulating the expression of Erk-5 and ameliorating ED using in vitro and in vivo models. Primary human umbilical vein endothelial cells (pHUVECs) viability was measured by MTT assay; mRNA and protein expression by RT-qPCR and Western blotting; tube-formation assay was performed to examine endothelialness. In in-vivo experiments, normal chow-fed mice (control) or high-fat diet (HFD)-fed mice were administered Sym or Erk-5 inhibitor (BIX02189) and body weight, blood glucose, plasma-LDL, oxLDL levels, and expression of EC markers in the aorta were examined. Sym (5 µg/ml) maintained the viability and tube-formation ability of oxLDL exposed pHUVECs. Sym increased the expression of Erk-5, vWF, and eNOS and decreased ICAM-1 at transcription and translation levels in oxLDL-exposed pHUVECs. In HFD-fed mice, Sym reduced the body weight, blood glucose, LDL-cholesterol, and oxLDL levels, and increased the levels of vWF and eNOS along with Erk-5 and decreased the level of ICAM-1 in the aorta. These data suggest that Sym could be a potent anti-atherosclerotic agent that could elevate Erk-5 level in the ECs and prevent ED caused by oxidized LDL during HFD-induced obesity in mice.


Asunto(s)
Aterosclerosis , Silimarina , Humanos , Animales , Ratones , Molécula 1 de Adhesión Intercelular , Transducción de Señal , Células Cultivadas , Silimarina/efectos adversos , Glucemia , Factor de von Willebrand , Lipoproteínas LDL/toxicidad , Lipoproteínas LDL/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Aterosclerosis/inducido químicamente , Peso Corporal
7.
Sci Transl Med ; 16(735): eadk1867, 2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38381847

RESUMEN

Snakebite envenoming is a major global public health concern for which improved therapies are urgently needed. The antigenic diversity present in snake venom toxins from various species presents a considerable challenge to the development of a universal antivenom. Here, we used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins produced by numerous medically relevant snakes. Our antibody bound diverse toxin variants with high affinity, blocked toxin binding to the nicotinic acetylcholine receptor in vitro, and protected mice from lethal venom challenge. Structural analysis of the antibody-toxin complex revealed a binding mode that mimics the receptor-toxin interaction. The overall workflow presented is generalizable for the development of antibodies that target conserved epitopes among antigenically diverse targets, and it offers a promising framework for the creation of a monoclonal antibody-based universal antivenom to treat snakebite envenoming.


Asunto(s)
Antivenenos , Mordeduras de Serpientes , Humanos , Animales , Ratones , Antivenenos/química , Mordeduras de Serpientes/tratamiento farmacológico , Neurotoxinas/toxicidad , Anticuerpos ampliamente neutralizantes , Venenos de Serpiente
8.
Diagn Microbiol Infect Dis ; 109(1): 116212, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38387214

RESUMEN

Pseudomonas aeruginosa, one of the most notorious organisms, causes fatal diseases like-, meningitis, pneumonia as well as worsens the prognosis of cystic fibrosis patients. It is also multi-drug resistant and resists a wide range of antibiotics. Attempts have been made to reduce its virulence/pathogenic potential using a number of organic compounds. For this purpose, the Quorum sensing (QS) system of P. aeruginosa was targeted, which regulates its virulence. Pseudomonas Quinolone System (PQS), one of the four quorum sensing systems, producing pyocyanin pigment was chosen. 2-heptyl-3-hydroxy-4-quinolone (HHQ) is a ligand which binds to PQS protein is responsible for pyocyanin pigment production. Attempts were made to find a compound analogous to HHQ which could bind to PQS active site and inhibit the pigment formation. In-silico analysis was performed to estimate possible interactions and to find/predict the possible PQS inhibitors.


Asunto(s)
Infecciones por Pseudomonas , Quinolonas , Humanos , Percepción de Quorum/fisiología , Pseudomonas aeruginosa/metabolismo , Pseudomonas/metabolismo , Piocianina/metabolismo , Quinolonas/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Proteínas Bacterianas/metabolismo
9.
Sci Rep ; 13(1): 21662, 2023 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-38066189

RESUMEN

Snakebite envenoming is a global public health issue that causes significant morbidity and mortality, particularly in low-income regions of the world. The clinical manifestations of envenomings vary depending on the snake's venom, with paralysis, haemorrhage, and necrosis being the most common and medically relevant effects. To assess the efficacy of antivenoms against dermonecrosis, a preclinical testing approach involves in vivo mouse models that mimic local tissue effects of cytotoxic snakebites in humans. However, current methods for assessing necrosis severity are time-consuming and susceptible to human error. To address this, we present the Venom Induced Dermonecrosis Analysis tooL (VIDAL), a machine-learning-guided image-based solution that can automatically identify dermonecrotic lesions in mice, adjust for lighting biases, scale the image, extract lesion area and discolouration, and calculate the severity of dermonecrosis. We also introduce a new unit, the dermonecrotic unit (DnU), to better capture the complexity of dermonecrosis severity. Our tool is comparable to the performance of state-of-the-art histopathological analysis, making it an accessible, accurate, and reproducible method for assessing dermonecrosis in mice. Given the urgent need to address the neglected tropical disease that is snakebite, high-throughput technologies such as VIDAL are crucial in developing and validating new and existing therapeutics for this debilitating disease.


Asunto(s)
Mordeduras de Serpientes , Ponzoñas , Humanos , Ratones , Animales , Mordeduras de Serpientes/terapia , Antivenenos/farmacología , Salud Global , Necrosis
10.
Expert Opin Drug Deliv ; 20(12): 1839-1857, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38100459

RESUMEN

INTRODUCTION: The efficiency of brain therapeutics is greatly hindered by the blood-brain barrier (BBB). BBB's protective function, selective permeability, and dynamic functionality maintain the harmony between the brain and peripheral region. Thus, the design of any novel drug carrier system requires the complete study and investigation of BBB permeability, efflux transport, and the effect of associated cellular and non-vascular unit trafficking on BBB penetrability. The in vitro BBB models offer a most promising, and reliable mode of initial investigation of BBB permeability and associated factors as strong evidence for further preclinical and clinical investigation. AREA COVERED: This review work covers the structure and functions of BBB components and different types of in vitro BBB models along with factors affecting BBB model development and model selection criteria. EXPERT OPINION: In vivo models assume to reciprocate the physiological environment to the maximum extent. However, the interspecies variability, NVUs trafficking, dynamic behavior of BBB, etc., lead to non-reproducible results. The in vitro models are comparatively less complex, and flexible, as per the study design, could generate substantial evidence and help identify suitable in vivo animal model selection.


Asunto(s)
Barrera Hematoencefálica , Encéfalo , Animales , Transporte Biológico , Células Endoteliales , Permeabilidad
11.
Sci Rep ; 13(1): 19066, 2023 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-37925515

RESUMEN

Antibiotics are chemical compounds that are used to treat and prevent disease in humans and animals. They have been used in animal feed for over 60 years and are widely used in industrial farming. Antibiotics can have negative environmental impacts, including the potential to contribute to the development of antibiotic-resistant organisms. They can enter the environment through various pathways, including the manufacturing process, the direct application of antibiotic-laden manure to fields, and through grazing animals. Antibiotics that are given to animals can be excreted from where they can enter soil and groundwater which enable their entry in plants. Streptomycin is an antibiotic that is used against a range of gram-positive and gram-negative bacteria, but its use has led to the development of antibiotic resistance in some pathogens. It has also been shown to have negative impacts on a range of plant species, including tobacco, tomato, and wheat. Although, the major effect of streptomycin on plant physiology have been studied, the molecular mechanisms at play are barely understood in plant body. In current study, we examined the impact of streptomycin on germination of Brassica napus and then using docking, MM-GBBSA and MD simulations identified key proteins that interact with streptomycin by performing rigorous computational screening of 106 different proteins. Our finding suggest that streptomycin might be interacting with acyl-CoA oxidases, protochlorophyllide reductase B and leucoanthocyanidin dioxygenase based on simulation and docking analysis.


Asunto(s)
Brassica napus , Estreptomicina , Humanos , Animales , Estreptomicina/farmacología , Antibacterianos/farmacología , Simulación de Dinámica Molecular , Bacterias Gramnegativas , Bacterias Grampositivas
12.
J Neuroimmunol ; 384: 578197, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37770354

RESUMEN

In this study, we examined CD4 T cell activation using various stimuli in pediatric MOGAD patients (n = 4, untreated remission samples) and healthy controls (n = 5), to understand how both antigen-specific and bystander mechanisms contribute to CD4 T cell activation in MOGAD. TNFα, IL6, and MOG peptide pool were found to activate NF-κB or STAT3 pathways by measuring the expression of regulators (A20, IκBα) and phosphorylated subunits (phospho-p65 and phospho-STAT3) using immunolabeling. Prednisolone reversed activation of both NF-κB and STAT3 and increased the expression of A20 and IκBα. TNFR blocking partially reversed NF-κB activation in certain CD4 T cell subsets, but did not effect STAT3 activation. We observed that activation of NF-κB and STAT3 in response to various stimuli behaves mostly same in MOGAD (remission) and HC. IL6 stimulation resulted in higher STAT3 phosphorylation in MOGAD patients at 75 min, specifically in central and effector memory CD4 T cells (with unadjusted p-values). These findings suggest the potential therapeutic targeting of NF-κB and STAT3 pathways in MOGAD. Further investigation is needed to validate the significance of extended STAT3 phosphorylation and its correlation with IL6 receptor blocker treatment response.


Asunto(s)
Interleucina-6 , FN-kappa B , Niño , Humanos , Anticuerpos , Linfocitos T CD4-Positivos/metabolismo , Interleucina-6/metabolismo , FN-kappa B/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Factor de Transcripción STAT3
13.
Biochem Pharmacol ; 216: 115758, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37604290

RESUMEN

Snakebite envenoming is a neglected tropical disease that causes over 100,000 deaths annually. Envenomings result in variable pathologies, but systemic neurotoxicity is among the most serious and is currently only treated with difficult to access and variably efficacious commercial antivenoms. Venom-induced neurotoxicity is often caused by α-neurotoxins antagonising the muscle-type nicotinic acetylcholine receptor (nAChR), a ligand-gated ion channel. Discovery of therapeutics targeting α-neurotoxins is hampered by relying on binding assays that do not reveal restoration of receptor activity or more costly and/or lower throughput electrophysiology-based approaches. Here, we report the validation of a screening assay for nAChR activation using immortalised TE671 cells expressing the γ-subunit containing muscle-type nAChR and a fluorescent dye that reports changes in cell membrane potential. Assay validation using traditional nAChR agonists and antagonists, which either activate or block ion fluxes, was consistent with previous studies. We then characterised antagonism of the nAChR by a variety of elapid snake venoms that cause muscle paralysis in snakebite victims, before defining the toxin-inhibiting activities of commercial antivenoms, and new types of snakebite therapeutic candidates, namely monoclonal antibodies, decoy receptors, and small molecules. Our findings show robust evidence of assay uniformity across 96-well plates and highlight the amenability of this approach for the future discovery of new snakebite therapeutics via screening campaigns. The described assay therefore represents a useful first-step approach for identifying α-neurotoxins and their inhibitors in the context of snakebite envenoming, and it should provide wider value for studying modulators of nAChR activity from other sources.


Asunto(s)
Receptores Nicotínicos , Mordeduras de Serpientes , Humanos , Receptores Nicotínicos/metabolismo , Neurotoxinas/toxicidad , Neurotoxinas/química , Mordeduras de Serpientes/tratamiento farmacológico , Antivenenos/farmacología , Venenos Elapídicos/química , Músculos/metabolismo
14.
J Neuroinflammation ; 20(1): 131, 2023 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-37254147

RESUMEN

BACKGROUND: Multiple sclerosis (MS) is a disabling autoimmune demyelinating disorder affecting young people and causing significant disability. In the last decade, different microRNA (miRNA) expression patterns have been associated to several treatment response therapies such as interferon and glatiramer acetate. Nowadays, there is increasing interest in the potential role of miRNA as treatment response biomarkers to the most recent oral and intravenous treatments. In this study, we aimed to evaluate serum miRNAs as biomarkers of No Evidence of Disease Activity (NEDA-3) at 2 years in patients with relapsing remitting MS (RRMS) treated with fingolimod. MAIN BODY: A Discovery cohort of 31 RRMS patients treated with fingolimod were identified from the CLIMB study and classified as No Evidence of Disease Activity (NEDA-3) or Evidence of Disease Activity (EDA-3) after 2 years on treatment. Levels of miRNA expression were measured at 6 months using human serum miRNA panels and compared in EDA-3 and NEDA-3 groups using the Wilcoxon rank sum test. A set of differentially expressed miRNA was further validated in an independent cohort of 22 fingolimod-treated patients. We found that 548a-3p serum levels were higher levels in fingolimod-treated patients classified as NEDA-3, compared to the EDA-3 group in both the Discovery (n = 31; p = 0.04) and Validation (n = 22; p = 0.03) cohorts 6 months after treatment initiation; miR-548a-3p provided an AUC of 0.882 discriminating patients with NEDA-3 at 2 years in the Validation cohort. CONCLUSION: Our results show differences in miR-548a-3p expression at 6 months after fingolimod start in patients with MS with NEDA-3 at 2 years. These results provide class III evidence of the use of miR-548a-3p as biomarker of NEDA-3 in patients with fingolimod.


Asunto(s)
Enfermedades Autoinmunes , MicroARNs , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Adolescente , Clorhidrato de Fingolimod/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Biomarcadores
15.
Arch Microbiol ; 205(4): 107, 2023 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-36881156

RESUMEN

Indiscriminate use of antibiotics to treat microbial pathogens has caused emergence of multiple drug resistant strains. Most infectious diseases are caused by microbes that are capable of intercommunication using signaling molecules, which is known as quorum sensing (QS). Such pathogens express their pathogenicity through various QS-regulated virulence factors. Interference of QS could lead to decisive results in controlling such pathogenicity. Hence, QS inhibition has become an attractive new approach for the development of novel drugs. Many quorum sensing inhibitors (QSIs) of diverse origins have been reported. It is imperative that more such anti-QS compounds be found and studied, as they have significant effect on microbial pathogenicity. This review attempts to give a brief account of QS mechanism, its inhibition and describes some compounds with anti-QS potential. Also discussed is the possibility of emergence of quorum sensing resistance.


Asunto(s)
Antibacterianos , Percepción de Quorum , Antibacterianos/farmacología , Factores de Virulencia/genética
16.
Br J Neurosurg ; 37(5): 1315-1318, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33393846

RESUMEN

Bariatric surgery is an effective treatment for patients with idiopathic intracranial hypertension (IIH), a condition that is associated with skull base defects. A 55-year-old woman presented with symptoms of intractable nausea and vomiting, followed by headache and confusion two weeks after an elective laparoscopic vertical sleeve gastrectomy procedure. She had a presumed diagnosis of IIH and a remote history of CSF oto/rhinorrhea treated with a lumbar peritoneal (LP) shunt. Computed tomography (CT) scan of the head revealed tension pneumocephalus with midline shift and dehiscence of the tegmen. The patient underwent emergent craniotomy for decompression of the air-filled temporal lobe, clamping of the LP shunt, and repair of the skull base defect. Caution should be exercised in obese patients with a history of CSF leak secondary to a middle fossa skull base defect when being evaluated for bariatric surgery.


Asunto(s)
Cirugía Bariátrica , Rinorrea de Líquido Cefalorraquídeo , Neumocéfalo , Seudotumor Cerebral , Femenino , Humanos , Persona de Mediana Edad , Neumocéfalo/diagnóstico por imagen , Neumocéfalo/etiología , Neumocéfalo/cirugía , Rinorrea de Líquido Cefalorraquídeo/etiología , Tomografía Computarizada por Rayos X/efectos adversos , Resultado del Tratamiento , Cirugía Bariátrica/efectos adversos
18.
Molecules ; 27(20)2022 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-36296666

RESUMEN

Ladybird beetles (Coleoptera: Coccinellidae) possess strong chemical defences that are secreted in response to stress and are also found on the coating of eggs, which are rich in alkaloids that are responsible for their toxicity to other species. Recent studies have shown that alkaloids from several species of ladybird beetle can target nicotinic acetylcholine receptors (nAChRs) acting as receptor antagonists. Here, we have explored the actions of (-)-adaline, found in the 2-spot (Adalia bipunctata) and 10-spot (Adalia decempunctata) ladybirds, on both mammalian (α1ß1γδ, α7, α4ß2, α3ß4) and insect nAChRs using patch-clamp of TE671 cells and locust brain neurons natively expressing nAChRs, as well as two-electrode voltage clamp of Xenopus laevis oocytes recombinantly expressing nAChRs. All nAChR subtypes were antagonised by (-)-adaline in a time-dependent, voltage-dependent and non-competitive manner with the lowest IC50s at rat α3ß4 (0.10 µM) and locust neuron (1.28 µM) nAChRs, at a holding potential of -75 mV. The data imply that (-)-adaline acts as an open channel blocker of nAChRs.


Asunto(s)
Alcaloides , Escarabajos , Receptores Nicotínicos , Animales , Ratas , Piperidinas , Antagonistas Nicotínicos , Xenopus laevis , Mamíferos
19.
Pain Ther ; 11(4): 1451-1469, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36224489

RESUMEN

INTRODUCTION: Currently available treatments for chronic lower back pain (CLBP) do not adequately address both nociceptive and neuropathic components of pain. We evaluated efficacy and safety of fixed-dose combination (FDC) of low-dose pregabalin prolonged release 75 mg-etoricoxib 60 mg to address both pain components. METHODS: This randomized phase 3 trial conducted at 12 centres across India evaluated efficacy (based on mean change in numeric rating scale [NRS], Roland-Morris disability questionnaire [RDQ], visual analogue scale [VAS], patient global impression of improvement [PGI-I], clinical global impression of improvement [CGI-I] and rescue medication consumption) and safety of FDC in comparison to etoricoxib alone in adult patients with CLBP. Treatment duration was 8 weeks. RESULTS: Of the 371 patients screened, 319 were randomized and considered for efficacy and safety analysis. Both treatment groups had no significant difference in terms of demography and baseline disease characteristics. Significantly better outcomes with FDC compared to etoricoxib were observed at week 4 onwards. At week 8, both groups showed significant reduction in mean NRS score from baseline (- 4.00 ± 1.65 in FDC; - 2.92 ± 1.59 in etoricoxib) with mean NRS score being significantly less in the FDC group compared to etoricoxib group (3.26 ± 1.56 vs 4.31 ± 1.56; p < 0.0001). The FDC was more effective than etoricoxib in terms of significantly greater reduction in RDQ score (- 9.28 ± 4.48 vs - 6.78 ± 4.34; p < 0.0001) and VAS score (- 37.66 ± 18.7 vs - 28.50 ± 16.31; p < 0.0001) at week 8. The FDC was also better in terms of significantly more patients reporting their condition as 'very much better' (36.9% vs 5.0%; p < 0.0001) and clinicians reporting patient's condition as 'very much improved' (36.3% vs 5.7%; p < 0.0001). Overall, study medications were well tolerated. CONCLUSION: FDC of pregabalin and etoricoxib provided significant benefits in reducing pain and improving functional status compared with etoricoxib alone in patients with CLBP. Pregabalin prolonged release-etoricoxib FDC could be one of the treatment options for early and sustained pain relief and improvement in quality-of-life in treating CLBP as it addresses both neuropathic and nociceptive components of pain. TRIAL REGISTRATION: CTRI/2018/10/015886.


Low back pain is one of the most common causes of loss of productivity worldwide. About 60% of Indians suffer from low back pain at some point. Low back pain that persists for more than 3 months is classified as chronic low back pain which mostly includes both nociceptive and neuropathic components. Monotherapies, if prescribed, are not completely effective, as they generally only target either nociceptive or neuropathic components of pain. Multiple drugs are usually needed at multiple times a day, at higher doses for optimal effectiveness, and in most cases they have significant side effects if taken over prolonged periods and also add to the pill burden. To minimize treatment-associated adverse effects, and to increase treatment compliance, while addressing both the components of pain, we developed a fixed-dose combination of low-dose pregabalin prolonged release and etoricoxib. A phase 3 trial was designed to assess the efficacy and safety of the fixed-dose combination in comparison with etoricoxib alone in treating chronic low back pain. The combination demonstrated statistically and clinically significant improvement in patient-reported outcomes­pain, functionality and quality of life­as early as 4 weeks after starting the medication. No severe or serious adverse effects were reported. Thus, the combination of low-dose pregabalin prolonged release and etoricoxib could provide an option for optimal management of chronic low back pain. This would provide multiple benefits, such as addressing both nociceptive and neuropathic components of chronic low back pain, reducing drug-related adverse effects because of low dose, reducing pill burden and thereby increasing drug compliance.

20.
Biomed Res Int ; 2022: 2476126, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35865665

RESUMEN

This study evaluated the groundwater using the Entropy Weightage Quality Index model (EWQI). Eighteen samples were taken from the different wellbores during premonsoon seasons in 2021. The present study is aimed at developing a comprehensive approach for groundwater quality assessment and associated health risk along with the cancer risk due to the presence of heavy metals. The water quality of Ranchi city was found to be better except in the western zone. Principal component analysis (PCA) revealed that arsenic (As) was the most influencing element that deteriorated the potability of water which supports our study. The study looked at cancer and noncancer health hazards connected with heavy metal music. The value of hazardous quotient (HQ) was observed to be relatively higher in As (HQ > 1) and Ni, followed by Mn > Fe > Zn > Cu. Also, the children were at higher risk than adults. The cancer risk associated with arsenic was investigated and found that the northern part and southeast-west (lapung block) of the study are at higher risk. Prolonged ingestion of As causes diseases like arsenicosis that leads to enhanced chances of cancer risk. This research provides an immense research database to assess the potability of drinking water in a similar city like Ranchi.


Asunto(s)
Arsénico , Agua Subterránea , Metales Pesados , Neoplasias , Contaminantes Químicos del Agua , Adulto , Arsénico/análisis , Arsénico/toxicidad , Niño , Entropía , Monitoreo del Ambiente , Humanos , India/epidemiología , Metales Pesados/análisis , Metales Pesados/toxicidad , Neoplasias/epidemiología , Medición de Riesgo , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad
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