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The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 µM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 µM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.
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Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Humanos , Isoindóis/química , Isoindóis/farmacologia , Isoindóis/síntese química , Estrutura MolecularRESUMO
A comprehensive study of the interactions of human serum albumin (HSA) and α-1-acid glycoprotein (AAG) with two isoquinoline alkaloids, i.e., allocryptopine (ACP) and protopine (PP), was performed. The UV-Vis spectroscopy, molecular docking, competitive binding assays, and circular dichroism (CD) spectroscopy were used for the investigations. The results showed that ACP and PP form spontaneous and stable complexes with HSA and AAG, with ACP displaying a stronger affinity towards both proteins. Molecular docking studies revealed the preferential binding of ACP and PP to specific sites within HSA, with site 2 (IIIA) being identified as the favored location for both alkaloids. This was supported by competitive binding assays using markers specific to HSA's drug binding sites. Similarly, for AAG, a decrease in fluorescence intensity upon addition of the alkaloids to AAG/quinaldine red (QR) complexes indicated the replacement of the marker by the alkaloids, with ACP showing a greater extent of replacement than PP. CD spectroscopy showed that the proteins' structures remained largely unchanged, suggesting that the formation of complexes did not significantly perturb the overall spatial configuration of these macromolecules. These findings are crucial for advancing the knowledge on the natural product-protein interactions and the future design of isoquinoline alkaloid-based therapeutics.
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Simulação de Acoplamento Molecular , Ligação Proteica , Humanos , Sítios de Ligação , Dicroísmo Circular , Orosomucoide/química , Orosomucoide/metabolismo , Alcaloides de Berberina/química , Alcaloides de Berberina/metabolismo , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Benzofenantridinas/química , Benzofenantridinas/metabolismo , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismoRESUMO
Bicyclic peptides have attracted the interest of pharmaceutical companies because of their remarkable properties, putting them on a new path in medicine. Their conformational rigidity improves proteolytic stability and leads to rapid penetration into tissues via any possible route of administration. Moreover, elimination of renal metabolism is of great importance, for example, for people with a history of liver diseases. In addition, each ring can function independently, making bicyclic peptides extremely versatile molecules for further optimization. In this paper, we compared the potentiometric and spectroscopic properties studied by UV-vis, MCD, and EPR of four synthetic analogues of the bi-cyclic peptide c(PKKHP-c(CFWKTC)-PKKH) (BCL). In particular, we correlated the structural and spectral properties of complexes with coordinating abilities toward Cu(II) ions of MCL1 (Ac-PKKHPc(CFWKTC)PKKH-NH2) that contains the unbinding cycle and N- and C-terminal linear parts with two histidine residues, one per part; two monocyclic ligands containing one histidine residue, both in the N-terminal position, i.e., MCL2 (Ac-PKKHPc(CFWKTC)PKKS-NH2) and in the C-terminal position, i.e., MCL3 (Ac-PKKSPc(CFWKTC)PKKH-NH2), respectively; and the linear structure LNL (Ac-PKKHPSFWKTSPKKH-NH2). Potentiometric results have shown that the bicyclic structure promotes the involvement of the side chain imidazole donors in Cu(II) binding. On the other hand, the results obtained for the mono-cyclic analogues lead to the conclusion that the coordination of the histidine moiety as an anchoring group is promoted by its location in the peptide sequence further from the nonbinding cycle, strongly influencing the involvement of the amide donors in Cu(II) coordination.
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Cobre , Peptídeos Cíclicos , Cobre/química , Peptídeos Cíclicos/química , Complexos de Coordenação/química , Ligantes , Íons/química , PotenciometriaRESUMO
From the point of view of the search for new pharmaceuticals, pyridazinone derivatives are a very promising group of compounds. In our previous works, we have proved that newly synthesized ligands from this group have desirable biological and pharmacokinetic properties. Therefore, we decided to continue the research evaluating the activity of pyrrolo[3,4-dpyridazinone derivatives. In this work, we focused on the interactions of five pyridazinone derivatives with the following biomolecules: DNA and two plasma proteins: orosomucoid and gamma globulin. Using several of spectroscopic methods, such as UV-Vis, CD, and fluorescence spectroscopy, we proved that the tested compounds form stable complexes with all biomacromolecules selected for analysis. These findings were also confirmed by the results obtained by molecular modeling. All tested pyridazinone derivatives bind to the ctDNA molecule via groove binding mechanisms. All these molecules can also be bound and transported by the tested plasma proteins; however, the stability of the complexes formed is lower than those formed with serum albumin.
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Anti-Inflamatórios , Antioxidantes , DNA/química , Modelos Moleculares , Proteínas Sanguíneas , Simulação de Acoplamento MolecularRESUMO
Adrenocortical carcinoma (ACC) is a rare cancer in childhood. ACC is frequently associated with germline TP53 variants, with founder effects especially due to the p.Arg337His mutation. ACC leads to the secretion of adrenocortical hormones, resulting in endocrine syndromes, which is the usual trigger for establishing the diagnosis. We present a surprising ACC pathology in a non-secreting, ectopic retroperitoneal tumour in a 4-year-old boy, successfully controlled with chemotherapy and mitotane after microscopically incomplete tumour resection with spillage. Genomic analysis (gene panel sequencing and copy-number microarray) demonstrated a novel p.Phe338Leu tetramerisation domain (TD) TP53 variant in the proband and his cancer-free mother and a monoallelic deletion encompassing the TP53 locus in cancer tissue, consistent with cancer-predisposition syndrome. While the recurrent p.Arg337His variant translates into high ACC risk, residue 338 and, in general, TD domain variants drive heterogeneous clinical scenarios, despite generally being considered less disruptive than TP53 DNA-binding domain mutations.
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Lymphangioleiomyomatosis (LAM) is characterized by lung cysts that cause lung deterioration, changes in the lymphatic system, and tumors in the kidneys. It mainly affects women of reproductive age and is a progressive disease. LAM can occur as an isolated disease or coexist with tuberous sclerosis (TSC). The source of LAM cells is unknown. Patients with confirmed LAM should be treated with an mTOR inhibitor, sirolimus, or everolimus. We present a case of LAM with TSC in a patient whose symptoms, including those in the lymph nodes and chyaloperitoneum, mainly concern the abdominal cavity.
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Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-d]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that N-acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-d]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-d]pyridazinone. Novel compounds 5a-c-7a-c were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title N-acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins-AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability.
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Inibidores de Ciclo-Oxigenase , Hidrazonas , Inibidores de Lipoxigenase , Piridazinas , Pirróis , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacocinética , Hidrazonas/farmacologia , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacocinética , Inibidores de Ciclo-Oxigenase/farmacologia , Piridazinas/síntese química , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/farmacologia , Pirróis/síntese química , Pirróis/química , Pirróis/farmacocinética , Pirróis/farmacologia , Humanos , Fibroblastos , Simulação por Computador , Permeabilidade da Membrana Celular , Linhagem CelularRESUMO
One of the groups of organic compounds with potential use in medicine and pharmacy is phthalimide derivatives. They are characterized by a wide range of properties such as antibacterial, antifungal, and anti-inflammatory. In this study, we focused on research on four phthalimide derivatives with proven non-toxicity, which are cyclooxygenase inhibitors. With the use of molecular docking study and spectroscopic methods, such as fluorescence, circular dichroism, and FT-IR spectroscopies, we analyzed the way the tested compounds interact with plasma proteins. Among the many proteins present in the plasma, we selected three: albumin, α1-acid glycoprotein, and gamma globulin, which play significant roles in the human body. The obtained results showed that all tested compounds bind to the analyzed proteins. They interact most strongly with albumin, which is a transport protein. However, interactions with serum albumin and orosomucoid do not cause significant changes in their structures. Only in the case of gamma globulins significant changes were observed in protein secondary structure.
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Despite the widespread and easy access to NSAIDs, effective and safe treatment of various inflammatory disorders is still a serious challenge because of the severe adverse effects distinctive to these drugs. The Mannich base derivatives of pyrrolo[3,4-c]pyrrole are potent, preferential COX-2 inhibitors with a COX-2/COX-1 inhibitory ratio better than meloxicam. Therefore, we chose the six most promising molecules and subjected them to further in-depth research. The current study presents the extensive biological, spectroscopic and in silico evaluation of the activity and physicochemical properties of pyrrolo[3,4-c]pyrrole derivatives. Aware of the advantages of dual COX-LOX inhibition, we investigated the 15-LOX inhibitory activity of these molecules. We also examined their antioxidant effect in several in vitro experiments in a protection and regeneration model. Furthermore, we defined how studied compounds interact with artificial models of cell membranes, which is extremely important for drugs administered orally with an intracellular target. The interactions and binding mode of the derivatives with the most abundant plasma proteins-human serum albumin and alpha-1-acid glycoprotein-are also described. Finally, we used computational techniques to evaluate their pharmacokinetic properties. According to the obtained results, we can state that pyrrolo[3,4-c]pyrrole derivatives are promising anti-inflammatory and antioxidant agents with potentially good membrane permeability.
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In this project, we combine two areas of research, experimental characterization and molecular docking studies of the interaction of positively charged oligopeptides with crucial blood plasma proteins. The investigated peptides are rich in NH2 groups of amino acid side chains from Dap, Orn, Lys, and Arg residues, which are relevant in protein interaction. The peptides are 9- and 11-mer with the following sequences: (Lys-Dab-Dab-Gly-Orn-Pro-His-Lys-Arg-Lys-Dbt), (Lys-Dab-Ala-Gly-Orn-Pro-His-Lys-Arg), and (Lys-Dab-Dab-Gly-Orn-Pro-Phe(2-F)-Lys-Arg). The net charge of the compound strongly depends on the pH environment and it is an important aspect of protein binding. The studied oligopeptides exhibit therapeutic properties: anti-inflammatory activity and the capacity to diminish reactive oxygen species (ROS). Therefore, the mechanism of potential binding with blood plasma components is the next challenge. The binding interaction has been investigated under pseudo-physiological conditions with the main blood plasma proteins: albumin (BSA), α1-acid glycoprotein (AAG), and γ-globulin fraction (GGF). The biomolecular quenching constant (kq) and binding constant (Kb) were obtained by fluorescence spectroscopy at various temperatures. Simultaneously, the changes in the secondary structure of proteins were monitored by circular dichroism (CD) and infrared spectroscopy (IR) by quantity analysis. Moreover, molecular docking studies were conducted to estimate the binding affinity, the binding domain, and the chemical nature of these interactions. The results show that the investigated oligopeptides could be mainly transported by albumin, and the binding domain I is the most favored cavity. The BSA and GGF are able to form stable complexes with the studied compounds as opposed to AAG. The binding reactions are spontaneous processes. The highest binding constants were determined for Lys-Dab-Dab-Gly-Orn-Pro-His-Lys-Arg-Lys-Dbt peptide, in which the values of the binding constants Kb to BSA and GGF were 10.1 × 104 dm3mol-1 and 3.39 × 103 dm3mol-1, respectively. The positively charged surface of peptides participated in salt bridge interaction with proteins; however, hydrogen bonds were also formed. The secondary structure of BSA and GGF after contact with peptides was changed. A reduction in the α-helix structure was observed with an increase in the ß-sheet and ß-turn and random coil structures.
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Oligopeptídeos , Peptídeos , Sequência de Aminoácidos , Simulação de Acoplamento Molecular , Peptídeos/química , Oligopeptídeos/química , Lisina/química , Proteínas Sanguíneas , AlbuminasRESUMO
The application of biomass as a co-feed in coal power plants and in standalone biomass power plants, as well as in char production for soil remediation, is a currently important issue. This paper reports on the investigation of biochar formation from agricultural waste crops that are used for soil upgrading, but which do not meet the standards of EU crops, as well as largescale food processing waste. These were compared to test results from basket willow, which is commonly used for energy generation. Food industry waste is often produced in cities on a large scale and is generally easier to process due to lack of other stream components. The key parameters, namely, the content of volatiles, energy content of the formed biochar and the composition of the ash, were determined for a number of herbaceous materials locally available in the European Union. All of them can be used as a cheap source of biochar. A novel procedure of capturing volatiles and hence minimizing the PAH content in the biochar, as well as enabling the recovery of energy from the volatiles is presented. Knowledge of the composition and form of elements in ash is very important for designing ash management systems if co-combustion is implemented. The aim of this study was to determine if the types of biomass are better suited for biochar production or energy generation.
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BACKGROUND: Vascular anomalies often result in aesthetic flaws, pain, and impair the quality of life. They require challenging treatments that frequently do not provide the desired results. The mammalian target of rapamycin (mTOR) is directly involved in the development of these malformations. However, the exact mechanism behind mTOR dysregulation has not been unambiguously defined. The purpose of this study is to investigate the activation of selected substrates of mTOR to partially assess its involvement in the disease process. METHODS: We analyzed tissue samples collected from patients with vascular anomalies treated in our department. We included patients with histopathological diagnoses of lymphatic, venous, capillary malformations, mixed lesions, and a control group of healthy skin samples. We stained the samples using H and E and immunohistochemistry. We used primary antibodies against p70 S6 Kinase, 4EBP1, and p-4EBP1. We graded their color reactions. The statistical analyses were performed using the FactoMineR and factoextra R v.4.1 packages. p-values < 0.05 were considered statistically significant. RESULTS: The analysis of 82 patients showed that healthy tissue vessels expressed lower levels of tested mTOR pathway substrates compared to high activation in vascular malformations. Elevated substrate expression in a comparison between sexes revealed higher P-4EBP1 expression in the female malformation group. We observed a decrease in mTOR substrate expression with age. CONCLUSION: The higher expression of mTOR substrates in vascular malformations compared to healthy tissue confirms their involvement in abnormal vascular development. Age-related changes in mTOR substrate expression highlight the need for timely intervention. Our study contributes to the understanding of the mTOR signaling pathway in vascular malformations and highlights its potential as a therapeutic target, contributing to personalized medicine.
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There is growing interest in bicyclic peptides among scientists. This group of compounds has more advantageous properties than monocyclic ligands and their application in medicine and biological sciences is possible. It is known that sometimes the presence of metal ions is crucial for the activity of peptides in biological systems, like in the case of oxytocin or vasopressin. Therefore, in this study, we performed a series of experiments with the new bicyclic peptide c(PKKHP-c(CFWKTC)-PKKH) (BCL) that was designed and synthesized by a fully automated induction-assisted solid phase synthesizer. We analyzed the coordination abilities of BCL relative to copper(II) ions. The new bicyclic peptide contains two histidine moieties, separated by proline residues, with two distinct sites for metal ion coordination. The obtained results showed that in all analyzed systems both mono- and dinuclear complexes are formed.
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Cobre , Histidina , Cobre/química , Histidina/química , Íons , Ligantes , Peptídeos/químicaRESUMO
Many publications in databases deal with the interactions of new drugs with albumin. However, it is not only albumin that is responsible for binding pharmaceutical molecules to proteins in the human body. There are many more proteins in plasma that are important for the study of the ADME pathway. Therefore, in this study, we have shown the results of the interactions between the plasma proteins albumin, orosomucoid, and gamma globulins and non-toxic anti-inflammatory phthalimide analogs, which due to the promising obtained results, may be potential candidates in the group of analgesic and anti-inflammatory drugs. Using spectroscopic methods and molecular modeling, we showed that all four tested compounds form complexes with the analyzed proteins. The formation of a complex with proteins raises the pharmacological efficacy of the drug. Therefore, the obtained results could be a step in the study of the pharmacokinetics and pharmacodynamics of new potential pharmaceuticals.
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Pró-Fármacos , Albuminas , Analgésicos , Humanos , Simulação de Acoplamento Molecular , Orosomucoide/metabolismo , Ftalimidas/química , Ftalimidas/farmacologia , Pró-Fármacos/farmacologiaRESUMO
An analysis of the literature generated within the past 20 year-span concerning risks of uterine fibroids (UFs) occurrence and dietary factors was carried out. A link between Vitamin D deficiency and UFs formation is strongly indicated, making it a potent compound in leiomyoma therapy. Analogs of the 25-hydroxyvitamin D3, not susceptible to degradation by tissue 24-hydroxylase, appear to be especially promising and tend to show better therapeutic results. Although research on the role of Vitamin A in the formation of fibroids is contradictory, Vitamin A-enriched diet, as well as synthetic retinoid analogues, may be preventative or limit the growth of fibroids. Unambiguous conclusions cannot be drawn regarding Vitamin E and C supplementation, except for alpha-tocopherol. Alpha-tocopherol as a phytoestrogen taking part in the modulation of estrogen receptors (ERs) involved in UF etiology, should be particularly avoided in therapy. A diet enriched in fruits and vegetables, as sources of carotenoids, polyphenols, quercetin, and indole-3-carbinol, constitutes an easily modifiable lifestyle element with beneficial results in patients with UFs. Other natural substances, such as curcumin, can reduce the oxidative stress and protect against inflammation in leiomyoma. Although the exact effect of probiotics on uterine fibroids has not yet been thoroughly evaluated at this point, the protective role of dairy products, i.e., yogurt consumption, has been indicated. Trace elements such as selenium can also contribute to antioxidative and anti-inflammatory properties of a recommended diet. In contrast, heavy metals, endocrine disrupting chemicals, cigarette smoking, and a diet low in antioxidants and fiber were, alongside genetic predispositions, associated with UFs formation.
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Leiomioma , Neoplasias Uterinas , Dieta , Feminino , Crescimento e Desenvolvimento , Humanos , Leiomioma/epidemiologia , Neoplasias Uterinas/tratamento farmacológico , Vitamina A/uso terapêutico , Vitamina D/uso terapêutico , Vitaminas/uso terapêuticoRESUMO
Antimicrobial peptides are a promising group of compounds used for the treatment of infections. In some cases, metal ions are essential to activate these molecules. Examples of metalloantibiotics are, for instance, bleomycin and dermcidin. This study is focused on three new pseudopeptides with potential biological activity. The coordination behavior of all ligands with Cu(II) and Ni(II) ions has been examined. Various analytical methods such as potentiometric titration, UV-Vis and CD spectroscopies, and mass spectrometry were used. All compounds are convenient chelators for metal ion-binding. Two of the ligands tested have histidine residues. Surprisingly, imidazole nitrogen is not involved in the coordination of the metal ion. The N-terminal amino group, Dab side chains, and amide nitrogen atoms of the peptide bonds coordinated Cu(II) and Ni(II) in all the complexes formed. The cytotoxicity of three pseudopeptides and their complexes was evaluated. Moreover, their other model allowed for assessing the attenuation of LPS-induced cytotoxicity and anti-inflammatory activities were also evaluated, the results of which revealed to be very promising.
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Cátions/química , Complexos de Coordenação/química , Cobre/química , Inflamação/tratamento farmacológico , Níquel/química , Peptídeos/química , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/metabolismo , Células Cultivadas , Complexos de Coordenação/farmacologia , Inflamação/metabolismo , Ligantes , Estrutura Molecular , Peptídeos/metabolismoRESUMO
Regarding that the chronic use of commonly available non-steroidal and anti-inflammatory drugs (NSAIDs) is often restricted by their adverse effects, there is still a current need to search for and develop new, safe and effective anti-inflammatory agents. As a continuation of our previous work, we designed and synthesized a series of 18 novel N-substituted-1,2,4-triazole-based derivatives of pyrrolo[3,4-d]pyridazinone 4a-c-9a-c. The target compounds were afforded via a convenient way of synthesis, with good yields. The executed cell viability assay revealed that molecules 4a-7a, 9a, 4b-7b, 4c-7c do not exert a cytotoxic effect and were qualified for further investigations. According to the performed in vitro test, compounds 4a-7a, 9a, 4b, 7b, 4c show significant cyclooxygenase-2 (COX-2) inhibitory activity and a promising COX-2/COX-1 selectivity ratio. These findings are supported by a molecular docking study which demonstrates that new derivatives take position in the active site of COX-2 very similar to Meloxicam. Moreover, in the carried out in vitro evaluation within cells, the title molecules increase the viability of cells pre-incubated with the pro-inflammatory lipopolysaccharide and reduce the level of reactive oxygen and nitrogen species (RONS) in induced oxidative stress. The spectroscopic and molecular modeling study discloses that new compounds bind favorably to site II(m) of bovine serum albumin. Finally, we have also performed some in silico pharmacokinetic and drug-likeness predictions. Taking all of the results into consideration, the molecules belonging to series a (4a-7a, 9a) show the most promising biological profile.
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Anti-Inflamatórios/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Derme/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Piridazinas/química , Pirróis/química , Triazóis/química , Anti-Inflamatórios/química , Sobrevivência Celular , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase/química , Derme/citologia , Derme/enzimologia , Desenho de Fármacos , Fibroblastos/citologia , Fibroblastos/enzimologia , Humanos , Técnicas In Vitro , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: The aim of the study was to examine management of pediatric appendiceal neuroendocrine tumors (ANETs) in Poland. METHODS: Records of 27 patients with ANET diagnosed incidentally after appendectomy in the last decade. RESULTS: Well-differentiated NET G1/G2 was diagnosed in 25 and well-differentiated neuroendocrine carcinoma G3 in 2 patients. Extended surgery was performed primarily in one instance and secondarily in 10 patients (right hemicolectomy in 9, ileocecal resection in 1) without adjuvant chemotherapy. Follow-up range was 1-121 months. Recurrence after secondary surgery was observed in 1 (3.7%) patient. CONCLUSIONS: Applying ENETS guidelines resulted in 100% overall survival of patients with NET.
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INTRODUCTION: Thoracic surgeries are associated with intense postoperative pain. General opioid analgesia is still the main anaesthetic method. Due to the large number of opioid-induced side effects, alternative methods of pain relief are sought. One of them is the use of balanced analgesia, which consists of regional analgesia, non-opioid painkillers, and small doses of opioids. MATERIAL AND METHODS: The objective of this study was to assess the effectiveness of preoperative thoracic paravertebral block (ThPVB) in the treatment of postoperative pain after video-assisted thoracic surgery (VATS) by measuring hormone levels in blood serum or saliva. It was a randomised, open-label study conducted in a single university hospital setting between May 2018 and September 2019. In total, 119 patients were scheduled for elective video-assisted thoracic surgery. Performed interventions included: preoperative thoracic paravertebral block with 0.5% bupivacaine, followed by postoperative oxycodone combined with nonopioid analgesics. Follow-up period comprised first 24 hours and one, two, and six months after surgery. Main outcomes were measured by pain intensity assessed using the Numerical Rating Scale (NRS) and the levels of the following hormones: testosterone, cortisol, α-amylase activity, sIgA, and ß-endorphin. RESULTS: A total of 119 patients were randomised into two groups and, of these, 49 were subsequently excluded from the analysis. The final analysis included 37 patients from the study group and 33 from the control group. There were no statistically significant differences in the analysed parameters the relative change T1-T0. There was a tendency towards statistical significance in the relative change T2-T0 in testosterone levels. At rest, no statistically significant differences were found between groups and time in the percentage of patients with NRS ≥ 1. During cough, the percentage of patients with NRS ≥ 1 was higher at T1 and T2 time points in the ThPVB group. Of the factors considered, only α-amylase levels statistically significantly increased the chance for higher NRS score after a month [OR = 1.013; 95% PU: 1.001-1.025; p < 0.01]. CONCLUSIONS: ThPVB is effective and safe for patients undergoing VATS. It can be an effective alternative for general anaesthesia using high doses of opioids.
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Analgesia , Cirurgia Torácica Vídeoassistida , Analgésicos Opioides , Humanos , Hidrocortisona , Imunoglobulina A Secretora , Dor Pós-Operatória/tratamento farmacológico , Testosterona , alfa-Amilases , beta-EndorfinaRESUMO
The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b-6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable.