Andrographis paniculata as Promising Novel Protective Therapy of Oxidative Stress in Indomethacin-Induced Gastric Ulcer in Rats

This research investigated the effect of Andrographis paniculata (AP) on oxidative stress following indomethacin-induced gastric ulcer in rats. A total of 20 male albino Wistar rats (150-180g) used for this study were grouped into four (n=5): 1, Negative Control; 2, Positive Control and 3, test group treated with normal chow, 20mg/kg indomethacin, 20 mg/kg indomethacin plus omeprazole at 20mg/kg and 20mg/kg indomethacin plus AP at 16.7 mg/kg respectively. After treatment period, estimation of oxidative stress parameters was carried out on the animals. The LD50 of aqueous extract of AP was 50mg/kg bw. Body weight change was significantly reduced in omeprazole treated group compared to all other groups while extract treated group had significantly increased body weight change. There was a significant increase in malondialdehyde (MDA) level of ulcer untreated group compared to other groups. The two treated groups had significantly reduced MDA compared to ulcer untreated group. There was a significant decrease in the levels of GPx and SOD of ulcer untreated group compared to control. Meanwhile, these were significantly increased in extract and omeprazole treated groups compared to ulcer untreated group. Catalase was significantly increased in all three groups when compared to control but its level was significantly increased in extract treated group compared to ulcer untreated and omeprazole treated groups. From this study, AP has proved to protect against oxidative stress implicated in the pathogenesis of ulcer. If this result is applicable to humans, further research and use of AP in ameliorating debilitating consequences of peptic ulcer should be encouraged.

A novel nano-formulation of olmesartan medoxomil with improved delivery and efficacy in the treatment of indomethacin-induced duodenitis in rats

There are few studies addressing duodenal inflammation. This study was designed to investigate the effects of a recently developed biotechnological product, a nano-formulation of olmesartan medoxomil (OM) - olmesartan medoxomil zeinmersomes (OMZ) - for the treatment of indomethacin-induced duodenitis in rats. Adult male Wistar rats were given indomethacin (10 mg/kg/day) for four weeks. They were divided into a positive control group (PC, untreated) and two groups treated orally with 3 mg/kg per day of OM or OMZ for the last two weeks of the 4-week indomethacin-treatment. At end of the four weeks, blood and duodenum were collected. Duodenal homogenate was used for measurement of levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, reduced glutathione (GSH), and cleaved caspase-3. Duodenal sections were stained with H&E. Gene expressions of nuclear factor kappa B (NF-κB p65), Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2) by RT-PCR, and protein expression of survivin by western blot were assessed. Plasma and duodenal olmesartan concentrations were measured by high performance liquid chromatography mass spectrometry. The duodenitis rats showed significantly higher duodenal levels of myeloperoxidase, TNF-α, IL-6, malondialdehyde, and cleaved caspase-3, a significantly lower GSH level, and histopathological alterations. Moreover, they showed upregulated gene expressions of NF-κB p65 and Bax, downregulated gene expression of Bcl-2, decreased Bcl-2/Bax ratio, and lower protein expression of survivin. OMZ was more effective in protecting the duodenum from indomethacin-induced injuries compared to OM due to improved delivery, higher bioavailability, and better anti-inflammatory, antioxidant, and antiapoptotic effects. OMZ could be a better choice for hypertensive patients with non-steroidal anti-inflammatory drugs-induced duodenitis.

Paroxysmal Hemicrania-Trigeminal Neuralgia (PH-Tic) syndrome with no structural lesion in a Brazilian woman: the first case-report / Síndrome de Neuralgia Paroxística Hemicrânia-Trigêmea (PH-Tic) sem lesão estrutural em mulher brasileira: primeiro relato de caso

Introduction: In Brazil there is only one case report of a patient diagnosed with Paroxysmal Hemicrania-Trigeminal (PH-Tic) syndrome reported, however it was observed in a patient with Chiari I malformation. Objective: Here, we describe the first case of primary PH-Tic syndrome in the country. Method: Case report. CARE guideline was used to guide the structuring of this article. This case report was approved by the ethics committee and has been registered under the protocol number 70705623.7.0000.5440 on "Plataforma Brasil". Results:A 72-year-old woman with a five-month history of headaches was admitted at our headache outpatient clinic. The pain was sharp, intense, localized in the periorbital and left temporal regions. Blood counts, liver, renal and thyroid function were normal, as well as brain magnetic resonance imaging. Despite using carbamazepine, the patient had pain in only the left side of the face. Indomethacin was added until the dose of 100 mg a day and resulted in improvement of headache frequency. Conclusion: PH-Tic should be hypothesized in patients with short-lasting headaches associated with facial pain that partially improve with carbamazepine or indomethacin.

Introdução: No Brasil há apenas um relato de caso de paciente com diagnóstico de síndrome Paroxística Hemicrania-Trigeminal (PH-Tic), porém foi observado em um paciente com malformação de Chiari I. Objetivo: Descrevemos aqui o primeiro caso de síndrome PH-Tic primária no país. Método: Relato de caso. A diretriz CARE foi utilizada para orientar a estruturação deste artigo. Este relato de caso foi aprovado pelo comitê de ética e registrado sob o número de protocolo 70705623.7.0000.5440 na "Plataforma Brasil". Resultados: Uma mulher de 72 anos com história de cefaleias há cinco meses foi internada em nosso ambulatório de cefaleias. A dor era aguda, intensa, localizada nas regiões periorbital e temporal esquerda. Os hemogramas, as funções hepática, renal e tireoidiana estavam normais, assim como a ressonância magnética cerebral. Apesar do uso de carbamazepina, o paciente apresentava dor apenas no lado esquerdo da face. A indometacina foi adicionada até a dose de 100 mg ao dia e resultou em melhora da frequência da cefaleia. Conclusão: O PH-Tic deve ser hipotetizado em pacientes com cefaleias de curta duração associadas a dores faciais que melhoram parcialmente com carbamazepina ou indometacina.

Pancreatic duct stent combined with indomethacin suppository for prevention of pancreatitis after difficult bile duct intubation during endoscopic retrograde cholangiopancreatography / 中华消化内镜杂志

Objective:To explore the preventive effects of pancreatic duct stent combined with rectal administration of indomethacin suppository for post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) after difficult bile duct intubation during endoscopic retrograde cholangiopancreatography (ERCP).Methods:From January 2019 to December 2021, patients with biliary and pancreatic diseases undergoing ERCP in Hangzhou Hospital Affiliated to Nanjing Medical University were given 100 mg indomethacin suppository to anal canal 30 minutes before the operation. And those with difficult bile duct intubation during the operation ( n=204) were included in this study. According to the random number table, they were divided into the combination group (implanted with pancreatic duct stent during the operation, n=104) and the indomethacin group (not implanted with stent, n=100). The incidences of hyperamylasemia and PEP were compared between the two groups. Results:The incidences of postoperative hyperamylasemia [21.2% (22/104) VS 34.0% (34/100), χ2=4.22, P=0.040] and PEP [14.4% (15/104) VS 32.0% (32/100), χ2=8.88, P=0.003] in the combination group were significantly lower than those in the indomethacin group. There was no significant difference in the incidence of severe PEP between the two groups [1.0% (1/104) VS 1.0% (1/100), χ2=0.001, P=0.978]. Conclusion:Compared with rectal administration of indomethacin suppository alone, the incidences of hyperamylasemia and PEP after difficult bile duct intubation during ERCP can be further reduced when it is combined with pancreatic duct stent placement.

Cisteína oral N-Acetyl versus indometacina retal para prevenção de pancreatite pós-CPRE: um ensaio controlado randomizado multinacional multicêntrico / Oral n-acetyl cysteine versus rectal indomethacin for prevention of post ercp pancreatitis: a multicenter multinational randomized controlled trial

ABSTRACT Background This multicenter multinational RCT designed to compare the efficacy of suppository indomethacin and NAC for prevention of PEP. Methods: During a 6-month period, all of the ERCP cases in seven referral centers were randomly assigned to receive either 1200 mg oral NAC, indomethacin suppository 100 mg, 1200 mg oral NAC plus indomethacin suppository 100 mg or placebo 2 hours before ERCP. The primary outcomes were the rate and severity of any PEP. Results: A total of 432 patients included (41.4% male). They were originally citizens of 6 countries (60.87% Caucasian). They were randomly allocated to receive either NAC (group A, 84 cases), rectal indomethacin (group B, 138 cases), NAC + rectal indomethacin (group C, 115 cases) or placebo (group D, 95 cases). The rate of PEP in groups A, B and C in comparison with placebo were 10.7%, 17.4%, 7.8% vs 20% (P=0.08, 0.614 & 0.01 respectively). The NNT for NAC, indomethacin and NAC + indomethacin was 11, 38 and 8 respectively. Conclusion: Oral NAC is more effective than rectal indomethacin when compared to placebo for prevention of PEP and the combination of NAC and Indomethacin had the lowest incidence of PEP and may have synergistic effect in preventing of PEP (IRCT20201222049798N1; 29/12/2020).

RESUMO Contexto: Este estudo randomizado, controlado multicêntrico e multinacional foi projetado para comparar a eficácia da indometacina supositório e N-acetil cisteína (NAC) para prevenção de pancreatite pós colangiografia endoscópica. Métodos: Durante um período de 6 meses, todos os pacientes submetidos à CPRE em sete centros de referência foram aleatoriamente atribuídos para receber 1200 mg de NAC oral, supositório de indometacina 100 mg, 1200 mg de NAC oral mais supositório de indometacina 100 mg ou placebo 2 horas antes do procedimento. Os resultados primários foram a taxa e a gravidade de qualquer pancreatite pós procedimento (PPP). Resultados: Um total de 432 pacientes foram incluídos (41,4% do sexo masculino). Eram originalmente cidadãos de seis países (60,87% caucasianos). Foram alocados aleatoriamente para receber NAC (grupo A, 84 casos), indometacina retal (grupo B, 138 casos), NAC + indometacina retal (grupo C, 115 casos) ou placebo (grupo D, 95 casos). A taxa de PPP nos grupos A, B e C em comparação com o placebo foi de 10,7%, 17,4%, 7,8% vs 20% (P=0,08, 0,614 e 0,01, respectivamente). Conclusão A NAC oral é mais eficaz do que a indometacina retal quando comparado ao placebo para prevenção de PPP e a combinação de NAC e indometacina teve a menor incidência de PPP e pode ter efeito sinérgico na sua prevenção de PPP. (IRCT20201222049798N1; 29/12/2020).

Caracterización fisicoquímica y evaluación in vitro de sistemas autoemulsionables de liberación de indometacina

Objetivo: incorporar la indometacina en sistemas autoemulsionables de liberación con la finalidad de aumentar su solubilidad en medio acuoso, la velocidad de disolución y permeación in vitro. Metodología: se llevaron a cabo ensayos de solubilidad al equilibrio para preparar formulaciones con los excipientes, en los cuales la indome-tacina presentó mayor incremento de solubilidad; los sistemas fueron caracterizados por medio del tiempo de autoemulsificación, estabilidad física, tamaño de partícula, potencial zeta, perfiles de disolución y permeación a través de membrana sintética. Resultados: el diseño experimental de los sistemas autoemulsionables de liberación permitió crear formulaciones que aumentaron la solubilidad de la indometacina en un orden de 105 veces con respecto a la solubilidad acuosa. Las formulaciones que resultaron viables presentaron tiempos de autoemulsificación menores que 60 segundos, además, las distribuciones de tamaño de partícula de las dispersiones fueron inferiores a los 300 nm, presentó índices de polidispersión inferiores a 0,3 y valores de potencial zeta menores de -25 mV. Los perfiles de disolución mostraron que las formulaciones cumplen con un valor de factor de similitud mayor que 50, además, la permeabilidad a través de membrana sintética es mayor para las formulaciones autoemulsionables que el producto de referencia. Conclusiones: la formulación de indometacina en sistemas autoemulsionables de liberación incrementa la solubilidad en medio acuoso, aumenta la disolución y liberación. Estos resultados sugieren que la administración oral de indometacina incorporada en sistemas autoe-mulsionables puede acelerar el inicio del efecto farmacológico.

SUMMARY Aim: To load indomethacin into self-emulsifying delivery systems in order to increase, water-solubility, rate dissolution and in vitro permeation. Methodology: Equilibrium solubility tests were carried out to prepare formulations with the excipients, in which indomethacin presented a greater increase in solubility; the systems were characterized by self-emulsification time, physical stability, particle size, zeta potential, dissolution profiles and permeation through synthetic membrane. Results: The experimental design of self-emulsifying delivery systems allowed to create formulations that increase the solubility of indomethacin in an order of 105 times with respect to the aqueous solubility. The feasible formulations presented autoemulsification times less than 60 seconds, in addition, the particle size distributions of the dispersions were less than 300 nm, with polydispersity index smaller than 0.3, and zeta potential values lower than -25 mV. The dissolution profiles showed that the formulations comply with a similarity factor value greater than 50, in addition, the permeability through a synthetic membrane is higher for the self-emulsifying formulations than the reference product. Conclusion: The formulation of indomethacin into self-emulsifying delivery systems enhances the solubility in aqueous medium, increases dissolution and accelerate release. These results suggest that the oral administration of indomethacin incorporated into self-emulsifying delivery systems can accelerate the onset of the pharmacological effect.

Objetivo: incorporar a indometacina em sistemas de liberação autoemulsificantes a fim de aumentar sua solubilidade em meio aquoso, a taxa de dissolução e permeação in vitro. Metodologia: foram realizados testes de solubilidade de equilíbrio para preparar formulações com os excipientes, nas quais a indometacina apresentou maior aumento na solubilidade; os sistemas foram caracterizados quanto ao tempo de autoemulsificação, estabilidade física, tamanho de partícula, potencial zeta, perfis de dissolução e permeação através de membrana sintética. Resultados: o desenho experimental dos sistemas de liberação autoemulsificantes permitiu a criação de formulações que aumentaram a solubilidade da indometacina na ordem de 105 vezes em relação à solubilidade aquosa. As formulações que se mostraram viáveis apresentaram tempos de autoemulsificação inferiores a 60 segundos, além disso, as distribuições granulométricas das dispersões foram inferiores a 300 nm, apresentaram índices de polidispersidade inferiores a 0,3 e valores de potencial zeta inferiores a -25 mV. Os perfis de dissolução mostraram que as formulações atendem a um valor de fator de similaridade maior que 50, além disso, a permeabilidade através da membrana sintética é maior para as formulações autoemulsionantes do que para o produto de referência. Conclusões: a formulação de indometacina em sistemas de liberação autoemulsificantes aumenta a solubilidade em meio aquoso, aumenta a dissolução e a liberação. Esses resultados sugerem que a administração oral de indometacina incorporada em sistemas autoemulsificantes pode acelerar o início do efeito farmacológico.

Effectiveness of Indomethacin Suppositories in the Prevention of Post-endoscopic Retrograde Cholangiopancrea- tography Pancreatitis ：A Reevaluation of Systematic Review / 中国药房

OBJECTIVE：To overview the systematic review on the effectiveness of indomethacin in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis （PEP），and to provide reliable evidence-based reference for the prevention of PEP. METHODS ：Retrieved from PubMed ，the Cochrane Library ，Embase，CBM，CNKI，Wanfang database and VIP，systematic review on indomethacin in the prevention of PEP were collected during the inception to Nov. 2020. The methodological quality ，report quality and evidence quality of the included studies were evaluated by AMSTAR 2 scale，PRISMA statement and GRADE method. The effectiveness of PEP prevention was described. RESULTS ：Finally，23 systematic reviews were obtained ，including 12 in Chinese and 11 in English. Tweenty-two systematic reviews showed that compared with placebo ， indomethacin could effectively reduce the incidence of PEP. Eight systematic reviews showed that indomethacin significantly reduced the incidence of moderate and severe PEP compared with placebo. Five systematic reviews showed that indomethacin could reduce the incidence of postoperative hyperamylasemia compared with placebo. Three systematic reviews showed that indomethacin also had a good preventive effect on people with high risk of PEP. PRISMA score of included systematic reviews ranged from 15 to 25. The quality evaluation of AMSTAR 2 methodology included in systematic reviews was low ，and the key items of complete report were 4，9，11 and 13. The GRADE evidence quality evaluation of the included systematic reviews showed that the quality of the evidence was concentrated in the low level. CONCLUSIONS ：Indomethacin has a certain effect in the prevention of PEP ，but the overall evidence quality of the included literatures is generally not high. It needs to be further validated by high-quality clinical research.

Herb-drug interaction in the protective effect of Alpinia officinarum against gastric injury induced by indomethacin based on pharmacokinetic,tissue distribution and excretion studies in rats / 药物分析学报

Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis,abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effects.However,the role of herb-drug interaction between indomethacin and A.officinarum based on pharmacokinetic,tissue distribution and excretion still remains unknown.In this study,an ultra-fast liquid-tandem mass spectrometry(UFLC-MS/MS)method was developed for simultaneous determina-tion of indomethacin and its three metabolites,O-desmethylindomethacin(ODI),deschlor-obenzoylindomethacin(NDI)and indomethacin acyl-β-D-glucuronide(IDAβG)by oral administration of indomethacin solution with and without the ethanolic extract of A.officinarum and applied to comparative pharmacokinetic,tissue distribution and excretion studies.Our results clarified that oral administration of A.officinarum produced significant alterations in the pharmacokinetic parameters of indomethacin.And the pharmacokinetic interaction between indomethacin and A.officinarum reduced the systemic exposure of indomethacin and increased its elimination.Tissue distribution results demonstrated that co-administration of A.Officinarum could not reduce the accumulation of indo-methacin in the target tissue of the stomach,but could accelerate the excretions of indomethacin and its three metabolites including ODI,NDI and IDAβG in the bile and feces of rats in the excretion study.Therefore,A.Officinarum might have a gastrointestinal protective effect through the interaction role with indomethacin based on the pharmacokinetics and excretion in rats.

Antiulcerogenic effect of Capparis cartillaginea decne on indomethacin induced gastric ulcer in wistar rats

Background: Peptic ulcer disease is a non-malignant, mucosal lesion of the stomach or duodenum. The mucosal defect reaches the muscularis mucosa and sometimes, beyond causing life threatening complications, including haemorrhage, perforations, gastrointestinal obstruction and malignancy.Methods: The animals were pre-treated with omeprazole 20 mg/kg and 300 mg/kg of Capparis cartillaginea decne orally for 14 days. On the 15th day, ulcers were induced using indomethacin 30 mg/kg and 4 hours post ulcer induction, they were sacrificed. Ulcer index, pH, total acidity and volume were determined.Results: Extensive lesions were seen in indomethacin ulcerated rats with mean ulcer score of (1.260±0.18). In comparison, there were minimal areas of erosion on animals pre-treated with omeprazole (0.14±0.025) and plant extracts (0.280±0.097). Indomethacin-induced ulcer treated animals showed the highest volume of gastric juice output (3.14±0.21 ml), whereas the animals pre-treated with omeprazole had lower gastric juice output (2.20±0.2 9ml). This was comparable to animals pre-treated with the plant extract (1.80±0.13 ml). The pH was high in animals pre-treated with omeprazole (5.02±0.53). This was also seen in animals pre-treated with the extract (4.82±0.31). This was in comparison to the low pH seen in indomethacin ulcerated animals (2.20±0.16). Indomethacin-induced ulcer treated animals showed high levels of total acidity (88.64±1.71 mEq/L). Whereas the animals pre-treated with omeprazole had lower total acidity (55.26±3.77 mEq/L), which was also mirrored in animals pre-treated with the plant extracts (61.44±2.42 mEq/L).Conclusions: The extracts of Capparis cartillaginea decne showed anti-ulcer effect on indomethacin induced ulcers in Wistar rats.

Efectividad de la indometacina vs analgésico habitual en el tratamiento del dolor posthisterectomía / Effectiveness of using indomethacin vs usual analgesic in the management of postoperative pain in hysterectomy

Resumen: OBJETIVO: Determinar la efectividad de la indometacina, por vía rectal, en el tratamiento del dolor posthisterectomía versus paracetamol o metamizol administrados por vía intravenosa. MATERIALES Y MÉTODOS: Estudio experimental, comparativo y prospectivo llevado a cabo en el Hospital Central del Estado de Chihuahua entre noviembre y diciembre de 2019. Criterios de inclusión: pacientes histerectomizadas, con expediente clínico completo y de cualquier edad. Criterios de exclusión: pacientes con alteraciones en el umbral del dolor, inconsistencias en el expediente, histerectomía total no ginecológica. Criterios de eliminación: pacientes con limitantes en la información que no permitieron relacionar la variable dependiente con la independiente. El seguimiento del dolor referido se efectuó con la escala análoga del dolor y valoraciones a las 12 y 24 horas posteriores a la cirugía. RESULTADOS: Se reunieron 141 pacientes, que se dividieron en tres grupos. Grupo 1: metamizol intravenoso e indometacina por vía rectal (n = 24). Grupo 2: paracetamol intravenoso e indometacina por vía rectal (n = 19). Grupo 3: paracetamol y metamizol intravenosos (n = 98). La mayoría de las pacientes de los grupos 1 y 2 reportaron, a las 24 h, una escala visual análoga menor de 3 vs las del grupo 3. Diez de 98 pacientes requirieron tratamiento en el servicio de Anestesiología. CONCLUSIÓN: La administración de indometacina por vía rectal a pacientes histerectomizadas demostró menor dolor que con metamizol y paracetamol, y evolución clínica y alta hospitalaria más temprana.

Abstract: OBJECTIVE: To determine the effectiveness of indomethacin in the treatment of post-hysterectomy pain versus paracetamol or metamizole administered intravenously. MATERIALS AND METHODS: Experimental, comparative and prospective study at the Central Hospital of the State of Chihuahua, period November to December 2019, patients undergoing hysterectomy with complete clinical record, any age. Patients with alterations in the pain threshold, inconsistencies in the file, total non-gynecological hysterectomy were excluded, patients with information limitations were eliminated, which did not allow to relate the dependent variable, with the independent one. RESULTS: 141 patients were collected, which were divided into three groups. Group 1: intravenous metamizole and indomethacin rectally (n = 24). Group 2: intravenous paracetamol and indomethacin rectally (n = 19). Group 3: intravenous paracetamol and metamizole (n = 98). Most of the patients in groups 1 and 2 reported, at 24 hours, a visual analog scale of less than 3 vs those of group 3. Ten of 98 patients required treatment in the Anesthesiology service. CONCLUSION: The administration of indomethacin rectally in postoperative patients of hysterectomy has been shown to reduce pain more effectively than conventional analgesics such as metamizole and paracetamol, relating to clinical evolution and early hospital discharge.

The Protective Effect of Lercanidipine on Indomethacin-Induced Gastric Ulcers in Rats

Abstract Nonsteroidal anti-inflammatory drugs (NSAID) are among the aggressive factors causing gastric ulcer. They cause oxidative damage in the gastric tissue and lead to intracellular calcium deposition. Lercanidipine is a calcium channel blocker derived from the third generation dihydropyridine. The aim of this study is to analyse the effect of lercanidipine on indomethacin-induced gastric ulcers. A total of 24 albino Wistar male rats were divided into four groups; those who received indomethacin 25 mg/kg (IND), 5 mg mg/kg lercanidipine +25 mg/kg indomethacin (LC-5), 10 mg/kg lercanidipine+25mg/kg indomethacin (LC-10) and healthy rats who received 0.5 mL distilled water. Six hours after the application of indomethacin, the animals were sacrificed by high dose thiopental sodium. The stomachs of the animals were excised to perform a macroscopic analysis and the ulcerous region was measured on millimeter paper. All the stomachs were subjected to a biochemical analysis. Macroscopic analysis revealed hyperaemia on the gastric surface of the indomethacin group. Ulcerous tissues formed by oval, circular or irregular mucosal defects in varying diameters and depths were observed on the whole surface of the stomach. Hyperaemia was lower and ulcerous region was smaller in groups LC-5 and LC-10 compared to IND group. Malondialdehyde and myeloperoxidase levels were significantly lower and total glutathione and cyclooxygenase-1 activity were higher in groups LC-5 and LC-10. Lercanidipine did not change the cyclooxygenase-2 activity. Lercanidipine in doses 10 mg/kg is more effective compared to 5 mg/kg. Lercanidipinine can be useful in the treatment of NSAID-induced gastric damage.

Indomethacin attenuates mechanical allodynia during the organization but not the maintenance of the peripheral neuropathic pain induced by nervus ischiadicus chronic constriction injury

The neurochemical mechanisms underlying neuropathic pain (NP) are related to peripheral and central sensitization caused by the release of inflammatory mediators in the peripheral damaged tissue and ectopic discharges from the injured nerve, leading to a hyperexcitable state of spinal dorsal horn neurons. The aim of this work was to clarify the role played by cyclooxygenase (COX) in the lesioned peripheral nerve in the development and maintenance of NP by evaluating at which moment the non-steroidal anti-inflammatory drug indomethacin, a non-selective COX inhibitor, attenuated mechanical allodynia after placing one loose ligature around the nervus ischiadicus, an adaptation of Bennett and Xie's model in rodents. NP was induced in male Wistar rats by subjecting them to chronic constriction injury (CCI) of the nervus ischiadicus, placing one loose ligature around the peripheral nerve, and a sham surgery (without CCI) was used as control. Indomethacin (2 mg/kg) or vehicle was intraperitoneally and acutely administered in each group of rats and at different time windows (1, 2, 4, 7, 14, 21, and 28 days) after the CCI or sham surgical procedures, followed by von Frey's test for 30 min. The data showed that indomethacin decreased the mechanical allodynia threshold of rats on the first, second, and fourth days after CCI (P<0.05). These findings suggested that inflammatory mechanisms are involved in the induction of NP and that COX-1 and COX-2 are involved in the induction but not in the maintenance of NP.

Reduction-Responsive Nanocarrier Co-delivery Indomethacin and Doxorubicin for Overcoming Multi-drug Resistant Breast Cancer / 中国药学杂志

OBJECTIVE: To prepare a reduction-responsive nanoparticle (HID-NPs) for indomethacin (IND) and doxorubicin (DOX) delivering and investigate their effects on reversing multidrug resistance in breast cancer. METHODS: Hyaluronic acid-based amphiphilic substances (HA-SS-PA) were prepared by amidation reaction, and their structures were confirmed by NMR. HID-NPs were prepared by nano-precipitation method. The particle size measurement and morphology observation of the HID-NPs were measured by dynamic light scanning (DLS) and transmission electron microscopy (TEM), respectively. The reduction-responsive drug release behavior of HID-NPs was determined by dialysis method. Cell uptake HID-NPs on human breast cancer MCF-7/ADR cells were observed by laser confocal microscopy. The cytotoxicity of HID-NPs on human breast cancer MCF-7 and MCF-7/ADR cells was determined by MTT assay. RESULTS: 1H-NMR spectrum indicated that HA-SS-PA was successfully prepared. The results of DLS and TEM showed that HID-NPs were round and evenly distributed with an average particle size of (103±3.2) nm. Drug release assay indicates that HID-NPs have good reduction-responsiveness ability. Cell uptake experiments demonstrated that HID-NPs significantly increased DOX accumulation in MCF-7/ADR cells compared with free DOX; MTT assays showed that HID-NPs could significantly destroy MCF-7/ADR cells. CONCLUSION: HID-NPs shows good reduction-responsiveness and obvious reverse DOX resistance, which can be used for the treatment of multidrug resistance of breast tumors.

Preparation and Characterization of Ternary Indomethacin Solid Dispersion Based on Quality by Design (QbD) Concept / 中国药学杂志

OBJECTIVE: To prepare a ternary supersaturated indomethacin (IND) solid dispersion and investigate its characteristics by screening carrier materials with different functions based on quality by design (QbD) concept. METHODS: Based on dissolution tests, the carriers with solubilization function were selected and the appropriate drug loading ratio of binary solid dispersion was determined. The material as inhibitor of precipitation was chosen using the solvent shift method. The IND ternary supersaturated solid dispersion was prepared by the hot melt extrusion of IND, solubilization material and precipitation inhibitor. The dispersion state of IND was identified by differential scanning calorimetry and powder X-ray diffraction, and its characteristics were explored by the powder wettability test and the stability test. RESULTS: The binary IND solid dispersion with Eudragit EPO could sharply increase IND dissolution rate with a behavior of more than 80%dissolution within 5 min but subsequently followed an obvious concentration decline. Kollidon VA64 had a satisfactory effect of precipitation inhibition for IND supersaturated solution in that the concentration of 0.1% could keep the 50 μg•mL-1 IND solution unchanged within 30 min. The ternary solid dispersion with a mass ratio of 1:2:0.3 (IND:EPO:VA64) could significantly increase the dissolution of IND, eliminating the crystallization and precipitation of the drug in the supersaturated system during the dissolution process and enabling the drug to maintain amorphous form within 3 months. CONCLUSION: Based on the understanding of the functions of different carrier materials and the QbD concept, it could effectively improve the formulation design of solid dispersions. The prepared ternary IND solid dispersions have excellent drug dissolution behavior.

Mechanistic evaluation of gastro-protective effects of KangFuXinYe on indomethacin-induced gastric damage in rats / 中国天然药物

KangFuXinYe (KFX), the ethanol extract of the dried whole body of Periplaneta americana, is a well-known important Chinese medicine preparation that has been used to treat digestive diseases such as gastric ulcers for many years in China. However, its therapeutic effect and mechanism are not yet well understood. Thus, the aim of this study was to investigate the gastro-protective effects of KangFuXinYe (KFX) in indomethacin-induced gastric damage. Rats were randomly divided into six groups as follows: control, treated with indomethacin (35 mg·kg), different dosages of KFX (2.57, 5.14 and 10.28 mL·kg, respectively) plus indomethacin, and sucralfate (1.71 mL·kg) plus indomethacin. After treatment, rat serum, stomach and gastric homogenates were collected for biochemical tests and examination of histopathology firstly. Rat serum was further used for metabolomics analysis to research possible mechanisms. Our results showed that KFX treatment alleviated indomethacin-induced histopathologic damage in rat gastric mucosa. Meanwhile, its treatment significantly increased cyclooxygenase-1 (COX-1), prostaglandin E (PGE) and epidermal growth factor (EGF) levels in rat serum and gastric mucosa. Moreover, KFX decreased cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) levels. Nine metabolites were identified which intensities significantly changed in gastric damage rats, including 5-hydroxyindoleacetic acid, indoxylsulfuric acid, indolelactic acid, 4-hydroxyindole, pantothenic acid, isobutyryl carnitine, 3-methyl-2-oxovaleric acid, sphingosine 1-phosphate, and indometacin. These metabolic deviations came to closer to normal levels after KFX intervention. The results indicate that KFX (10.28 mL·kg) exerts protective effects on indomethacin-induced gastric damage by possible mechanisms of action (regulating tryptophan metabolism, protecting the mitochondria, and adjusting lipid metabolism, and reducing excessive indomethacin).

Influence of Bacopa monnieri in suppressing the arthritis induced by MSU crystal in Wistar albino female rats: Through biochemical and histopathological approach

Gouty arthritis is caused due to the accumulation of uric acid crystals in joints which is the by-product of purinemetabolism in our body. The elevated level of uric acid in the blood is known as hyperuricemia that may resultsin deposition and inflammation of joints. This research experiment has examined the protective effect of Bacopamonnieri, an herb against the monosodium urate crystal-induced gouty arthritis in female Wistar albino rats. The ratswere divided into four groups with six rats in each group. Group-I was normal control rats, group-II rats were inducedwith monosodium urate crystal, group-III was administrated with B. monnieri in monosodium urate crystal-inducedrats, and group-IV was administrated with indomethacin in monosodium urate crystal-induced rats. The rats wereexamined for liver enzyme markers, antioxidant assays, and paw histopathology. The results of B. monnieri werecompared with that of standard drug indomethacin. The symptoms of arthritis, such as the elevation of paw volume,increased liver enzyme markers, decreased antioxidant enzymes, and histopathological changes, were found to bereversed to the normal level by the treatment with B. monnieri which is due to its anti-inflammatory properties. Asconclusion, B. monnieri has shown its anti-arthritic properties against gouty arthritis.

Tratamiento farmacológico del conducto arterioso permeable en recién nacidos prematuros / Pharmacological treatment of patent ductus arteriosus in premature infants

Resumen Introducción. Por lo general, el manejo farmacológico del conducto arterioso permeable (CAP) comprende inhibidores no selectivos de la enzima ciclooxigenasa, en especial indometacina e ibuprofeno. En años recientes también se ha sugerido al acetaminofén como alternativa terapéutica. Objetivo. Realizar una revisión narrativa de la literatura acerca del manejo farmacológico del CAP. Materiales y métodos. Se realizó una búsqueda estructurada de la literatura en las bases de datos ProQuest, EBSCO, ScienceDirect, PubMed, LILACS, Embase, Trip Database, SciELO y Cochrane Library con los términos "Ductus Arteriosus, patentAND therapeutics"; "Ductus Arteriosus, patent AND indometacin"; "Ductus Arteriosus, PatentAND ibuprofen", y "Ductus Arteriosus, patent AND acetaminophen". La búsqueda se hizo en inglés con sus equivalentes en español. Resultados. Se encontraron 69 artículos con información relevante para llevar a cabo la presente revisión. Conclusiones. En neonatos prematuros, la base del tratamiento farmacológico del CAP continúa siendo los inhibidores no selectivos de la ciclooxigenasa, indometacina e ibuprofeno, ambos con perfiles similares de seguridad y eficacia. La evidencia disponible sugiere que el acetaminofén podría constituir una alternativa útil para el manejo, pero resulta insuficiente para realizar recomendaciones definitivas respecto a la eficacia y seguridad de este medicamento.

Abstract Introduction: Pharmacological management ofpatent ductus arteriosus (PDA) usually includes non-selective inhibitors of the enzyme cyclooxygenase, especially indomethacin and ibuprofen. Recently, acetaminophen has also been suggested as a therapeutic alternative. Objective: To conduct a narrative review of the literature on pharmacological management of PDA. Materials and methods: Structured literature search conducted on the ProQuest, EBSCO, ScienceDirect, PubMed, LILACS, Embase, Trip Database, SciELO and Cochrane Library databases, with the terms "Ductus Arteriosus, patentAND therapeutics"; "Ductus Arteriosus, patent AND indometacin"; "Ductus Arteriosus, Patent AND ibuprofen", and "Ductus Arteriosus, patent AND acetaminophen", and their equivalents in Spanish. Results: 69 articles had relevant information to carry out the present review. Conclusions: In premature infants, the mainstay of pharmacological treatment for PDA continues to be non-selective cyclooxygenase inhibitors, indomethacin and ibuprofen, all with similar safety and efficacy profiles. The available evidence suggests that acetaminophen may be a useful alternative for management, but it is insufficient to make definitive recommendations regarding the efficacy and safety of this drug.

Evaluation of antiulcer activity of ethanolic leaf extract of Coccinia grandis in indomethacin induced gastric ulcer model

Background: Gastric mucosal ulceration is the most common adverse effect with NSAIDS. Antacids, H2 blockers and PPIs are considered novel in treating ulcers but are not devoid of side effects. Hence, there a need for a drug which is effective against NSAID induced ulcers with no side effects. Coccinia grandis plant is traditionally used for the treatment of gastric/peptic ulcers. Hence, this study has been undertaken to scientifically validate the antiulcer activity of Coccinia grandis leaves against indomethacin induced gastric ulcer model.Methods: Following preparation of the extract, 24 Wistar rats were divided into 4 groups with 6 rats in each group (n=6). Group 1 received 1% CMC, group 2 received 1% CMC +indomethacin 40 mg/kg, group 3 received ethanolic leaf extract of Coccinia grandis 200 mg/kg +indomethacin 40 mg/kg and group 4 received omeprazole (2 mg/kg) +indomethzacin 40 mg/kg for 7 days. Calculation of ulcer score was done using ulcer index and percentage protection.Results: The ulcer index score (2.12�21) and percentage protection (69.71%) was comparable with the standard drug (1.76�11, 74.85%) respectively.Conclusions: The ethanolic leaf extract of Coccinia grandis showed significant antiulcer activity against indomethacin-induced gastric ulcer. Further studies are warranted to elucidate the exact mechanism of antiulcer activity.

Evaluation of antiulcerogenic activity of combination of Aloe vera and Aegle marmelos in indomethacin induced gastric ulcers

Background: Most important adverse effect of NSAID is peptic ulceration. Even though H2 blockers and proton pump inhibitors are effective in preventing NSAID associated peptic ulceration, they are not without side effects. Hence there is a need for drugs which are effective in preventing NSAID induced peptic ulcer without producing side effects. Two plant products Aloe vera leaf extract and Aegle marmalos leaves are commonly used in Indian traditional medicine for treatment of peptic ulcers. Hence this study is undertaken to assess the antiulcerogenic potential of combination of these two drugs in comparison with ranitidine in preventing NSAID induced peptic ulcers.Methods: 18 albino rats were divided into 3 groups of 6 rats each. Group A: received ulcerogen only. Group B: pretreated with ranitidine before exposing to ulcerogen. Group C: pretreated with combination of Aloe vera and Aegle marmelos before exposing to ulcerogen. Two doses of indomethacin were administered at an interval of 15 hrs. Animals were sacrificed 6 hrs after the second dose of Indomethacin. Number of ulcers was noted, and ulcer index was calculated.Results: There was significant reduction in total score, mean score and ulcer index in ranitidine pretreated group and test compound group as compared to control group. Even though the total score and ulcer index in test group were lesser as compared to standard control group, it was not statistically significant.Conclusions: Combination of Aloe vera leaf extract and Aegle marmelos leaf extract produced very significant protection against indomethacin induced gastric ulcer.

Periapical bone response to bacterial lipopolysaccharide is shifted upon cyclooxygenase blockage

Abstract Objectives: Infection, inflammation and bone resorption are closely related events in apical periodontitis development. Therefore, we sought to investigate the role of cyclooxygenase (COX) in osteoclastogenesis and bone metabolism signaling in periapical bone tissue after bacterial lipopolysaccharide (LPS) inoculation into root canals. Methodology: Seventy two C57BL/6 mice had the root canals of the first molars inoculated with a solution containing LPS from E. coli (1.0 mg/mL) and received selective (celecoxib) or non-selective (indomethacin) COX-2 inhibitor. After 7, 14, 21 and 28 days the animals were euthanized and the tissues removed for total RNA extraction. Evaluation of gene expression was performed by qRT-PCR. Statistical analysis was performed using analysis of variance (ANOVA) followed by post-tests (α=0.05). Results: LPS induced expression of mRNA for COX-2 (Ptgs2) and PGE2 receptors (Ptger1, Ptger3 and Ptger4), indicating that cyclooxygenase is involved in periapical response to LPS. A signaling that favours bone resorption was observed because Tnfsf11 (RANKL), Vegfa, Ctsk, Mmp9, Cd36, Icam, Vcam1, Nfkb1 and Sox9 were upregulated in response to LPS. Indomethacin and celecoxib differentially modulated expression of osteoclastogenic and other bone metabolism genes: celecoxib downregulated Igf1r, Ctsk, Mmp9, Cd36, Icam1, Nfkb1, Smad3, Sox9, Csf3, Vcam1 and Itga3 whereas indomethacin inhibited Tgfbr1, Igf1r, Ctsk, Mmp9, Sox9, Cd36 and Icam1. Conclusions: We demonstrated that gene expression for COX-2 and PGE2 receptors was upregulated after LPS inoculation into the root canals. Additionally, early administration of indomethacin and celecoxib (NSAIDs) inhibited osteoclastogenic signaling. The relevance of the cyclooxygenase pathway in apical periodontitis was shown by a wide modulation in the expression of genes involved in both bone catabolism and anabolism.