ABSTRACT
This study aimed to investigate the therapeutic effect of Leonuri Herba aqueous decoction on primary dysmenorrhea(PD) and explore the underlying mechanism in conjunction with untargeted metabolomics. Forty adult female rats were randomly divi-ded into a normal group, a model control group, ibuprofen(0.12 g·kg~(-1)) group, and high-and low-dose Leonuri Herba aqueous decoction(5 and 2.5 g·kg~(-1)) groups, with eight rats in each group. The PD rat model was prepared using intramuscular injection of estradiol benzoate combined with intraperitoneal injection of pitocin. Drugs were administered by gavage from the 4th day of modeling for 7 d. After the last administration, pitocin was injected intraperitoneally, and the writhing latency and writhing times within 30 min were recorded. The uterine and ovarian coefficients were determined. Estradiol(E_2), progesterone(Prog), oxytocin(OT), cyclooxyge-nase 2(COX-2), prostaglandin E_2(PGE_2), prostaglandin F_(2α)(PGF_(2α)), and Ca~(2+) levels in uterine tissues were measured by ELISA and biochemical kits. Morphological changes in uterine and ovarian tissues were observed by hematoxylin-eosin(HE) staining. The protein expression of oxytocin receptor(OTR), prostaglandin E_2 receptor 3(EP3), and estrogen receptor alpha(ERα) in uterine tissues was detected by immunohistochemistry. The mRNA expression of OTR, PGE_2 receptors 1-4(EP1, EP2, EP3, and EP4), and PGF_(2α) receptor(FP) in uterine tissues was detected by quantitative real-time PCR. Untargeted metabolomics analysis was performed by ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(LC-QTOF-MS) technology to screen potential biomarkers and enrich metabolic pathways. The results showed that Leonuri Herba was able to significantly reduce the writhing times in PD rats(P<0.05 or P<0.01), significantly reduce the uterine and ovarian coefficients(P<0.01), and improve their histomorphology. After treatment with Leonuri Herba, PGE_2 content was significantly increased(P<0.05), COX-2, PGF_(2α) and Ca~(2+) content, and PGF_(2α)/PGE_2 was significantly decreased(P<0.05 or P<0.01), and OT content was decreased, while E_2 and Prog content tended to further increase in uterine tissues of PD rats. Correspondingly, OTR and EP3 protein expression was significantly downregulated(P<0.05 or P<0.01) and ERα protein expression was upregulated(P<0.05) in uterine tissues. The mRNA expression of FP and EP4 in uterine tissues was significantly downregulated(P<0.01), and the mRNA expression of EP1, EP3, and OTR showed a decreasing trend. The untargeted metabolomics results showed that 10 differential metabolites were restored in the plasma of PD rats after Leonuri Herba treatment. The results indicate that Leonuri Herba is effective in the prevention and treatment of PD, and the underlying mechanism may be attributed to the regulation of PGs synthesis and corresponding receptor binding.
Subject(s)
Humans , Rats , Female , Animals , Estrogen Receptor alpha , Oxytocin , Dysmenorrhea/metabolism , Cyclooxygenase 2 , Dinoprostone , RNA, Messenger/metabolism , DinoprostABSTRACT
RESUMEN Introducción: se sabe que las concentraciones plasmáticas de hormona antidiurética o vasopresina son más altas en las mujeres con dismenorrea primaria (DiPr) y podría ser causa de retención de agua con signos y síntomas concomitantes que agravan su cuadro clínico. La monoterapia con AINEs en ocasiones alcanza solo un alivio parcial porque no incide sobre la vasopresina. Objetivo: evaluar la eficacia y tolerabilidad del dexketoprofeno + pamabrom en la DiPr tomando como referencia el acetaminofén. Materiales y métodos: estudio doble ciego, controlado, randomizado, en pacientes con DiPr asignados al azar. Fueron aleatorizadas 172 pacientes, 86 en cada grupo 1) Grupo casos (DP): dexketoprofeno + pamabrom o 2) Grupo control (AC): acetaminofén. Se evaluó la evolución de la intensidad del dolor, el alivio del dolor, la gravedad de otros síntomas presentes y la satisfacción global del médico y paciente. Se registró las reacciones adversas. Resultados: la disminución de la intensidad del dolor, de los síntomas acompañantes y el alivio del dolor evaluados por la EVA, la PID, la SPID, el PAR y el TOTPAR respectivamente es mayor y más rápida de modo significativo en todos los tiempos para la combinación DP. Las reacciones adversas fueron mínimas. La satisfacción global de pacientes y médicos respecto al tratamiento es significativa a favor de la combinación DP. Conclusiones: dexketoprofeno + pamabrom es significativamente más eficaz y rápido en el control del dolor y otros síntomas presentes en la dismenorrea primaria que acetaminofén demostrando la validez de añadir un diurético suave a un AINE para incrementar su eficacia. El tratamiento DP es bien tolerado (AU).
ABSTRACT Background: It is known that plasma concentrations of antidiuretic hormone or vasopressin are higher in women with primary dysmenorrhea (DiPr) and could cause water retention with concomitant signs and symptoms that aggravate the illness. Monotherapy with NSAIDs sometimes achieves only partial relief because it does not affect vasopressin. Objective: The aim was to evaluate the efficacy and tolerability of dexketoprofen + pamabrom in DiPr taking as reference acetaminophen. Materials and methods: Double-blind, controlled, randomized study in patients with DiPr random to 1) Case group (PD): dexketoprofen + pamabrom or 2) Control group (CA): acetaminophen. The evolution of pain intensity, pain relief, severity of other present symptoms and overall satisfaction of the doctor and patient were evaluated. Adverse reactions were recorded. Results: 172 patients were randomized, 86 in each group. The decrease in pain intensity, accompanying symptoms and pain relief evaluated by VAS, PID, SPID, PAR and TOTPAR respectively is significantly greater and faster at all times for the combination DP. Adverse reactions were minimal. The overall satisfaction of patients and doctors regarding treatment is significant in favor of the DP combination. Conclusions: Dexketoprofen + pamabrom is significantly more effective and faster in the control of pain and other symptoms present in primary dysmenorrhea than acetaminophen demonstrating the validity of adding a mild diuretic to an NSAID to increase its effectiveness. DP treatment is well tolerated (AU).
Subject(s)
Humans , Female , Vasopressins/pharmacology , Dysmenorrhea/drug therapy , Treatment Outcome , Drug Combinations , Dysmenorrhea/classification , Dysmenorrhea/metabolism , Dysmenorrhea/pathology , Observational Studies as TopicABSTRACT
En este trabajo se ha determinado el contenido de cobre y zinc en suero sanguíneo de 39 mujeres con edades comprendidas entre 17 y 21 años de edad, n = 25 con dismenorrea primaria diagnosticada clínicamente y n = 14 grupo control con diagnóstico negativo para la patología estudia-da. Las muestras de suero sanguíneo se obtuvieron antes (a) y durante (d) la menstruación. Fueron analizadas por Espectroscopia de Absorción Atómica con inyección en flujo continuo (EAA-IFC). Las concentraciones obtenidas fueron de 1,56 ± 0,43 mgL-1 de cobre y 1,28 ± 0,34 mgL-1 de zinc antes de la menstruación y 1,06 ± 0,23 mgL-1 de co bre y 1,21 ±0,4 mgL-1 de zinc durante la menstruación, para el grupo control y 1,64 ± 0,52 mgL-1 de cobre y 1,88 ± 0,61 mgL-1 de zinc antes de la menstruación y 1,21 ± 0,34 mgL-1 de cobre y 0,94 ± 0,27 mgL-1 de zinc durante la mens ruaciónt en el grupo estudio. Los elementos determinados en ambos grupos antes del periodo menstrual, no observaron diferencias significativas con p= 0,63 y 0,16 para cobre y zinc, respectivamente. Sin embargo, durante la menstruación, fue evidente una diferencia con p < 0,005. Este resultado nos hace presumir, que el aumento brusco de los niveles séricos de cobre se deba probablemente por la alteración de las prostaglandinas, siendo este bioelemento uno de los responsables de las molestias que se presentan en esta patología y otros efectos secundarios motivados por el descenso brusco del zinc. La relación cobre/zinc se calculo en ambos grupos, con valores de 1,47 y 1,06 antes y durante, respectivamente para el grupo control y para el grupo bajo estudio 1,36 y 1,97 antes y durante, respectivamente.
In this work has determined the copper content and zinc in sanguineous serum of women with primary dysmenorrheal diagnosed clinically and a group of women control with I diagnose negative for the studied pathology. The samples of sanguineous serum taken before (a) and during (d) the second day of the menstruation come from 39 women in ages between 17 and 21 years of age, n = 14 controls and n = 25 women with primary dysmenorrheal. They were processed by Spectroscopy of Atomic Absorption with injection in con-tinuous flow (EAA-IFC). The concentrations obtained of 1.56± 0.43 mgL-1 of copper and 1.28± 0.34 mgL-1 of zinc before menstruation and 1.06 ±0.23 mgL-1 of copper and 1.21 ±0.4 mgL-1 of zinc during the menstruation (second day), for the group control and 1.64 ±0.52 mgL-1 of copper and 1.88 ±0.61 mgL-1 of zinc before menstruation and 1.21± 0.34 mgL-1 of copper and 0.94± 0.27 mgL-1 of zinc during the menstruation in the group study. In relation to the serum levels it initiates to them in both groups were not significant differences (p = 0.63). The zinc, observe he himself behavior, between both groups before the menstruation was not observed significant differences with p = 0.16, nevertheless, during the menstruation I throw p = 0.0033. This result evi-dence that indeed the copper is affected by the alteration of the prostaglandins, being probably one of the people in charge of the annoyances that appear in this pa hologyt and other indirect effect motivated by the abrupt reduction of the zinc, such as alteration in the synthesis and excretion of the hormone stimulating follicle (FSH), of the luteinizante hormone (LH), abnormal development of the ovary, alterations of the menstrual cycle. The copper/zinc re ationl I calculate both groups, with values of 1.47 and 1,06 before and during res pectively for the group control and the group under study 1,36 and 1.97 before and during respectively.