Histological changes caused by meclofenamic acid in androgen independent prostate cancer tumors: evaluation in a mouse model

ABSTRACT Meclofenamic acid is a nonsteroidal anti-inflammatory drug that has shown therapeutic potential for different types of cancers, including androgen-independent prostate neoplasms. The antitumor effect of diverse nonsteroidal anti-inflammatory drugs has been shown to be accompanied by histological and molecular changes that are responsible for this beneficial effect. The objective of the present work was to analyze the histological changes caused by meclofenamic acid in androgen-independent prostate cancer. Tumors were created in a nude mouse model using PC3 cancerous human cells. Meclofenamic acid (10 mg/kg/day; experimental group, n=5) or saline solution (control group, n=5) was administered intraperitoneally for twenty days. Histological analysis was then carried out on the tumors, describing changes in the cellular architecture, fibrosis, and quantification of cellular proliferation and tumor vasculature. Meclofenamic acid causes histological changes that indicate less tumor aggression (less hypercellularity, fewer atypical mitoses, and fewer nuclear polymorphisms), an increase in fibrosis, and reduced cellular proliferation and tumor vascularity. Further studies are needed to evaluate the molecular changes that cause the beneficial and therapeutic effects of meclofenamic acid in androgen-independent prostate cancer.

Gap Junction Contributions to the Goldfish Electroretinogram at the Photopic Illumination Level

Understanding how the b-wave of the electroretinogram (ERG) is generated by full-field light stimulation is still a challenge in visual neuroscience. To understand more about the origin of the b-wave, we studied the contributions of gap junctions to the ERG b-wave. Many types of retinal neurons are connected to similar and different neighboring neurons through gap junctions. The photopic (cone-dominated) ERG, stimulated by a small light beam, was recorded from goldfish (Carassius auratus) using a corneal electrode. Data were obtained before and after intravitreal injection of agents into the eye under a photopic illumination level. Several agents were used to affect gap junctions, such as dopamine D1 and D2 receptor agonists and antagonists, a nitric oxide (NO) donor, a nitric oxide synthase (NOS) inhibitor, the gap junction blocker meclofenamic acid (MFA), and mixtures of these agents. The ERG b-waves, which were enhanced by MFA, sodium nitroprusside (SNP), SKF 38393, and sulpiride, remained following application of a further injection of a mixture with MFA. The ERG b-waves decreased following NG-nitro-L-arginine methyl ester (L-NAME), SCH 23390, and quinpirole administration but were enhanced by further injection of a mixture with MFA. These results indicate that gap junction activity influences b-waves of the ERG related to NO and dopamine actions.

Role of nitric oxide and prostaglandin in the maintenance of cortical and renal medullary blood flow

This study was undertaken in anesthetized dogs to evaluate the relative participation of prostaglandins (PGs) and nitric oxide (NO) in the maintenance of total renal blood flow (TRBF), and renal medullary blood flow (RMBF). It was hypothesized that the inhibition of NO should impair cortical and medullary circulation because of the synthesis of this compound in the endothelial cells of these two territories. In contrast, under normal conditions of perfusion pressure PG synthesis is confined to the renal medulla. Hence PG inhibition should predominantly impair the medullary circulation. The initial administration of 25 µM kg-1 min-1 NG-nitro-L-arginine methyl ester produced a significant 26 percent decrease in TRBF and a concomitant 34 percent fall in RMBF, while the subsequent inhibition of PGs with 5 mg/kg meclofenamate further reduced TRBF by 33 percent and RMBF by 89 percent. In contrast, the initial administration of meclofenamate failed to change TRBF, while decreasing RMBF by 49 percent. The subsequent blockade of NO decreased TRBF by 35 percent without further altering RMBF. These results indicate that initial PG synthesis inhibition predominantly alters the medullary circulation, whereas NO inhibition decreases both cortical and medullary flow. This latter change induced by NO renders cortical and RMBF susceptible to a further decrease by PG inhibition. However, the decrease in medullary circulation produced by NO inhibition is not further enhanced by subsequent PG inhibition.

Pharmacokinetics of sodium meclofenamate in pre-ruminant cattle

O perfil do meclofenamato sódico, uma droga antiinflamatória não-esteroidal, foi determinado em seis bezerros pré-ruminantes após administração intravenosa e intramuscular na dose de 2,2mg/kg de peso vivo. As concentrações de meclofenamato foram medidas empregando-se cromatografía líquida de alta performance. A farmacocinética do meclofenamato sódico, após as administrações intravenosa e intramuscular, caracterizou-se por rápida fase de distribuição (t½a ), 15,45±4,85min e 23,14± 7,24min para a administração intravenosa e intramuscular, respectivamente, seguida por longa fase de eliminação (t½b ), após a aplicação intramuscular (17,55±6,52h.). O volume aparente de distribuição (Vd) da administração intravenosa da droga foi moderado (0,72±0,12l/kg), e após um lapso da aplicação intramuscular, foi alta (3,51±1,05l/kg). Isso pode ser explicado pelo efeito flip-flop ou por evitar a via enteroépatica. A biodisponibilidade obtida após administração intramuscular foi de 61 por cento.

Attenuating Effect of cAMP on Hypoxic Pulmonary Vasoconstriction in the Isolated Perfused Rat Lungs / 대한마취과학회지

BACKGROUND: Pulmonary vessels constrict when they are exposed to hypoxia, unlike other vessels. It is hypothesized that the decreased concentration of cAMP in the hypoxic condition causes this reaction, HPV (hypoxic pulmonary vasoconstriction). When cAMP concentration is increased by either activating adenylate cyclase, using adenosine, or inhibiting the cAMP hydrolysing enzyme, phosphodiesterase type 3, using amrinone, then HPV can be reversed. The aims of this study were to develop HPV in an isolated perfused rat lung preparation, and to investigate the vasodilating effects of adenosine and amrinone on HPV. METHODS: Isolated lungs from male rats (270 330 g) were ventilated with a normoxic gas mixture (21%O2-5%CO2-74%N2) or a hypoxic gas mixture (3%O2-5%CO2-92%N2) alternately, and perfused with calcium-containing perfusate solution. Adenosine (6 x 100-2 microgram, n = 6) and amrinone (5 x 101-3 microgram, n = 6) were mixed to perfusate solution, and the initial hypoxic pressor response { Pin = Pmax (maximum pulmonary artery pressure) - Pin (initial pulmonary artery pressure)} and hypoxic pressor responses after drug administration { Pdrug = Pmax (maximum pulmonary artery pressure) - Pbase (baseline pulmonary artery pressure)} were measured. Meclofenamate was used to block prostaglandin-mediated vasorelaxation. RESULTS: Adenosine did not decrease Pdrug compared to Pin. But amrinone inhibited HPV effectively a with a linear dose-response relationship (r = 0.842, P< 0.05). y = 26.72 x log (x) 35.79y: % relaxation = 100 [ Pdrug/ Pin] 100 , x: amount of drug, microgram, CONCLUSIONS: Amrinone attenuated HPV, and it can be concluded that increased levels of cAMP helpful to relax pulmonary vessels in hypoxic condition.

A Comparative Study of Inhibition of Postsurgical Adhesion Formation in the Rat Model by Nonsteroid Antiinflammatory Drugs , Heparin , Hyskon , and TC-7 / 대한산부인과학회잡지

The purpose of this study was to evaluate and compare the effect of inhibition of postsurgical adhesion formation in the rat model by meclofenamate, tolmetin, TC-7, Hyskon, and heparin. Laparotomies were performed on grossly healthy, mature nonpregnant female rats, and proximal 1 cm of each uterine horn was traumatized with unipolar electrocautery. Each rat was randomly assigned to one of six different groups(control, meclofenamate, tolmetin, heparin, TC-7, and Hyskon group), and different solutions or an adhesion barrier were placed into traumatized uterine horn before closure. One week later adhesion formation was scored according to percent involvement of each traumatized uterine horn(0 to 4), and adhesion density(0 to 2), and compared using one-way analysis of variance and Fishers exact test. Compared with the control group, postsurgical adhesion formation was significantly decreased in the TC-7 group(average adhesion score, 1.72), the meclofenamate group(2.19), the Hyskon group(2.53), and the tolmetin group(2.93). The TC-7 group was also significantly decreased in adhesion formation compared with the Hyskon, tolmetin, heparin groups, and meclofenamate group was significantly decreased in adhesion formation compared with tolmetin and heparin groups. There were no significant differences between groups in adhesion density. So we suggest that meclofenamate is a cost-effective agent in inhibition of postsurgical adhesion formation.

Effect of glomerulopressin on GFR of rats, role of cyclooxygenase inhibitors and saralasin

En trabajos anteriores se ha demostrado que la glomerulopresina aumenta la filtración glomerular (FG) en sapos, ratas y perros. El efecto de la glomerulopresina es bloqueado por inhibidores de la ciclooxigenasa en varios sistemas. Este trabajo se llevó a cabo con el propósito de estudiar si los inhibidores de la ciclooxigenasa y el bloqueador de los receptores de Ang II, saralasina, impiden el efecto de la glomerulopresina sobre la FG de la rata. Se midió la depuración de inulina en ratas infundidas durante todo el experimento con indometacina o meclofenamato o con saralasina por la vena yugular. Se consideró un período de control durante el cual se infundió Krebs-Ringer-Bicarbonato (KRB) por la arteria femoral y un período experimental durante el cual, en alguns grupos, se cambió la infusión de KRB por la de glomerulopresina. Los inhibidores de la ciclooxigenasa y la saralasina impidieron el aumento de la FG producido por la glomerulopresina. Parece razonable proponer que la glomerulopresina puede aumentar la FG sólo cuando los receptores de la Ang II están libres y que su acción es mediada por la síntesis de prostaglandinas

Efecto del ácido meclofenámico sobre la pérdida de sangre menstual en mujeres hipermenorreicas usuarias de dispositivo intrauterino / Effect of meclofenamic acid on menstrual bleeding of hypermenorrheic women users of intrauterine devices

Con el objeto de evaluar el efecto del ácido meclofenámico sobre la pérdida de sangre menstrual en mujeres usuarias de dispositivo intrauterino, afectas a hipermenorrea, se administró este producto en dosis de 100 mg cada 8 horas por 3 días durante 2 ciclos menstruales consecutivos a una población seleccionada de pacientes de nuestro consultorio de planificación familiar, en las que la medición de la pérdida de sangre menstrual promedio durante dos ciclos consecutivos con la administración de un placebo fue de 60 o más ml por período. De un total de 40 pacientes reclutadas, 20 iniciaron la ingesta del fármaco en el período premenstrual inmediato y 20 iniciaron la ingesta del fármaco en el primer día menstrual. En el grupo menstrual, el 80% de las pacientes presentó una reducción de la pérdida de sangre menstrual al comparar los 2 ciclos placebo versus ciclos de tratamiento (reducción promedio de 25,2 ml por ciclo). En el grupo premenstrual el 70% de las pacientes presentó respuesta reductora de la pérdida de sangre menstrual, con reducción promedio de 30,3 ml por ciclo (25,1%). La similitud de respuesta, sumada a otras ventajas, aconseja el inicio de la ingesta del ácido meclofenámico en el primer día menstrual. La magnitud de la respuesta reductora de la pérdida de sangre menstrual representa un importante efecto benéfico sobre el balance del metabolismo del fierro en mujeres usuarias de dispositivo intrauterino. La no respuesta del total de pacientes al ácido meclofenámico permite entrever la existencia de otros factores, ajenos a las prostaglandinas, en la hipermenorrea que se presenta en las usuarias de dispositivos intrauterinos no hormonales