Effects of dipyrone on the digestive tract

Dipyrone (metamizole), acting through its main metabolites 4-methyl-amino-antipyrine and 4-amino-antipyrine, has established analgesic, antipyretic, and spasmolytic pharmacological effects, which are mediated by poorly known mechanisms. In rats, intravenously administered dipyrone delays gastric emptying (GE) of liquids with the participation of capsaicin-sensitive afferent fibers. This effect seems to be mediated by norepinephrine originating from the sympathetic nervous system but not from the superior celiac-mesenteric ganglion complex, which activates β2-adrenoceptors. In rats, in contrast to nonselective non-hormonal anti-inflammatory drugs, dipyrone protects the gastric mucosa attenuating the development of gastric ulcers induced by a number of agents. Clinically, it has been demonstrated that dipyrone is effective in the control of colic-like abdominal pain originating from the biliary and intestinal tracts. Since studies in humans and animals have demonstrated the presence of β2-adrenoceptors in biliary tract smooth muscle and β2-adrenoceptor activation has been shown to occur in dipyrone-induced delayed GE, it is likely that this kind of receptors may participate in the reduction of smooth muscle spasm of the sphincter of Oddi induced by dipyrone. There is no evidence that dipyrone may interfere with small bowel and colon motility, and the clinical results of its therapeutic use in intestinal colic appear to be due to its analgesic effect.

Effect of selective beta-adrenoceptor blockade and surgical resection of the celiac-superior mesenteric ganglion complex on delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

There is evidence for participation of peripheral β-adrenoceptors in delayed liquid gastric emptying (GE) induced in rats by dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At). The present study aimed to determine whether β-adrenoceptors are involved in delayed GE induced by phenylpyrazole derivatives and the role of the prevertebral sympathetic nervous system in this condition. Male Wistar rats weighing 220-280 g were used in the study. In the first experiment rats were intravenously pretreated with vehicle (V), atenolol 30 mg/kg (ATE, β1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, β2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, β3-adrenergic antagonist). In the third experiment, rats were subjected to surgical resection of the celiac-superior mesenteric ganglion complex or to sham surgery. The groups were intravenously treated with saline (S), 240 µmol/kg Dp, AA, or At, 15 min after pretreatment with the antagonists or V and nine days after surgery. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. The %GR (means±SE, n=6) values indicated that BUT abolished the effect of Dp (BUT+Dp vs V+Dp: 35.0%±5.1% vs 56.4%±2.7%) and At (BUT+At vs V+At: 33.5%±4.7% vs 52.9%±2.6%) on GE, and significantly reduced (P<0.05) the effect of AA (BUT+AA vs V+AA: 48.0%±5.0% vs 65.2%±3.8%). ATE, SRA, and sympathectomy did not modify the effects of treatments. These results suggest that β2-adrenoceptor activation occurred in delayed liquid gastric emptying induced by the phenylpyrazole derivatives dipyrone, 4-aminoantipyrine, and antipyrine. Additionally, the released neurotransmitter did not originate in the celiac-superior mesenteric ganglion complex.

Evidence for the involvement of peripheral -adrenoceptors in delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

Dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At) delay liquid gastric emptying (GE) in rats. We evaluated adrenergic participation in this phenomenon in a study in male Wistar rats (250-300 g) pretreated subcutaneously with guanethidine (GUA), 100 mg·kg−1·day−1, or vehicle (V) for 2 days before experimental treatments. Other groups of animals were pretreated intravenously (iv) 15 min before treatment with V, prazosin (PRA; 1 mg/kg), yohimbine (YOH; 3 mg/kg), or propranolol (PRO; 4 mg/kg), or with intracerebroventricular (icv) administration of 25 µg PRO or V. The groups were treated iv with saline or with 240 µmol/kg Dp, AA, or At. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. %GR (mean±SE, n=8) indicated that GUA abolished the effect of Dp (GUA vs V=31.7±1.6 vs 47.1±2.3%) and of At (33.2±2.3 vs 54.7±3.6%) on GE and significantly reduced the effect of AA (48.1±3.2 vs 67.2±3.1%). PRA and YOH did not modify the effect of the drugs. %GR (mean±SE, n=8) indicated that iv, but not icv, PRO abolished the effect of Dp (PRO vs V=29.1±1.7 vs 46.9±2.7%) and At (30.5±1.7 vs 49±3.2%) and significantly reduced the effect of AA (48.4±2.6 vs 59.5±3.1%). These data suggest activation of peripheral β-adrenoceptors in the delayed GE induced by phenylpyrazolone derivatives.

Revisión de la literatura: relación e importancia de los canales de potasio en esclerosis múltiple / Literature review: value and importance of potassium channels in multiple sclerosis / Revisão de literatura: valor ea importância dos canais de potássio em esclerose múltipla

[{"text": "La esclerosis múltiple (EM) es una enfermedad inflamatoria del sistema nervioso central (SNC), caracterizada por la \r\ndesmielinización, con una preservación relativa de los axones. En pacientes con EM se han atribuido muchos signos \r\ny síntomas neurológicos a la conducción subyacente de déficits neurológicos de terminaciones neuronales. La idea de \r\nque la función neurológica podría mejorar si la conducción pudiera ser restaurada en axones desmielinizados lleva a \r\npensar en una prueba de mejoría bajo bloqueo de canales de potasio (K(+)) que pueda ser usada como un tratamiento \r\nsintomático de la patología. Hasta la fecha solo se han identificado dos posibles terapéuticas de amplio espectro del \r\ncanal de K(+) de tipo bloqueadores: 4-aminopiridina (4-AP) y 3,4-diaminopiridina (3,4-DAP), probados con éxito \r\nen pacientes con EM. Aunque ambos producen claros beneficios a nivel neurológico, su uso ha sido limitado por la \r\ntoxicidad. En este artículo se revisa el estado actual de las investigaciones sobre el uso de los bloqueadores de canales \r\nde potasio y su importancia a futuro en la terapéutica de la esclerosis múltiple y la ciencia básica aplicada a la inves\r\n-\r\ntigación clínica relacionada con la orientación terapéutica de canales de voltaje- K(+) canales (K(v)). Con base en las \r\núltimas publicaciones y en la experiencia de manejo en rehabilitación, su objetivo es ofrecer una perspectiva sobre \r\nel conocimiento del manejo clínico de este subtipo de canal de K en patologías desmielinizantes, que ha demostrado \r\nuna mejoría notable en la velocidad de marcha de pacientes que padecen esclerosis múltiple por medio de la molécula \r\nbloqueadora de canales de potasio (K).", "_i": "es"}, {"text": "Multiple sclerosis (MS) is an inflammatory disease \r\nof the central nervous system (CNS) characterized by \r\ndemyelination, with relative preservation of axons. In \r\nMS patients, many neurological signs and symptoms \r\nhave been attributed to the underlying neuronal endings \r\nconduction deficits. The idea that neurological function \r\ncould be improved if conduction could be restored in \r\ndemyelinated axons leads to an improvement in test block \r\npotassium channels (K+) and be used as a symptomatic \r\ntreatment of the disease. To date, there are only two \r\npotential therapeutic spectrum K+ channel type blockers, \r\n4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-\r\nDAP), that have been successfully tested in patients with \r\nMS. Although both 4-AP and 3,4-DAP level produce \r\nclear neurological benefits, their use has been limited as \r\na result of toxicity. This article reviews the current state \r\nof research on the use of potassium channel blockers and \r\ntheir importance to the future of multiple sclerosis thera\r\n-\r\npeutics and the basic science and clinical research related \r\nto therapeutic targeting of voltage K+ in MS. By bringing \r\ntogether the most recent articles and publications based \r\non experiences in rehabilitation management of this \r\ndisease, the aim of this article is to provide a perspective \r\non knowledge about K+ channels in clinical treatments \r\nfor patients with multiple sclerosis and other demyelina\r\n-\r\nting diseases, which has shown that blocking K+ channels \r\nresulted in a significant improvement in walking speed of \r\npatients suffering from multiple sclerosis.", "_i": "en"}, {"text": "A esclerose múltipla (EM) é uma doença inflamatória do \r\nsistema nervoso central (SNC) caracterizada pela desmie\r\n-\r\nlinização, com uma preservação relativa dos axônios. \r\nMuitos síntomas neurológicos presentes em pacientes \r\ncom EM são atribuídos à condução subjacente de déficits \r\nneurológicos das terminações nervosas. A idéia de que a \r\nfunção neurológica poderia ser melhorada se a condução \r\nem axônios desmielinizados fosse restaurada indica uma \r\nmelhoria através de um bloqueio de canais de potássio \r\n(K(+)) para ser usado como um tratamento sintomático da \r\npatología. Até esta data foram identificados dois possíveis \r\nbloqueadores: 4-aminopiridina (4-AP) e 3,4-diaminopi\r\n-\r\nridina (3,4-DAP), testados com êxito em pacientes com \r\nEM. Apesar de ambos 4-AP e DAP produzirem claros \r\nbenefícios ao nível neurológico, seu uso foi limitado pela \r\nsua toxicidade. Neste artigo, é revisado o estado atual \r\ndas investigações sobre o uso de bloqueadores de canais \r\nde potássio e sua importância no futuro terapêutico \r\nda esclerose múltipla e na ciência voltada à canais de \r\nvoltagem K(+)( canais (K(v)). Com base nas últimas publi\r\n-\r\ncações de artigos e na gestão terapêutica, o objetivo deste \r\nartigo é oferecer uma perspectiva sobre o conhecimento \r\nda gestão clínica deste subtipo de canal K em patológicas \r\ndesmielinizantes, o qual tem demonstrado um progresso \r\nnotável na velocidade de melhoria dos pacientes que \r\npossuem esclerose múltipla ­ uma das principais patolo\r\n-\r\ngías do tipo desmielinizaste.", "_i": "pt"}]

Synthesis of New VO(II), Co(II), Ni(II) and Cu(II) Complexes with Isatin-3-Chloro-4-Floroaniline and 2-Pyridinecarboxylidene-4-Aminoantipyrine and their Antimicrobial Studies

The complexes of tailor made ligands with life essential metal ions may be an emerging area to answer the problems of multi drug resistance. The coordination complexes of VO(II), Co(II), Ni(II) and Cu(II) with the Schiff bases derived from isatin with 3-chloro-4-floroaniline and 2-pyridinecarboxaldehyde with 4-aminoantipyrine have been synthesized by conventional as well as microwave methods. These compounds have been characterized by elemental analysis, molar conductance, electronic spectra, FT-IR, FAB mass and magnetic susceptibility measurements. FAB mass data show degradation of complexes. Both the ligands behave as bidentate and tridentate coordinating through O and N donor. The complexes exhibit coordination number 4, 5 or 6. The Schiff base and metal complexes show a good activity against the bacteria; Staphylococcus aureus, Escherichia coli and Streptococcus fecalis and fungi Aspergillus niger, Trichoderma polysporum, Candida albicans and Aspergillus flavus. The antimicrobial results also indicate that the metal complexes are better antimicrobial agents as compared to the Schiff bases. The minimum inhibitory concentrations of the metal complexes were found in the range 10~40 microg/mL.

Spectrophotometric assay of phenylephrine hydrochloride using 4-aminoantipyrine and copper [II]

A new spectrophotometric method is proposed for the determination of phenylephrine hydrochloride. The method is based on the coupling of 4-aminoantipyrine [4-AAP] with Phenylephrine Hydrochloride [PEH] to give a new ligand that reacts with copper [II] in the presence of sodium tetraborate buffer solution of pH9 at 50[degree sign]C with an intensely red colored chelate having maximum absorption at 480 nm. The method has been used for the determination of 2.0-50.0 micro g ml-1 of PEH with molar absorptivity of 5.357x103 L.mol-1cm-1, average recovery of 101.28% and Relative Standard Deviation [RSD] of 1.25%. The results of the method were compared with those of the official method. The mechanism of the chemical reaction has been proposed. The proposed method was successfully applied for the determination of the PEH in pharmaceutical syrup formulations

Phenylpyrazolone derivatives inhibit gastric emptying in rats by a capsaicin-sensitive afferent pathway

Dipyrone (Dp), 4-aminoantipyrine (AA) and antipyrine (At) administered iv and Dp administered icv delay gastric emptying (GE) in rats. The participation of capsaicin (Cps)-sensitive afferent fibers in this phenomenon was evaluated. Male Wistar rats were pretreated sc with Cps (50 mg/kg) or vehicle between the first and second day of life and both groups were submitted to the eye-wiping test. GE was determined in these animals at the age of 8/9 weeks (weight: 200-300 g). Ten minutes before the study, the animals of both groups were treated iv with Dp, AA or At (240 μmol/kg), or saline; or treated icv with Dp (4 μmol/animal) or saline. GE was determined 10 min after treatment by measuring percent gastric retention (GR) of saline labeled with phenol red 10 min after orogastric administration. Percent GR (mean ± SEM, N = 8) in animals pretreated with Cps and treated with Dp, AA or At (35.8 ± 3.2, 35.4 ± 2.2, and 35.6 ± 2 percent, respectively) did not differ from the GR of saline-treated animals pretreated with vehicle (36.8 ± 2.8 percent) and was significantly lower than in animals pretreated with vehicle and treated with the drugs (52.1 ± 2.8, 66.2 ± 4, and 55.8 ± 3 percent, respectively). The effect of icv administration of Dp (N = 6) was not modified by pretreatment with Cps (63.3 ± 5.7 percent) compared to Dp-treated animals pretreated with vehicle (62.3 ± 2.4 percent). The results suggest the participation of capsaicin-sensitive afferent fibers in the delayed GE induced by iv administration of Dp, AA and At, but not of icv Dp.

Effect of 4-aminoantipyrine on gastric compliance and liquid emptying in rats

Dipyrone (Dp) delays gastric emptying (GE) in rats. There is no information about whether 4-aminoantipyrine (AA), one of its metabolites, has the same effect. The objectives of the present study were to assess the effects of AA and Dp on GE when administered intravenously (iv) and intracerebroventricularly (icv) (240 æmol/kg and 4 æmol/animal, respectively) and on gastric compliance when administered iv (240 æmol/kg). GE was determined in male Wistar rats weighing 250-300 g (5-10 per group) after icv or iv injection of the drug by measuring percent gastric retention (GR) of a saline meal labeled with phenol red 10 min after administration by gavage. Gastric compliance was estimated in anesthetized rats (10-11 per group), with the construction of volume-pressure curves during intragastric infusion of a saline meal. Compliance was significantly greater in animals receiving Dp (mean ± SEM = 0.26 ± 0.009 mL/mmHg) and AA (0.24 ± 0.012 mL/mmHg) than in controls (0.19 ± 0.009 mL/mmHg). AA and Dp administered iv significantly increased GR (64.4 ± 2.5 and 54.3 ± 3.8 percent, respectively) compared to control (34 ± 2.2 percent), a phenomenon observed only with Dp after icv administration. Subdiaphragmatic vagotomy reduced the effect of AA (GR = 31.4 ± 1.5 percent) compared to sham-treated animals. Baclofen, a GABA B receptor agonist, administered icv significantly reduced the effect of AA (GR = 28.1 ± 1.3 percent). We conclude that Dp and AA increased gastric compliance and AA delayed GE, with the participation of the vagus nerve, through a pathway that does not involve a direct action of the drug on the central nervous system.

Evidence of the effect of dipyrone on the central nervous system as a determinant of delayed gastric emptying observed in rats after its administration

Dipyrone administered intravenously (iv) delays gastric emptying (GE) in rats. The objectives of the present study were to assess: 1) the effect of the dose of dipyrone and time after its iv administration on GE in rats, 2) the effect of subdiaphragmatic vagotomy (VgX) and bilateral electrolytic lesion of the paraventricular nucleus (PVNX) on the delayed GE induced by the drug, and 3) the intracerebroventricular (icv) action of dipyrone and of one of its metabolites, 4-aminoantipyrine on GE. Male Wistar rats received saline labeled with phenol red intragastrically as a test meal. GE was indirectly assessed by the determination of percent gastric retention (GR) of the test meal 10 min after administration by gavage. Dipyrone delays GE in a dose- and time-dependent manner. Thirty minutes after the iv administration of 80 mg/kg dipyrone, the animals showed significantly higher GR (mean = 62.6 percent) compared to those receiving vehicle (31.5 percent). VgX and PVNX significantly reduced the iv effect of 80 mg/kg dipyrone (mean percentGR: VgX = 28.3 vs Sham = 55.5 and PVNX = 34.5 vs Sham = 52.2). Icv administration of 4 æmol dipyrone caused a significant increase in GR (54.1 percent) of the test meal 10 min later, whereas administration of 4 æmol 4-aminoantipyrine had no effect (34.4 percent). Although the dipyrone dose administered icv was 16 times lower than that applied iv, for the same time of action (10 min), the GR of animals that received the drug icv (54.1 percent) or iv (54.5 percent) did not differ significantly. In conclusion, the present results suggest that the effect of dipyrone in delaying GE is due to the action of the drug on the central nervous system, with the participation of the PVN and of the vagus nerve