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 ß2-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 ß2-adrenoceptors in biliary tract smooth muscle and ß2-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.

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.

Dipyrone in association with atropine inhibits the effect on gastric emptying induced by hypoglycemia in rats.

Atropine (AT) and dipyrone (Dp) induce a delay of gastric emptying (GE) of liquids in rats by inhibiting muscarinic receptors and activating ß2-adrenergic receptors, respectively. The objective of the present study was to determine the effects of pretreatment with AT and Dp, given alone or in combination, on the effect of hypoglycemia in the liquid GE in rats. Male Wistar adult rats (280-310 g) were pretreated intravenously with AT, Dp, AT plus Dp or their vehicle and then treated 30 min later with iv insulin or its vehicle (n=8-10 animals/group). Thirty min after treatment, GE was evaluated by determining, in awake rats, the percent gastric retention (%GR) of a saline meal labeled with phenol red administered by gavage. The results indicated that insulin induced hypoglycemia in a dose-dependent manner resulting in a significant reduction in %GR of liquid only at the highest dose tested (1 U/kg). Pretreatment with AT significantly increased %GR in the rats treated with 1 U/kg insulin. Surprisingly, after pretreatment with AT, the group treated with the lowest dose of insulin (0.25 U/kg) displayed significantly lower %GR compared to its control (vehicle-treated group), which was not seen in the non-pretreated animals. Pretreatment with Dp alone at the dose of 40 mg/kg induced an increase in %GR in both vehicle and 0.25 U/kg-treated rats. A higher dose of Dp alone (80 mg/kg) significantly reduced the effect of a marked hypoglycemia induced by 1 U/kg of insulin on GE while in combination with AT the effect was completely abolished. The results with AT suggest that moderate hypoglycemia may render the inhibitory mechanisms of GE ineffective while Dp alone and in combination with AT significantly overcame the effect of hypoglycemia on GE.

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.

Effect of selective ß-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 ß-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 ß-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, ß1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, ß2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, ß3-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 ß2-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 ß-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 ß-adrenoceptors in the delayed GE induced by phenylpyrazolone derivatives.

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.

Gastric emptying of water in children with severe functional fecal retention.

The objective of this study was to evaluate gastric emptying (GE) in pediatric patients with functional constipation. GE delay has been reported in adults with functional constipation. Gastric emptying studies were performed in 22 children with chronic constipation, fecal retention and fecal incontinence, while presenting fecal retention and after resuming regular bowel movements. Patients (18 boys, median age: 10 years; range: 7.2 to 12.7 years) were evaluated in a tertiary pediatric gastroenterology clinic. Gastric half-emptying time of water (reference range: 12 ± 3 min) was measured using a radionuclide technique immediately after first patient evaluation, when they presented fecal impaction (GE1), and when they achieved regular bowel movements (GE2), 12 ± 5 weeks after GE1. At study admission, 21 patients had reported dyspeptic symptoms, which were completely relieved after resuming regular bowel movements. Medians (and interquartile ranges) for GE1 and GE2 were not significantly different [27.0 (16) and 27.5 (21) min, respectively (P = 0.10)]. Delayed GE seems to be a common feature among children with chronic constipation and fecal retention. Resuming satisfactory bowel function and improvement in dyspeptic symptoms did not result in normalization of GE data.

Gastric emptying of water in children with severe functional fecal retention

The objective of this study was to evaluate gastric emptying (GE) in pediatric patients with functional constipation. GE delay has been reported in adults with functional constipation. Gastric emptying studies were performed in 22 children with chronic constipation, fecal retention and fecal incontinence, while presenting fecal retention and after resuming regular bowel movements. Patients (18 boys, median age: 10 years; range: 7.2 to 12.7 years) were evaluated in a tertiary pediatric gastroenterology clinic. Gastric half-emptying time of water (reference range: 12 ± 3 min) was measured using a radionuclide technique immediately after first patient evaluation, when they presented fecal impaction (GE1), and when they achieved regular bowel movements (GE2), 12 ± 5 weeks after GE1. At study admission, 21 patients had reported dyspeptic symptoms, which were completely relieved after resuming regular bowel movements. Medians (and interquartile ranges) for GE1 and GE2 were not significantly different [27.0 (16) and 27.5 (21) min, respectively (P = 0.10)]. Delayed GE seems to be a common feature among children with chronic constipation and fecal retention. Resuming satisfactory bowel function and improvement in dyspeptic symptoms did not result in normalization of GE data.

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.

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 micromol/kg), or saline; or treated icv with Dp (4 micromol/animal) or saline. GE was determined 10 min after treatment by measuring % 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%, respectively) did not differ from the GR of saline-treated animals pretreated with vehicle (36.8 +/- 2.8%) 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%, respectively). The effect of icv administration of Dp (N = 6) was not modified by pretreatment with Cps (63.3 +/- 5.7%) compared to Dp-treated animals pretreated with vehicle (62.3 +/- 2.4%). 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 micromol/kg and 4 micromol/animal, respectively) and on gastric compliance when administered iv (240 micromol/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%, respectively) compared to control (34 +/- 2.2%), a phenomenon observed only with Dp after icv administration. Subdiaphragmatic vagotomy reduced the effect of AA (GR = 31.4 +/- 1.5%) compared to sham-treated animals. Baclofen, a GABAB receptor agonist, administered icv significantly reduced the effect of AA (GR = 28.1 +/- 1.3%). 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.

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.

Effect of antipyrine on the gastric emptying of liquid in rats.

Antipyrine (At) and dipyrone (Dp) delay gastric emptying (GE) in rats. The objective of the present study was to assess the effects of intravenous (iv) and intracerebroventricular (icv) administration of At and Dp on the GE of liquid by rats. GE was assessed in male Wistar rats (5-10 in each group) 10 min after the icv or iv drug injection by measuring percent gastric retention (%GR) of a saline test meal labeled with phenol red 10 min after administration by gavage. The At iv group was significantly higher (64.4 +/- 2.6%) compared to control (33.4 +/- 1.5%) but did not differ from the Dp group (54.3 +/- 3.8%). After icv administration of At, %GR (34.2 +/- 2%) did not differ from control (32.6 +/- 1.9%), but was significantly higher after Dp (54.5 +/- 2.3%). Subdiaphragmatic vagotomy significantly reduced %GR in the At group (30.2 +/- 0.7%) compared to the sham group, but was significantly higher than in the controls (23.0 +/- 0.5%). In the animals treated with At iv, baclofen significantly reduced %GR (28.3 +/- 2.4%) compared to vehicle-treated animals (55.2 +/- 3.2%). The same occurred in the animals treated iv with vehicle and icv with baclofen. Although vagotomy and baclofen reduced %GR per se, the reduction was twice more marked in the animals treated with At. The results suggest that At administered iv, but not icv, delays GE of liquid in rats with the participation, at least in part, of the vagus nerve and that this phenomenon is blocked by the activation of GABA B receptors in the central nervous system.

Effect of antipyrine on the gastric emptying of liquid in rats

Antipyrine (At) and dipyrone (Dp) delay gastric emptying (GE) in rats. The objective of the present study was to assess the effects of intravenous (iv) and intracerebroventricular (icv) administration of At and Dp on the GE of liquid by rats. GE was assessed in male Wistar rats (5-10 in each group) 10 min after the icv or iv drug injection by measuring percent gastric retention ( percentGR) of a saline test meal labeled with phenol red 10 min after administration by gavage. The At iv group was significantly higher (64.4 ± 2.6 percent) compared to control (33.4 ± 1.5 percent) but did not differ from the Dp group (54.3 ± 3.8 percent). After icv administration of At, percentGR (34.2 ± 2 percent) did not differ from control (32.6 ± 1.9 percent), but was significantly higher after Dp (54.5 ± 2.3 percent). Subdiaphragmatic vagotomy significantly reduced percentGR in the At group (30.2 ± 0.7 percent) compared to the sham group, but was significantly higher than in the controls (23.0 ± 0.5 percent). In the animals treated with At iv, baclofen significantly reduced percentGR (28.3 ± 2.4 percent) compared to vehicle-treated animals (55.2 ± 3.2 percent). The same occurred in the animals treated iv with vehicle and icv with baclofen. Although vagotomy and baclofen reduced percentGR per se, the reduction was twice more marked in the animals treated with At. The results suggest that At administered iv, but not icv, delays GE of liquid in rats with the participation, at least in part, of the vagus nerve and that this phenomenon is blocked by the activation of GABA B receptors in the central nervous system.

Effect of the GABAB agonist baclofen on dipyrone-induced delayed gastric emptying in rats.

Dipyrone administered intravenously (iv) or intracerebroventricularly (icv) delays gastric emptying (GE) in rats. Gamma-aminobutyric acid (GABA) is the most potent inhibitory neurotransmitter of the central nervous system. The objective of the present study was to determine the effect of icv baclofen, a GABAB receptor agonist, on delayed GE induced by dipyrone. Adult male Wistar rats received a saline test meal containing phenol red as a marker. GE was indirectly evaluated by determining the percent of gastric retention (%GR) of the meal 10 min after orogastric administration. In the first experiment, the animals were injected iv with vehicle (Civ) or 80 mg/kg (240 micromol/kg) dipyrone (Dpiv), followed by icv injection of 10 microl vehicle (bac0), or 0.5 (bac0.5), 1 (bac1) or 2 microg (bac2) baclofen. In the second experiment, the animals were injected icv with 5 microl vehicle (Cicv) or an equal volume of a solution containing 4 micromol (1333.2 microg) dipyrone (Dpicv), followed by 5 microl vehicle (bac0) or 1 microg baclofen (bac1). GE was determined 10 min after icv injection. There was no significant difference between control animals from one experiment to another concerning GR values. Baclofen at the doses of 1 and 2 microg significantly reduced mean %GR induced by iv dipyrone (Dpivbac1 = 35.9% and Dpivbac2 = 26.9% vs Dpivbac0 = 51.8%). Similarly, baclofen significantly reduced the effect of dipyrone injected icv (mean %GR: Dpicvbac1 = 30.4% vs Dpicvbac0 = 54.2%). The present results suggest that dipyrone induces delayed GE through a route in the central nervous system that is blocked by the activation of GABAB receptors.

Effect of the GABA B agonist baclofen on dipyrone-induced delayed gastric emptying in rats

Dipyrone administered intravenously (iv) or intracerebroventricularly (icv) delays gastric emptying (GE) in rats. Gamma-aminobutyric acid (GABA) is the most potent inhibitory neurotransmitter of the central nervous system. The objective of the present study was to determine the effect of icv baclofen, a GABA B receptor agonist, on delayed GE induced by dipyrone. Adult male Wistar rats received a saline test meal containing phenol red as a marker. GE was indirectly evaluated by determining the percent of gastric retention ( percentGR) of the meal 10 min after orogastric administration. In the first experiment, the animals were injected iv with vehicle (Civ) or 80 mg/kg (240 æmol/kg) dipyrone (Dp iv), followed by icv injection of 10 æl vehicle (bac0), or 0.5 (bac0.5), 1 (bac1) or 2 æg (bac2) baclofen. In the second experiment, the animals were injected icv with 5 æl vehicle (Cicv) or an equal volume of a solution containing 4 æmol (1333.2 æg) dipyrone (Dp icv), followed by 5 æl vehicle (bac0) or 1 æg baclofen (bac1). GE was determined 10 min after icv injection. There was no significant difference between control animals from one experiment to another concerning GR values. Baclofen at the doses of 1 and 2 æg significantly reduced mean percentGR induced by iv dipyrone (Dp iv bac1 = 35.9 percent and Dp iv bac2 = 26.9 percent vs Dp iv bac0 = 51.8 percent). Similarly, baclofen significantly reduced the effect of dipyrone injected icv (mean percentGR: Dp icv bac1 = 30.4 percent vs Dp icv bac0 = 54.2 percent). The present results suggest that dipyrone induces delayed GE through a route in the central nervous system that is blocked by the activation of GABA B receptors.

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

Use of erythromycin for the treatment of severe chronic constipation in children

The efficacy of erythromycin was assessed in the treatment of 14 children aged 4 to 13 years with refractory chronic constipation, and presenting megarectum and fecal impaction. A double-blind, placebo- controlled, crossover study was conducted at the Pediatric Gastroenterology Outpatient Clinic of the University Hospital. The patients were randomized to receive placebo for 4 weeks followed by erythromycin estolate, 20 mg kg-1 day-1, divided into four oral doses for another 4 weeks, or vice versa. Patient outcome was assessed according to a clinical score from 12 (most severe clinical condition) to 0 (complete recovery). At enrollment in the study and on the occasion of follow-up medical visits at two-week intervals, patient score and laxative requirements were recorded. During the first 30 days, the mean ± SD clinical score for the erythromycin group (N = 6) decreased from 8.2 ± 2.3 to 2.2 ± 1.0 while the score for the placebo group (N = 8) decreased from 7.8 ± 2.1 to 2.9 ± 2.8. During the second crossover phase, the score for patients on erythromycin ranged from 2.9 ± 2.8 to 2.4 ± 2.1 and the score for the patients on placebo worsened from 2.2 ± 1.0 to 4.3 ± 2.3. There was a significant improvement in score when patients were on erythromycin (P < 0.01). Mean laxative requirement was lower when patients ingested erythromycin (P < 0.05). No erythromycin-related side effects occurred. Erythromycin was useful in this group of severely constipated children. A larger trial is needed to fully ascertain the prokinetic efficacy of this drug as an adjunct in the treatment of severe constipation in children

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%) compared to those receiving vehicle (31.5%). VgX and PVNX significantly reduced the iv effect of 80 mg/kg dipyrone (mean %GR: VgX = 28.3 vs Sham = 55.5 and PVNX = 34.5 vs Sham = 52.2). Icv administration of 4 mol dipyrone caused a significant increase in GR (54.1%) of the test meal 10 min later, whereas administration of 4 mol 4-aminoantipyrine had no effect (34.4%). 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%) or iv (54.5%) 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.