Ondansetron does not block tramadol-induced analgesia in mice.

Tramadol is a weak opioid agonist and an inhibitor of the reuptake of noradrenaline and serotonin. This study was undertaken to assess a possible pharmacological interaction of ondansetron, a serotonin-3 (5-hydroxytryptamine-3, 5-HT3) antagonist, and tramadol in an animal model for acute pain. Sixty-three male albino mice were randomly given saline, tramadol (10, 20, and 40 mg kg(-1)), ondansetron (1, 2, and 4 mg kg(-1)), or ondansetron (1, 2, and 4 mg kg(-1)) and tramadol (20 mg kg(-1), given 10 min after ondansetron injection) intraperitoneally. Each mouse was assessed twice for tail-flick latency before saline or drug administration and 15, 30, 60, 90, and 120 min thereafter. Tramadol (10 mg kg(-1)) had no effect on pain threshold levels of mice, but tramadol doses of 20 or 40 mg kg(-1) increased pain threshold levels in a dose-dependent manner (p < 0.01 for 20 mg kg(-1) and p < 0.001 for 40 mg kg(-1)). Ondansetron doses of 1, 2, or 4 mg kg(-1) alone had no effect on pain threshold levels of mice. Tramadol (20 mg kg(-1)) and ondansetron (1, 2, and 4 mg kg(-1)) increased pain threshold levels at all doses (p < 0.001 for 1 and 2 mg kg(-1) ondansetron and p < 0.01 for 4 mg kg(-1) ondansetron). The pain threshold levels of mice given tramadol (20 mg kg(-1)) alone or tramadol and ondansetron (p > 0.05 for 1, 2, and 4 mg kg(-1)) were similar. Our results indicate that ondansetron-a 5-HT3 selective antagonist-does not decrease the analgesic effectiveness of tramadol in mice, which may be the result of different mechanisms involving 5-HT3 receptors.

Endotoxin-induced vascular hyporesponsiveness in rat aorta: in vitro effect of aminoguanidine.

The current study was designed to evaluate the endotoxin-induced alterations of the mechanisms involved in Ca(2+)handling within the rat thoracic aorta and further to examine whether in vitro inhibition of inducible nitric oxide synthase (iNOS) by aminoguanidine would account for this effect or not. Endothelium denuded aortic rings from rats injected with lipopolysaccharide (LPS) (5 mg kg(-1), i.p. 18 h prior to functional studies) or saline were mounted in isolated organ baths. Various experimental conditions were studied on paired rings of the same animal which were incubated in the presence or absence of aminoguanidine (100 microM). Phenylephrine contractility in Ca(2+)-containing buffer or in Ca(2+)-free buffer, contractions induced by K(+)depolarization and CaCl(2)in depolarized muscle and by caffeine exposure were significantly decreased in LPS-treated rings and were reversed by aminoguanidine exposure. Aminoguanidine also improved the contractions recorded while switching the Ca(2+)-free buffer to Ca(2+)-containing buffer. We conclude that endotoxin induces a generalized contractile defect in vascular smooth muscle including impairment in the influx of extracellular Ca(2+)and release of Ca(2+)from intracellular stores. An increase in iNOS activation leading to excessive nitric oxide synthesis, possibly non-endothelial in origin, may account for this defect.

Effects of aminoguanidine administration on vascular hyporeactivity in thoracic aorta from endotoxaemic rats.

Overproduction of nitric oxide has been implicated in the pathogenesis of the vascular hyporesponsiveness of endotoxic shock. In this study, we investigated the effects of aminoguanidine, an inducible nitric oxide synthase inhibitor, on the decreased vascular responsiveness in endotoxic shock. Male albino rats were administered intraperitoneally aminoguanidine (25, 50 or 75 mg kg(-1)) 1 h after they received saline or lipolysaccharide (Escherichia coli serotype 055:B5). The thoracic aortas were removed 18 h after lipopolysaccharide administration and suspended in organ baths containing Krebs solution, and tested for vascular reactivity. Contractile responses to phenylephrine and potassium chloride, and relaxant responses to acetylcholine were reduced in endotoxaemic animals. Aminoguanidine was ineffective in improving the vascular hypocontractility at 25 and 75 mg kg(-1) doses; but at 50 mg kg(-1) dose, it restored the decreased contractile responses toward normal values. Diminished relaxant responses to acetylcholine were restored by aminoguanidine at all three different doses. There were no significant differences in sodium nitroprusside induced relaxant responses between all groups. Administration of aminoguanidine in control animals did not change vascular responses to any agent. These data suggest that aminoguanidine treatment improves the vascular hyporesponsiveness to contractile- and endothelium-dependent relaxant agents observed in endotoxic shock.

Effect of nabumetone treatment on vascular responses of the thoracic aorta in rat experimental arthritis.

Nabumetone is a nonsteroidal anti-inflammatory (NSAI) drug which is known to cause less gastrointestinal damage than other NSAI drugs. This study was performed to evaluate whether nabumetone treatment might alter the vascular aberrations related to inflammation in a rat model of adjuvant-induced arthritis. Nabumetone treatment (120 or 240 mg x kg(-1) x day(-1), orally) was initiated on the 15th day of adjuvant inoculation and continued for 14 days. Arthritic lesions, vascular contractile and relaxant responses and gastroduodenal histopathological preparations were evaluated 29 days after adjuvant inoculation. The contractile responses of aortic rings to phenylephrine and KCl were increased in grade 2 arthritic rats. In grade 3 arthritis only the phenylephrine contractility was decreased. The relaxant responses to acetylcholine and sodium nitroprusside were decreased in grades 2 and 3. In healthy rats, nabumetone did not change the vascular responses. After treatment of arthritic rats with nabumetone, both the contractile and relaxant response of the aortic rings returned to normal, and arthritic score and paw swelling were reduced. Gastroduodenal histopathology did not show erosions or ulcers in any of the groups. In conclusion, nabumetone improved the systemic signs and vascular alterations in experimental arthritis without showing any gastrointestinal side effects.

Effects of MK-886, a leukotriene biosynthesis inhibitor, in a rabbit model of endotoxic shock.

Leukotrienes are one of the biological mediators that play a role in endotoxic shock. In this study, we investigated the effects of a leukotriene biosynthesis inhibitor, MK-886, in a rabbit model of endotoxic shock. Lipopolysaccharide (Escherichia coli serotype 055:B5) infusion (1 mg kg(-1) h(-1)) to rabbits caused a biphasic decline in arterial blood pressure and decreased the vasoresponsiveness to phenylephrine, potassium chloride, sodium nitroprusside and acetylcholine in abdominal aortic rings. Oral administration of MK-886 (3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl(-2,2-+ ++dimethylpropanoic acid) (5 mg/kg) 3 h prior to lipopolysaccharide infusion significantly inhibited the decline in arterial blood pressure and enhanced the responsiveness to phenylephrine and acetylcholine, whereas the changes in sodium nitroprusside and potassium chloride responses were not significant. However, the pD2 (-log EC50) values for sodium nitroprusside in this group were higher than those of the group that received lipopolysaccharide alone. Neither the administration of the vehicle alone to endotoxemic rabbits, nor MK-886 administration to control animals, caused significant changes. These data suggest that MK-886 attenuates the hypotension and partially reverses the impaired vascular responsiveness observed in endotoxic shock.

Effect of vitamin E on vascular responses of thoracic aorta in rat experimental arthritis.

1. Vascular contractile and relaxant responses were evaluated in isolated aortic rings of adjuvant-induced arthritic rats in comparison with control rats, and the effect of an antioxidant treatment on the development of the arthritis was investigated by vitamin E administration (100 mg/kg/day, i.m., for 26 days). 2. Arthritis was induced by an intradermal injection of Freund's complete adjuvant into rat paw. Vascular responses, arthritic lesions and serum copper levels were evaluated after 26 days from adjuvant inoculation. 3. Serum copper levels were significantly lower in arthritic rats than in the control. 4. The contractile response of aortic rings to phenylephrine (PE), but not to KCl, was increased in preparations from arthritic rats, which could be explained by an enhancement of intracellular calcium contents. 5. Acetylcholine (Ach)-mediated endothelium-dependent and sodium nitroprusside (SNP)-mediated endothelium-independent relaxations were not changed significantly in vascular preparations from arthritic rats. 6. In arthritic rats, vitamin E treatment improved arthritic lesions with an increase in copper levels. Despite this ameliorating effect, vitamin E treatment caused an increase in contractile response to PE and a decrease in the relaxant response to Ach and SNP in arthritic rats. 7. These data show that vitamin E provides ameliorating effects in improving systemic signs of experimental arthritis, but it fails to restore abnormalities in vascular function, indicating that adjuvant-induced alterations in vascular function may include mechanisms other than oxygen-free radical formation.

Systemic absorption of gentamicin in penile prosthesis operations.

Irrigation with antibiotic solutions is frequently used in penile prosthesis surgery to avoid infection. We carried out a prospective study to determine the degree of absorption of gentamicin after intracavernous irrigation in 10 patients who underwent penile implantation surgery. All obtained values were below the toxic level of 10 micrograms/ml and decreased gradually within a few hours. We concluded that highly concentrated gentamicin solutions could be used with safety for intracavernous irrigation.

Platelet aggregation and atrial natriuretic peptide.

1. Isolated human platelets were used to investigate the effect of atrial natriuretic peptide (ANP) on in vitro platelet aggregation induced by epinephrine, ADP, collagen and 5-hydroxytryptamine. As a direct stimulant of particulate guanylate cyclase, ANP is known to have no direct effect on platelets which contain soluble guanylate cyclase. 2. In our experiments ANP inhibited epinephrine- and partially ADP-induced aggregation in vitro and this effect was suggested to be the result of an interaction of the peptide with adenylate cyclase in platelets. However, the concentrations required to produce this effect were higher than those expected to be found in the circulation both physiologically and pathologically. 3. We therefore conclude that though the peptide may inhibit-aggregation via adenylate cyclase activation, it is unlikely that ANP may play a direct role in preventing platelets aggregating.

Age related differences in plasma theophylline levels.

Because of its special pharmacokinetic properties, plasma levels of theophylline show significant differences between individuals and also its therapeutic index is very low. So, plasma theophylline concentration measurements are essential for an effective and safe treatment. In the present study, age related differences in plasma theophylline levels were evaluated in patients from different age groups. Patients were divided randomly into two groups. Group I included patients under the age of 50 years, group II included patients over 50 years of age. Plasma theophylline levels were measured before and 3, 7, 12 and 19 h after a single dose given orally. The results show that 3, 7 and 19 h post dose, levels of theophylline were significantly higher in group II than in group I (P < 0.001).

Effects of ketamine, thiopental sodium and propofol on muscle contractures in rat diaphragm in vitro.

The effects of commonly used intravenous anaesthetic agents ketamine, thiopental sodium and propofol on the caffeine-alone or halothane-plus-caffeine-induced muscle contractures were investigated to determine safety for use in patients susceptible to malignant hyperthermia (MH). The muscle strips from rat diaphragm were exposed to one of these anaesthetic agents prior to challenge with caffeine 8 mmol/l alone or halothane 3% plus caffeine 8 mmol/l together. None of the three agents induced contractures when added alone. Ketamine 100 mumol/l and thiopental sodium 300 mumol/l augmented neither caffeine-alone nor caffeine-with-halothane contractures significantly and these two agents appear to be safe for use in MH-susceptible patients. In contrast, propofol 150 mumol/l augmented these contractile responses significantly and may not be recommended for use in patients known to be susceptible to this anaesthetic complication.