Amitriptyline and clomipramine increase the concentration of administered L-tryptophan in the rat brain

The tricyclic antidepressant amitriptyline has been shown to reduce concentrations of large neutral amino acids (LNAA) in rat plasma. Compounds with that property might interact with such amino acids used as therapeutic agents with a central site of action by causing a change in the relationship between the administered LNAA and its endogenous LNAA competitors for carrier-mediated transport through the blood-brain barrier into the brain. This study was performed to investigate if the antidepressant agents amitriptyline and clomipramine could, by such a mechanism, increase brain concentrations of administered tryptophan. Intraperitoneal administration of L-tryptophan alone (100 mg kg-1) resulted in an increase in the concentration of tryptophan in the rat brain from 14 +/- 0.7 to 100 +/- 4.3 nmol g-1 compared with rats given saline only. When rats were given tryptophan with amitriptyline (25 mg kg-1, i.p.) or clomipramine (25 mg kg-1, i.p.) brain concentrations of tryptophan were increased even further, to 150 +/- 4.5 and 157 +/- 10.2 nmol g-1, respectively. Administration of L-tryptophan alone resulted in an increase in the rat plasma tryptophan ratio [(concentration of tryptophan)/(total concentration of LNAAs)] from 0.14 +/- 0.003 to 0.42 +/- 0.011 compared with rats given saline only. When rats were given tryptophan with amitriptyline or clomipramine the plasma tryptophan ratios were increased even further to 0.52 +/- 0.017 and 0.54 +/- 0.025, respectively. All these effects were statistically significant (P < 0.001). These findings support the hypothesis that tricyclic antidepressants could interact with administered tryptophan by changing the relationship in plasma between tryptophan and its endogenous LNAA competitors for transport into the brain, resulting in higher concentrations of tryptophan in the brain. It is possible that this could be the mechanism of the previously reported finding that clomipramine and tryptophan potentiate each other in the treatment of depression.     

Kynurenic acid distribution into brain and peripheral tissues of mice

Kynurenic acid (KYN), an antagonist of excitatory amino acid receptors, is a putative antidote against neuroexcitatory amino acid toxicity. We studied various doses (0.05-3.17 mmol/kg, i.p.) and the effects of probenecid coadministration (0.70 mmol/kg, i.p.) on tissue distribution of KYN in male and female Swiss-Webster mice. After injection of [3H]KYN, samples of brain, heart, liver, kidney, skeletal muscle, and gut were collected at selected times and assayed for KYN by liquid scintillation counting. The substance was absorbed rapidly and distributed into all tissues. Its content (nmol/g, mean +/- SE) at 60 min was 0.26 +/- 0.05, 1.80 +/- 0.05, and 40.4 +/- 8.1 in brain (for 0.05, 0.53, and 3.17 mmol/kg), 1.43 +/- 0.11, 14.3 +/- 3.7, and 212 +/- 32 in heart, 1.16 +/- 0.21, 10.6 +/- 2.6, and 254 +/- 21 in liver, and 7.41 +/- 2.65, 180 +/- 63, and 1899 +/- 254 in kidney. Net accumulation of KYN in brain was much lower than in other tissues. Probenecid increased KYN concentration in brain 2.5-fold. Peak brain:blood concentration ratio occurred between 60 and 180 min, was inversely associated with dose, and was not affected by probenecid. Although brain content was similar, female mice had an earlier peak brain:blood ratio (120 min) than males (180 min) for the 0.05 mmol/kg dose. Our results suggest the presence of a restricted transfer process for KYN with delayed egress from brain.     

Inhibition of carnitine biosynthesis by valproic acid in rats--the biochemical mechanism of inhibition

The anticonvulsive drug, valproic acid (VPA), inhibits the biosynthesis of carnitine, and may contribute in this way to carnitine deficiency associated with VPA therapy. The conversion of [3H]-butyrobetaine into [3H]-carnitine was determined 60 min following a single intraperitoneal (i.p.) dose of 1.2 mmol/kg VPA in rats. The fraction of radioactivity found in [3H]-carnitine in the liver decreased from 63.2 +/- 1.50% to 39.2 +/- 1.11% (mean +/- SEM). Total carnitine in the liver also decreased, whereas the precursor butyrobetaine increased from 5.01 +/- 0.71 nmol/g to 8.22 +/- 0.82 nmol/g (mean +/- SEM). VPA also exhibited a dramatic effect on the conversion of an unlabeled loading amount of butyrobetaine. The increment in total carnitine caused by butyrobetaine in liver was reduced from 161 +/- 15.4 nmol/g to 53.2 +/- 5.11 nmol/g (mean +/- SEM). These data prove that VPA reduces the flux through butyrobetaine hydroxylase (EC 1.14.11.1.). The drug in vitro, however, did not inhibit the enzyme directly. Searching for the mechanism of action, we found that VPA decreased the level of alpha-ketoglutarate (alpha-KG; a cofactor of butyrobetaine hydroxylase) from 73.5 +/- 2.90 nmol/g to 52.9 +/- 2.2 nmol/g (mean +/- SEM) in the liver. The level of 1-glutamate showed a rather dramatic decrease in the liver. Moreover, alpha-KG proved to have a protective role against VPA in the [3H]-butyrobetaine conversion experiment.     

Comparative study of oral and parenteral administration of sho-saiko-to (xiao-chaihu-tang) extract on D-galactosamine-induced liver injury in rats

The preventive effect of Sho-saiko-to (Xiao-Chaihu-Tang) extract (TJ-9) on the progression of D-galactosamine (GaIN)-induced liver injury was examined in five week-old male Wistar rats with oral (p.o.) or intraperitoneal (i.p.) administration of the same dose of TJ-9. Rats treated once with GaIN (500 mg/kg body weight, i.p.) received TJ-9 at a dose of 1.0 g/kg body weight (p.o. or i.p.) 2 hours after GaIN treatment at which time an apparent liver injury occurred. Both p.o. and i.p. administration of TJ-9 showed similar significant prevention against the progression of liver injury 24 hours after GaIN injection. Although total protein and albumin concentrations in serum and protein concentration in the liver decreased with the progression of GaIN-induced liver injury, oral or i.p. administration of TJ-9 prevented these decreases in similar degree. However, decreases in serum and liver triglyceride concentration with the progression of liver injury were not attenuated after p.o. or i.p. administration of TJ-9. The activities of liver 5'-nucleotidase and glucose-6-phosphatase, marker enzymes of liver plasma and microsomal membranes, respectively, decreased during the progression of liver injury. A similar preventive effect on the decrease of both enzyme activities was found after p.o. or i.p. administration of TJ-9. These results indicate that the preventive effect on progression of GaIN-induced liver injury by oral or i.p. administration is approximately equal, and that the effect may be through improving the impaired liver protein synthesis and disrupted liver plasma and microsomal membranes in a similar degree.     

General pharmacology of S 15261, a new concept for treatment of diabetes

The new compound S 15261 (CAS 159978-02-6) is the I-isomer of 3-[2-[2-[4-[2-(alpha-Fluorenylacetylamino)ethyl]benzoyloxy]ethylam ino]-1- methoxyethyl]trifluoromethylbenzene. The general synthetic pathway used for the preparation of S 15261 and related esters is given in this paper. This compound was selected for its promising therapeutical action on blood glucose, insulin resistance and associated risk factors present in patients with non-insulin-dependent Diabetes mellitus (NIDDM). The general pharmacological profile of S 15261 was investigated. The data given in this paper show that S 15261 has presented a very low acute toxicity (lethal dose in mice greater than 1600 mg/kg orally) and did not induce significant behavioural changes in rats. A poor anorectic effects was observed after acute administration in rats. In guinea pigs S 15261 acutely induced a significant and dose-dependent hypoglycaemic effect (ED25 = 40 mg/kg orally). Biogenic amines and their metabolites in different structures of the brain were only slightly affected after acute administration of S 15261. Chronic administration of this compound (2.5 mg/kg bid for 14 days p.o.) did not cause significant alterations in the brain amines content, with the exception of an increase of serotonin (19%) in the striatum, a result not confirmed by the dose-effect study (from 1 mg/kg to 12.5 mg/kg bid for 14 days p.o.). In vitro binding assays with 31 different receptors did not show significant affinity of S 15261 for any of them. The rat arterial blood pressure was decreased (12 mmHg) after acute (25 mg/kg i.v.) or repeated administration (2.5 mg/kg bid for 14 days p.o.) without any dose-dependent effect. We therefore conclude that S 15261 may not have significant adverse effect even at doses higher than the pharmacological effective range of doses. Although the mechanism of action of this new class of compounds was not fully understood, other pharmacological data suggest that S 15261 acts at both the liver (intraportal infusion) and skeletal muscle (microdialysis studies) at least in part to enhance insulin sensitivity. For all these activities S 15261 may be useful to treat patients with NIDDM or insulin resistance known to be the major risk for onset of NIDDM.     

Predictive value of antepartum ultrasound examination for anomalies in twin gestations

RATIONALE AND OBJECTIVES: We investigated the potential of manganese (III) mesoporphyrin (Mn-mesoporphyrin) as a hepatobiliary contrast agent for magnetic resonance (MR) imaging in rabbits given VX-2 carcinoma liver implants. METHODS: Rabbits given VX-2 carcinoma liver implants (n = 8) were imaged before and after the intravenous (i.v.) administration of 0.04 mmol/kg Mn-mesoporphyrin. MR images were correlated with gross-specimen cross-sections. The distribution of Mn in various tissues following i.v. administration of 0.04 mmol/kg Mn-mesoporphyrin was determined using atomic absorption analysis. A standard panel of serum chemistries was followed over 7 days in six rabbits following this same dose of Mn-mesoporphyrin and compared with chemistries from two control rabbits. RESULTS: I.v. administration of 0.04 mmol/kg (25 mg/kg) Mn-mesoporphyrin resulted in improvement of tumor-to-liver contrast, with enhancement of normal liver (99.7 +/- 14.7%) and the gallbladder (442 +/- 116%), but not VX-2 tumor tissue (14.8 +/- 13.9%), (n = 8, p = .05). Analysis of tissue Mn levels 100 min after i.v. Mn-mesoporphyrin injection demonstrated preferential distribution of Mn to normal liver tissue (57.8 +/- 15.3 micrograms Mn/g) compared with VX-2 tumor (4.28 +/- 1.48 micrograms Mn/g). No significant change was found in the serum chemistries of six normal rabbits over a 7-day period after the i.v. administration of 0.04 mmol/kg Mn-mesoporphyrin. CONCLUSION: I.v. Mn-mesoporphyrin improved lesion-to-liver contrast because of preferential distribution of Mn-mesoporphyrin to normal liver parenchyma and bile.     

Attenuation of cocaine kindling by 7-nitroindazole, an inhibitor of brain nitric oxide synthase

Recent studies suggest the involvement of the N-methyl-D-aspartate (NMDA) type of glutamate receptors and nitric oxide synthase (NOS) in the process of increased sensitivity to the convulsive effect of cocaine ("cocaine kindling"). The present study was undertaken to analyze the various behavioral stages in the development of cocaine kindling and to investigate the effect of 7-nitroindazole (7-NI), a relatively selective inhibitor of the neuronal NOS isoform, on the induction and expression of sensitization to the convulsive effect of cocaine. Also, the effect of 7-NI on responses produced by acute systemic administration of cocaine or N-methyl-D,L-aspartate (NMDLA) was investigated. Cocaine kindling was assessed on a five-stage scale following the administration of a sub-convulsant dose of the drug (35 mg/kg/day; i.p.) to Swiss Webster mice for 10 days. Stage 5 seizures developed following the 9th day of cocaine administration. Pre-treatment with 7-NI (25 mg/kg/day; i.p.) 15 min before cocaine for 10 days completely prevented the appearance of stage 4 and 5 seizures, and it significantly attenuated stage 3 behavior in response to a challenge cocaine dose (35 mg/kg) given either 24 hr or 10 days after 7-NI/cocaine administration was stopped. A single injection of 7-NI (25 mg/kg; i.p.) completely prevented the expression of cocaine kindled seizures. Whereas 7-NI had no effect on the responses elicited by acute cocaine administration (60 mg/kg; i.p.), this agent partially attenuated the effects induced by systemic administration of the NMDA receptor agonist NMDLA (250 mg/kg; i.p.). The present study indicates that 7-NI attenuates both the induction and expression of sensitization to the convulsive effect of cocaine. The findings that 7-NI attenuated cocaine kindling and partially blocked the effects produced by activation of the NMDA receptor, but not the effects induced by acute cocaine administration, support the role of the NMDA receptor and brain NOS in the development of cocaine kindling rather than in the acute effects of the drug.     

An adenosine kinase inhibitor attenuates tactile allodynia in a rat model of diabetic neuropathic pain

The present study was conducted to characterize the development of tactile allodynia in the streptozotocin-induced rat model of diabetes, and to evaluate the antinociceptive effects of systemically administered morphine and the adenosine kinase inhibitor, 5'-deoxy-5-iodotubercidin (5'd-5IT) in this model. Rats were injected with 75 mg/kg streptozotocin (i.p.), and blood glucose levels were determined 3-4 weeks later. Diabetic (blood glucose levels > or = 250 mg/dl) and vehicle-injected rats were examined weekly for the development of tactile allodynia by measuring the threshold for hind paw withdrawal using von Frey hairs. Withdrawal thresholds were reduced to 6.8+/-0.6 g (mean+/-S.E.M.) in approximately one-third of streptozotocin-treated rats 7 weeks after streptozotocin treatment as compared to control thresholds (13.2+/-0.1 g), and this allodynia persisted for at least an additional 7 weeks. In additional experiments, morphine sulfate (5-21 micromol/kg, i.p.) produced dose-dependent antinociceptive effects on tactile allodynia for up to 2 h post-dosing. The adenosine kinase inhibitor, 5'd-5IT (2.5 and 5 micromol/kg, i.p.) also dose-dependently attenuated tactile allodynia. Pretreatment with the opioid receptor antagonist, naloxone (27 micromol/kg, i.p.) or the non-selective adenosine receptor antagonist, theophylline (111 micromol/kg, i.p.) significantly diminished the anti-allodynic effects of morphine and 5'd-5IT, respectively. The present study demonstrates that the potent and selective adenosine kinase inhibitor, 5'd-5IT, is equally effective as morphine in blocking tactile allodynia in this model.     

Assessment of possible protective roles of selenium, zinc, and cis-stilbene oxide against acute T-2 toxin poisoning: a preliminary report

The efficacy of two free radical scavengers, selenium and zinc, and a microsomal epoxide hydrolase-inducing agent, cis-stilbene oxide on the acute toxicity of T-2 toxin, a potent cytotoxic trichothecene, was investigated. Mice were pretreated daily for 3 consecutive days with either zinc sulfate (4.4 mg/kg, intraperitoneally [i.p.]), sodium selenite (1, 2, and 3 mg/kg i.p.) or cis-stilbene oxide (50 mg/kg i.p.). A full 24-hr after the final dosing with these agents, mice were given T-2 toxin (2, 2.5, or 3 mg/kg i.p.). The acute lethal toxicity of T-2 toxin (2.5 mg/kg) was reduced by administration of only sodium selenite (3 mg/kg) and cis-stilbene oxide (50 mg/kg). No significant effect on weight gain was observed.     

Effect of the bradykinin B2 receptor antagonist Hoe140 in experimental pneumococcal meningitis in the rat

To elucidate the role of bradykinin in the complex pathophysiology of bacterial meningitis we investigated the effect of the bradykinin B2 receptor antagonist Hoe140, icatibant (D-Arg[Hyp3-Thi5-D-Tic7-Oic8]-bradykinin), on pathophysiological alterations in experimental pneumococcal meningitis. Untreated rats injected intracisternally (i.c.) with heat-killed pneumococci developed an increase of regional cerebral blood flow (185.4 +/- 27.4%, baseline 100%, mean +/- S.D.), brain water content (79.16 +/- 0.23%), intracranial pressure (21.4 +/- 6.0 mm Hg), and white blood cell count in the cerebrospinal fluid (CSF) (4621 +/- 1894 cells/microliter) within 6 h after i.c. challenge. Treatment with Hoe140 (0.1 mg/kg i.v. at baseline and 0.05 mg/kg s.c. at 2 h after i.c. challenge) attenuated the increase of brain water content (78.53 +/- 0.28%; P < 0.05), intracranial pressure (7.5 +/- 2.2 mm Hg; P < 0.05), and regional cerebral blood flow (128.6 +/- 23.1%; P < 0.05), and reduced CSF pleocytosis (2690 +/- 1898 cells/microliter. N.S.). When treatment was started 4 h after i.c. challenge Hoe140 reduced intracranial pressure (P < 0.05), but was no more capable to significantly influence the other pathophysiological parameters. Treatment with lower (0.01 mg/kg i.v. at baseline, followed by 0.005 mg/kg s.c. at 2 h) and higher (2 mg/kg i.v., followed by 1 mg/kg s.c. at 2 h) concentrations of Hoe140 was ineffective. Likewise, i.c. injection of Hoe140, at different dosages (4 nmol, 40 nmol, 400 nmol) did not significantly alter the pathophysiological parameters in pneumococci-induced meningitis, but caused changes in mean arterial blood pressure at dosages greater than 4 nmol. We conclude that bradykinin is involved as an inflammatory mediator of microvascular changes, brain edema, and increased intracranial pressure during the early phase of experimental pneumococcal meningitis.     

Identification of a novel endogenous memory facilitating cyclic dipeptide cyclo-prolylglycine in rat brain

Using high-performance liquid chromatography, gas-chromatography and chromato-mass spectrometry methods a novel endogenous cyclic dipeptide cyclo-prolylglycine was identified in rat brain. Its content according to gas chromatography is 2.8 +/- 0.3 nmol/g wet brain. Synthetic cyclo-prolylglycine has demonstrated antiamnesic activity in the passive avoidance test in rats at a dose of 0.1 mg/kg i.p. Cyclic dipeptide cyclo-prolylglycine seems to be a memory facilitating substance and its presence in rat brain suggests the existence of a new mechanism of memory regulation.     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; i.p.), diazepam (0.3-10.0 mg/kg; i.p.) and pentobarbital (1.0-21.0 mg/kg; i.p.), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; i.p.), the 5-HT1 agonists TFMPP (0.3-5.6 mg/kg; i.p.) and RU 24969 (0.3-3.0 mg/kg; i.p.), and isopropanol (0.10-1.25 g/kg; i.p.). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.     

Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P

1. Piroximone was administered orally (p.o.) and intravenously (i.v.) to male Beagle dog. In vitro, piroximone was incubated with dog liver microsomes. 2. Piroximone was metabolized in vivo to five metabolites (1-5) representing approximately 20% of the total administered dose. 3. The parent drug and its metabolites were totally eliminated in urine. 4. Reduced piroximone (piroximole), representing approximately 10% of the administered dose, was identified as the major metabolic product in vivo. 5. In vitro, piroximone was metabolized by dog liver microsomes to isonicotinic acid (1) and piroximole (4), with the same ratio as in vivo (1:4 = 0.2). The Michaelis-Menten parameters were determined for piroximole formation and were: Kmapp = 733 microM and Vmax app = 232 pmol/mg protein/min. 6. Comparison of the pharmacokinetics of piroximone and piroximole revealed that both compounds were very well absorbed (F = 93 +/- 7 and 89 +/- 8% respectively), slightly distributed (Vd app = 0.78 +/- 0.04 and 1.02 +/- 0.09 l/kg p.o., and 0.95 +/- 0.05 and 0.76 +/- 0.13 1/kg i.v. respectively) and excreted into urine to the same extent (UEx = 54.7 +/- 1.2 and 53.2 +/- 12.6% p.o., and 59.1 +/- 5.3 and 51.2 +/- 5.7% i.v. respectively), except that the clearance of piroximone was two-fold higher than that observed for piroximole (ClT = 7.77 +/- 1.35 and 4.12 +/- 0.44 ml/min/kg p.o., and 7.68 +/- 1.25 and 4.06 +/- 0.51 ml/min/kg i.v. respectively).     

Protection against hypoxic-ischemic damage with corticosterone and dexamethasone: inhibition of effect by a glucocorticoid antagonist RU38486

We investigated whether the neuroprotection provided by dexamethasone against neonatal hypoxic-ischemic damage can be inhibited by a glucocorticoid antagonist and whether corticosterone, the endogenous glucocorticoid in the rat, also provides protection. Rats (6 days old) were treated with either vehicle (0.1 ml/10 g), corticosterone (3.5-80 mg/kg, s.c.) or dexamethasone alone or in combination with RU38486 (20-80 mg/kg, s.c.) 15 min prior to dexamethasone (0.1 mg/kg, i.p.). At 7 days of age, cerebral hypoxia-ischemia was produced by right carotid artery ligation under anesthesia and subsequent exposure to 2 h of hypoxia. Damage was quantified from brains perfusion-fixed and processed 2 days later. The reduction in somatic growth, thymus weight and the relatively elevated blood glucose levels at the end of hypoxia-ischemia were inhibited by RU38486. The protective effect of dexamethasone was also prevented by RU38486 (P < 0.001). Similar to pre-treatment with dexamethasone, administration of corticosterone (40-80 mg/kg) markedly reduced the extent of infarction compared to vehicle-treated controls (P < 0.0001). Thus, the endogenous glucocorticoid in the rat also provides protection against hypoxic-ischemic damage. RU38486 inhibits the beneficial effects of dexamethasone demonstrating that the neuroprotection observed with dexamethasone is a glucocorticoid receptor-mediated effect.     

Pharmacokinetics of enrofloxacin after intravenous, intramuscular and oral administration in houbara bustard (Chlamydotis undulata macqueenii)

The in-vitro activity of enrofloxacin against 117 strains of bacteria isolated from bustards was determined. Minimum inhibitory concentrations for 72% of the Proteus spp., E. coli, Salmonella spp. and Klebsiella spp. (n = 61) and for 48% of the Streptococci spp. and Staphylococci spp. (n = 31) were < or = 0.5 microg/mL. The minimum inhibitory concentration (MIC) of 76% of Pseudomonas spp. (n = 25) was < or = 2 microg/mL. Fourteen strains were resistant to concentrations > or = 128 microg/mL. The elimination half-lives (t1/2 elim beta) (mean +/- SEM) of 10 mg/kg enrofloxacin in eight houbara bustards (Chlamydotis undulata) were 6.80 +/- 0.79, 6.39 +/- 1.49 and 5.63 +/- 0.54 h after oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) administration, respectively. Enrofloxacin was rapidly absorbed from the bustard gastro-intestinal tract and maximum plasma concentrations of 1.84 +/- 0.16 microg/mL were achieved after 0.66 +/- 0.05 h. Maximum plasma concentration after i.m. administration of 10 mg/kg was 2.75 +/- 0.11 microg/mL at 1.72 +/- 0.19 h. Maximum plasma concentration after i.m. administration of 15 mg/kg in two birds was 4.86 microg/mL. Bioavailability was 97.3 +/- 13.7% and 62.7 +/- 11.1% after i.m. and oral administration, respectively. Plasma concentrations of enrofloxacin > or = 0.5 microg/mL were maintained for at least 12 h for all routes at 10 mg/kg and for 24 h after i.m. administration at 15 mg/kg. Plasma enrofloxacin concentrations were monitored during the first 3 days of treatment in five houbara bustards and kori bustards (Ardeotis kori) with bacterial infections receiving a single daily i.m. injection of 10 mg/kg for 3 days. The mean plasma enrofloxacin concentrations in the clinical cases at 27 and 51 h (3.69 and 3.86 microg/mL) and at 48 h (0.70 microg/mL) were significantly higher compared with the 3 h and 24 h time intervals from clinically normal birds. The maximum plasma concentration (Cmax)/MIC ratio was ranked i.v. (10/mg/kg) > i.m. (15 mg/kg) > i.m. (10 mg/kg) > oral (10 mg/kg), but it was only higher than 8:1 for i.v. and i.m. administrations of enrofloxacin at 10 mg/kg and 15 mg/kg, respectively, against a low MIC (0.5 microg/mL). A dosage regimen of 10 mg/kg repeated every 12 h, or 15 mg/kg repeated every 24 h, would be expected to give blood concentrations above 0. 5 microg/mL and hence provide therapeutic response in the bustard against a wide range of bacterial infections.     

The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA ('ecstasy')

The effect of varying the dose and frequency of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on both the acute hyperthermic response and the long term neurodegeneration of 5-hydroxytryptamine (5-HT) nerve terminals in the brain has been studied in Dark Agouti rats. A single injection (4-15 mg/kg i.p.) of MDMA produced immediate dose-related hyperthermia and a dose-related decrease in 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and [3H]paroxetine binding in regions of the brain 7 days later, with a dose of 4 mg/kg having no degenerative effect. This dose was also without effect when given once daily for 4 days, but produced a marked loss of [3H]paroxetine binding and indole concentration ( approximately 55%) when given twice daily for 4 days. When a dose of 4 mg/kg was given twice weekly for 8 weeks it had no effect on these serotoninergic markers, despite a clear anorectic effect of the drug being seen. These data demonstrate that MDMA-induced neurodegeneration is related to both the dose and frequency of administration and indicate that damage to 5-HT neurones can occur in the absence of a hyperthermic response to the drug. We suggest that damage occurs when endogenous free radical scavenging mechanisms become overwhelmed or exhausted.     

Cross-tolerance to acute administration of mu and kappa opioid agonists at the spinal cord level in the rat

Development of tolerance and cross-tolerance after acute administration of the mu agonist morphine and the kappa agonist U-50,488H was assessed in rats, through recording of a C-fiber-evoked spinal nociceptive reflex. Rats rendered tolerant to morphine (a single dose of 1 mg/kg i.p.) showed, after a 5-hour period, tolerance to morphine and cross-tolerance to the kappa-opioid receptor agonist U-50,488H, as revealed by depressed C-reflex responsiveness. In contrast, pretreatment with U-50,488H (a single dose of 1 mg/kg i.p.) rendered tolerant the rats to U-50,488H, but the animals did not develop cross-tolerance to morphine. Results indicate that acute administration of mu and kappa ligands leads to development of unidirectional cross-tolerance in rat spinal cord. This points to limitations in using alternated mu and kappa opioid agonists to bypass the problem of development of opioid tolerance in chronic pain complaints.     

Modulation of kinin B1 but not B2 receptors-mediated rat paw edema by IL-1beta and TNFalpha

The modulatory effects of IL-1beta and TNF alpha on the rat paw edema induced by B1 agonists have been analyzed. In naive rats, i.d. injection of B1 agonists, des-Arg9-bradykinin and des-Arg10-kallidin (up to 300 nmol), causes a minimal increase in paw volume, while the B2 agonist tyrosine8-bradykinin (0.3-10 nmol) induces graded paw edema. The injection of des-Arg9-bradykinin (10-100) nmol or des-Arg10-kallidin (1-100 nmol), in paws pre-treated with IL-1beta or TNF alpha (both 5 ng/paw; 60 and 30 min prior, respectively), caused a graded edema formation. The edemas induced by des-Arg9-bradykinin (100 nmol) were evident at 15 min, reaching the maximum 60 and 30 min after treatment with IL-1beta (0.64 +/- 0.06 ml) or TNF alpha (0.47 +/- 0.05 ml), respectively, being reduced at 360 min. The B1 antagonist des-Arg9-NPC 17731 (1-30 nmol), but not the B2 antagonist Hoe 140 (10 nmol), produced marked inhibition of des-Arg9-bradykinin-induced paw edema. Dexamethasone (0.5 mg/kg, s.c., 4 h) or cycloheximide (1.5 mg/kg, s.c., 6 h) significantly prevented the edema caused by des-Arg9-bradykinin (100 nmol) in rats treated with IL-1beta (81 +/- 5% and 59 +/- 3%) or TNF alpha (78 +/- 4% and 43 +/- 2%). Indomethacin (2 mg/kg, i.p.) or meloxicam (3 mg/kg, i.p.), 1 h prior, significantly reduced the edema induced by des-Arg9-bradykinin (100 nmol) in IL-1beta (40 +/- 6% and 69 +/- 8%) or TNF alpha (43 +/- 3% and 53 +/- 9%) treated rats. It is suggested that i.d. injection of the IL-1beta or TNF alpha, produced up-regulation of B1 receptor-mediated paw edema, being this effect sensitive to dexamethasone and cycloheximide and to cyclo-oxygenase pathway.     

Consumption of a high dietary dose of monosodium glutamate fails to affect extracellular glutamate levels in the hypothalamic arcuate nucleus of adult rats

We examined the effects of systemic or oral ad libitum monosodium glutamate (MSG) administration on glutamate levels in plasma, and on glutamate release from the arcuate nucleus of the hypothalamus (estimated using brain microdialysis). Systemic MSG administration (0.25, 0.5, 1 or 2 g/kg, i.p.) to adult rats caused dose-dependent increases in glutamate levels within arcuate nucleus dialysates. These levels increased during the initial 20 min after systemic MSG administration, and peaked during the second 20-min interval (maximally to 116 +/- 7%, 146 +/- 15%, 790 +/- 191% and 1230 +/- 676% of basal values, respectively). Plasma glutamate levels, measured simultaneously, were increased maximally during the initial 20 min after MSG administration. These increases were 10-, 13-, 76- and 163-fold after doses of 0.25, 0.5, 1 and 2 g/kg, i.p., respectively. In feeding experiments, consumption of 2.3 g/kg of MSG by previously-trained rats during an 1-h period increased plasma glutamate levels to 352 +/- 61% of basal values 140 min after the start of the feeding period. No changes were observed in glutamate levels of arcuate nucleus dialysates. These findings may explain why ad libitum dietary consumption of MSG apparently lacks neurotoxic potential.     

Experimental study on intraperitoneal sequential MTX/5-FU therapy for peritoneal seeding in comparison with intravenous administration

Sequential MTX/5-FU therapy (intravenous route) is powerful chemotherapy especially for poorly differentiated adenocarcinoma of the stomach and its peritoneal metastases. The authors had proposed the idea of intraperitoneal sequential MTX/5-FU chemotherapy for potential peritoneal metastases and micrometastases from advanced gastric carcinoma. This experimental study was planned to confirm this experimentally. Peritoneal seeding model of nude mice was made by the intraperitoneal inoculation of human gastric cancer cell line MKN-45. Control group (n = 5) had no treatment. The intraperitoneal (i.p.) group and intravenous (i.v.) group underwent the treatments on the 7th, 14th, and 21st day after cell implantation. Experimental chemotherapies consisted of intraperitoneal injection of MTX (15 mg/kg, 1.5 ml saline) and 5-FU (50 mg/kg, 1.0 ml saline) for i.p. group and intravenous injection of MTX (15 mg/kg, 0.2 ml saline) and 5-FU (50 mg/kg, 0.2 ml saline) for i.v. group. Interval time between MTX and 5-FU administration was 2 hours. On the 35th day after the cell implantation necropsies were performed. Counting of peritoneal metastatic nodules revealed the number of nodules of control group. (14.2 +/- 6.7) > i.v. group (5.3 +/- 4.1) > i.p. group (0.41 +/- 0.7) (p < 0.05). Weight of omental tumors showed Control group (0.246 +/- 0.136 g) > i.v. group (0.140 +/- 0.068 g) > i.p. group (0.051 +/- 0.017 g) (i.v.-i.p., p < 0.01). The mouse body weight decrease less in the i.p. group than in the i.v. group (p < 0.05) throughout this experiment. The results of this experiment demonstrated intraperitoneal sequential MTX/5-FU therapy was more effective than intravenous sequential MTX/5-FU therapy for potential peritoneal seeding and peritoneal micrometastases from the gastric cancer. Moreover, the side effect of intraperitoneal administration was milder than by the intravenous route.