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The effect of the nonsteroidal antiinflammatorydrug (NSAID) amtolmetin guacyl (AMG) on the gastricmucosa was studied in the rat by means of histologicaland functional techniques. AMG administered at 50-300 mg/kg intragastrically was virtuallydevoid of gastrolesive properties after either acute orrepeated treatment. By contrast, its metabolite,tolmetin (TOL, 15-60 mg/kg, intragastrically) caused dose-dependent gastric damage after bothtreatments. Light and electron microscopy revealed thatAMG induced minimal changes in the surface epitheliumlayer, without signs of vasocongestion or leukocytes adherence. AMG (50 mg/kg intragastrically) didnot change basal gastric potential difference (PD),whereas acetylsalicylic acid and ibuprofen induced fallsin PD of 22 and 27 mV, respectively. AMG (50 mg/kg intragastrically) reduced by 60% the fall in PDinduced by 50% ethanol; this inhibition was dependent onthe incubation time, and was maximal when AMG was given4 hr before ethanol. AMG (100 mg/kg intragastrically) induced an increase in NO synthase type 2(NOS2) activity, which was significantly different fromcontrol values, when AMG was administered 4 hr beforethe test. The metabolites of AMG, tolmetin, MED 5, and guaiacol were ineffective. Pharmacokineticanalysis of the residence time of AMG in the differentareas of the gastrointestinal tract, revealed that AMGremains in the gastrointestinal tract at least for 4 hr, the time necessary for a maximalinduction of NOS2 and for maximal protection againstethanol-induced damage. In conclusion, these dataindicate that the nonsteroidal antiinflammatory drugamtolmetin guacyl is devoid of gastrolesive properties;this gastrosparing effect seems to involve theproduction of nitric oxide, which can counteract thedamaging effects due to prostaglandin inhibition. Thepresence in the stomach of the native molecule ofamtolmetin guacyl seems to be necessary for theprotective effect observed.

Transection of the fimbria-fornix in adult rats is a useful model for producing impairments of cholinergic activity in the hippocampus (HIPP) and atrophy of the medial septum cholinergic perikarya, similar to those observed during senescence, that are possibly due to the lack of nerve growth factor (NGF) retrogradely transported from the hippocampus. In our investigation we used choline acetyltransferase (ChAT) as an index of cholinergic activity in HIPP, frontal cortex (FCX), septum and nucleus basalis magnocellularis (NBM) along with measurements of NGF levels in the HIPP. Three-month-old rats with unilateral total fimbria transection received acetyl- l -carnitine (ALCAR) (150 mg/kg/day in drinking water for 1 week before and 4 weeks after the lesion). ALCAR is a substance known to ameliorate some morphological and functional disturbances in the aging central nervous system (CNS). ChAT activity in septum and FCX, and NGF levels in HIPP were significantly increased in the treated group, compared with untreated control groups, while no changes were found in the NBM. On the other hand, a similar ALCAR treatment in unoperated animals induced an increase in ChAT activity in FCX but not in septum nor in NBM. These data are suggestive of a neurotrophic property of ALCAR exerted on those central cholinergic pathways typically damaged by aging.

The therapeutic efficacy of the immunomodulator 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (ST1959) in colonic inflammation was assessed in rats. One hour following colonic instillation of ethanolic 2,4,6-trinitrobenzene sulphonic acid (TNBS), intracolonic administration of 0.4 mg/kg ST1959 was started and continued once daily for 1 or 2 weeks. Daily administration of ST1959 for 1 week significantly reduced macroscopic and histological damage, myeloperoxidase activity, and colonic tissue levels of tumour necrosis factor-alpha and interferon-gamma. ST1959 did not affect interleukin-12 levels but significantly enhanced the production of interleukin-10 (sixfold increase). Two weeks of ST1959 treatment reduced the thickness of the colonic wall and myeloperoxidase activity to the same extent, and the histologic appearance of the mucosa was largely restored. The ameliorating effects seem to be ascribable to an impairment of both neutrophil infiltration/activation and tumour necrosis factor-alpha and interferon-gamma production, possibly consequent to the observed increase in the colonic tissue levels of the potent anti-inflammatory cytokine interleukin-10. Similar results were observed with the reference drug 5-aminosalycilic acid.

Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) 5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED(50) >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.

The prototypical dopamine and serotonin antagonist (+/-)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D(2) receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT(2) receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D(2) receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H(1) and the alpha(1) receptor, a moderate affinity for alpha(2) and D(3) receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D(2) receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (+/-)-5 for D(2) receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.

There is strong evidence that autonomic imbalance plays an important role in progression of heart failure. Analysis of heart rate variability (HRV) has achieved substantial acceptance as a noninvasive method for the assessment of autonomic tone. The purpose of this investigation was to study HRV in an experimental model of heart failure using cardiomyopathic (BIO TO.2) hamsters. Animals showed an autonomic imbalance of cardiac control that seems due to attenuation of parasympathetic activity and an enhanced sympathetic tone. The reduction of parasympathetic activity in BIO TO.2 hamsters is suggested by (a) the reduction of the high-frequency (HF) spectrum, and (b) the lack of atropine to generate a response. The increased sympathetic activity is indicated by (a) the decreased time-domain indexes, (b) the increased LF/HF ratio of the power spectrum, and (c) the alteration of HRV indexes induced by propranolol. These results support the notion that in heart failure, there is a similar autonomic imbalance in both human and hamster and suggest that the cardiomyopathic hamster is a suitable experimental model for studying the involvement of the autonomic nervous system in the progression of heart failure.

Transection of the fimbria-fornix bundle in adult rats results in degeneration of the septo-hippocampal cholinergic pathway, reminiscent of that occurring in aging as well as Alzheimer disease. We report here a study of the effect of a treatment with acetyl- l -carnitine (ALCAR) in three-month-old Fischer 344 rats bearing a partial unilateral fimbria-fornix transection. ALCAR is known to ameliorate some morphological and functional disturbances in the aged central nervous system (CNS). We used choline acetyltransferase (ChAT) and acetyl cholinesterase (AChE) as markers of central cholinergic function, and nerve growth factor (NGF) levels as indicative of the trophic regulation of the medio-septal cholinergic system. ChAT and AChE activities were significantly reduced in the hippocampus (HIPP) ipsilateral to the lesion as compared to the contralateral one, while no changes were observed in the septum (SPT), nucleus basalis magnocellularis (NBM) or frontal cortex (FCX). ALCAR treatment restored ChAT activity in the ipsilateral HIPP, while AChE levels were not different from those of untreated animals, and did not affect NGF content in either SPT or HIPP.

Aging is associated with a reduction in the maximum density of n-methyl-d-aspartate (NMDA)-sensitive glutamate binding sites in the hippocampus of Fischer 344 rats. This study was designed to investigate the effect of acetyl-l-carnitine (ALCAR) on NMDA receptors in the old rat (24 months) after chronic or single-dose treatments. The number of NMDA receptors was significantly decreased in the old rat hippocampus by 19.5% compared with the young rat. A six-month treatment with ALCAR in the old rat attenuated the loss of NMDA binding sites in the hippocampus. A single-dose treatment with ALCAR in the old rat increased the Bmax value by 35%, while no change was observed in the young group. We conclude that ALCAR can exert two actions: a trophic/neuro-preserving one when chronically administered during aging, and a stimulatory one when given at a single dose in the aged rat.

To ascertain the effects of bicuculline and of sodium valproate on the incorporation of glycerol into rat brain lipid, rats were divided into 5 groups: (a) controls; (b) treated with sodium valproate (400 mg/kg body wt); (c) treated with bicuculline (12.5 μmol/kg body wt); (d) treated with sodium valproate as in (b) + bicuculline as in (c); and (e) treated with bicuculline (25 μmol/kg body wt). Only rats of group (c) had seizures, which lasted until the end of the experiment. Each animal received 20 μCi of [2- 3 H]glycerol by intraventricular route and was sacrificed 12 min afterwards. Hippocampi and cerebella were taken and lipid extracted and separated by chromatography. The type of treatment influenced very much the fate of injected, labeled glycerol. Indeed, total recovered radioactivity increased following either convulsions or the administration of valproate, whereas both treatments decreased the amount of radioactivity incorporated into lipid. These effects were more evident in cerebella than in hippocampi. The distribution of radioactivity among lipid classes (diglyceride, triglyceride and total phospholipid) was also affected by seizures, which decreased the labeling ratio phospholipid/neutral lipid. The distribution of radioactivity among phospholipid classes was influenced by bicuculline (both at convulsant and non-convulsant doses) and these effects were sometimes antagonized by valproate. We conclude that some effects of bicuculline are exerted through the systemic modifications due to seizures and that other effects are probably connected to neuronal hyperfiring. The data reported in this paper are consistent with both mechanisms of action proposed for valproate, i.e. increased membrane permeability and modifications of GABAergic systems.