[A single effective way to reduce post-thyroidectomy discomfort: a clinical trial]. / Un metodo semplice ed efficace per ridure il discomfort dopo tiroidectomia: un trial clinico.

AIM: Nausea, with or without vomiting (postoperative nausea and vomiting, PONV), occurs up to 60-76% after thyroidectomy and other head and neck surgeries. Due to the fact that patients typically have only mild-to-moderate pain after thyroid or parathyroid surgery, PONV might be the main source of discomfort, and it may be perceived as the most unpleasant aspect of postoperative recovery. This study aims to assess the effects of a preoperative single dose of 8 mg dexamethasone on the nausea, vomiting, pain, and subjective vocal function after thyroidectomy in patients undergoing surgery for benign disease. METHODS: Seventy patients operated on for thyroidectomy were randomized in two groups: Group A, 8 mg/2 mL of dexamethasone administered in 100 mL of physiologic saline given intravenously (i.v.) 20 minutes before the induction of anesthesia; group B, 2 mL NaCl 0.9% in 100 mL of physiologic saline. Postoperative therapy has been standardized. PONV have been evaluated with a scale of 4, degrees (0-3), pain by a Visual Analog Scale (0-100) and subjective vocal function by a Visual Analog Scale (0-100) at 8, 24, 32 and 48 hours after surgery. RESULTS: The severity of nausea was less in patients of group A (P=0.0001); Dexamethasone patients reported significantly less pain (P=0.008); no differences were noted about the subjective voice analysis (P=0.693). No steroid-related complications occurred. CONCLUSION: Dexamethasone 8 mg i.v. is a safe and effective method to reduce PONV and pain after thyroid resection and we advise its routine use.

S22153, a melatonin antagonist, dissociates different aspects of photoperiodic responses in Syrian hamsters.

In the Syrian hamster, short photoperiod (SP) induces changes in several physiological functions (body mass, reproduction, hibernation), and these responses involve the pineal hormone melatonin. The present study investigated the effects of a melatonin antagonist, S22153, on photoperiodic adaptation of male Syrian hamster. When constantly released from subcutaneous implants, S22153 had no effect on body or testes masses of animals kept in long photoperiod. S22153 decreased the total hibernation duration observed in animals exposed to SP and low temperature. The decrease in hibernation duration was due to a marked reduction in the number and duration of hypothermic bouts. Moreover, S22153 significantly inhibited the increase of interscapular brown adipose tissue (BAT) mass induced by SP. However, neither the gonadal atrophy nor the body mass increase induced by SP were affected by S22153. These results show that S22153 affects only part of the physiological changes controlled by SP and cold. Whether the decreases in BAT mass and hibernation duration are linked still remains an open question.

Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands.

Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I1 and I2) and alpha-adrenergic (alpha1 and alpha2) receptor ligands. Their pKi values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases alpha-adrenergic affinity. I1 sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(2'-methoxyphenyl)-imidazoline (17) is one of the best I1 ligands ever reported (pKi = 8.53 and I1/I2 > 3388). On the other hand, I2 selectivity increases in the presence of a methyl group in the para position. The original compound, 2-(3'-fluoro-4'-tolyl)-imidazoline (31) is a new potent ligand for the I2 sites with high selectivity (pKi = 8.53 and I2/I1 > 3388).

Interactions between imidazoline binding sites and dopamine levels in the rat nucleus accumbens.

Imidazoline binding sites are present in the striatal complex and in the extended amygdala and have been implicated in mood disorders. In this report we analysed the influence of these sites on the functional activity of the mesolimbic dopaminergic transmission, one of the major brain systems involved in the regulation of motivation and reward. We studied the effects of two imidazoline ligands, S23229 and S23230 (respectively S(+) and R(-) enantiomers of the S22687 or (5-[2-methyl phenoxy methyl] 1,3-oxazolin-2-yl) amine), on extracellular dopamine in the nucleus accumbens using microdialysis in freely moving rats. We compared these imidazoline ligands to cocaine, a dopamine uptake blocker known to increase extracellular dopamine concentrations. S23229 dose-dependently increased extracellular dopamine and locomotor activity. S23230 dose-dependently increased extracellular dopamine and produced a near-significant dose-effect on locomotor activity. S23229 had a stronger efficacy than S23230 and increased dopamine levels in the nucleus accumbens at an extent similar to the one of cocaine. These results suggest that central imidazoline binding sites could contribute to the functional regulation of the mesolimbic dopaminergic system.

Synthesis and binding studies on a new series of arylpiperazino benzazol-2-one and benzoxazin-3-one derivatives as selective D4 ligands.

A series of new arylpiperazinomethyl derivatives was designed and studied as potential D4 ligands. The synthesis of these compounds required an original synthetic route. Some of the tested compounds were found to be as potent as clozapine at D4 receptors. Moreover, compounds which displayed a high D2/D4 selectivity ratio (>122) were selected for further pharmacological evaluation.

Reentrainment of the spontaneous locomotor activity rhythm to a daylight reversal in C57BL/6 and C3H/He mice: implication of melatonin.

The adaptation of the locomotor activity rhythm to a daylight reversal was previously found to be faster in C57BL/6 mice, which present a low level of melatonin, than in C3H/He mice, which exhibit a large nocturnal melatonin peak. Because pinealectomy has been shown to accelerate resynchronisation time in rats after a daylight reversal, we investigated the involvement of melatonin in the resynchronisation rate of locomotor activity rhythm in C57BL/6 and C3H/He strains. We first tested the effects of melatonin, administered at zeitgeber time (ZT) 20 (with ZT0 corresponding to light onset) for the 3 days preceding the daylight reversal, on the reentrainment of locomotor activity rhythm in both strains. Second, the effects of S-22153, a melatonin receptor antagonist, on the reentrainment of locomotor activity rhythm in C3H/He mice were examined. S-22153 was administered for the 3 days preceding the daylight reversal either at ZT12 or at ZT20, i.e., when endogenous melatonin levels are respectively low and high. Melatonin significantly delayed the resynchronisation of locomotor activity rhythm in C57BL/6 mice without affecting this parameter in C3H/He mice. S-22153 significantly accelerated the resynchronisation in C3H/He mice when administered at ZT20, but had no effect when administered at ZT12. These results support the hypothesis that the differences between C3H/He and C57BL/6 in the reentrainment of their locomotor activity rhythm depend, at least in part, on the interstrain differences in melatonin synthesis.

Anxiolytic-like properties of melatonin receptor agonists in mice: involvement of mt1 and/or MT2 receptors in the regulation of emotional responsiveness.

The anxiolytic-like properties of melatonin have been established in rodents. The present study investigated the possible involvement of melatonin receptors/binding sites in the regulation of emotional responsiveness in mice, using an mt1/MT2 receptor specific agonist (S 23478) and two specific ligands of MT3 binding sites with agonistic properties (N-acetylserotonin (NAS) and 5-methoxycarbonylamino N-acetyltryptamine (5-MCA-NAT)). We examined the behavioural effects of these compounds in C3H/He mice confronted with two anxiety models: the free-exploratory test, in which C3H/He mice present neophobic reactions ("trait" anxiety), and the light/dark choice test, which is an unconditioned conflict test (inducing "state" anxiety). Melatonin and S 23478 decreased anxious reactions in both the free-exploratory test (5-25 mg/kg) and the light/dark choice test (melatonin: 20 mg/kg; S 23478: 10-20-40 mg/kg). NAS exerted anxiolytic-like effects only at a dose of 35 mg/kg in the free-exploratory test and at a dose of 40 mg/kg in the light/dark choice test. Finally, 5-MCA-NAT was devoid of anxiolytic-like effects in both tests. These results suggest that the anxiolytic properties of melatonin could involve the activation of mt1 and/or MT2 receptors rather than of the MT3 binding site.

Substituted 3-amino and/or 3-aminomethyl-3,4-dihydro-2H-1-benzopyrans: synthesis and biological activity.

A series of new 3-amino, 3-aminomethyl-5-alkoxy-3,4-dihydro-2H-1-benzopyran and 5'-alkoxy-3',4'-dihydrospiro-[piperazine-2.3'(2'H)-benzopyran] derivatives was prepared and evaluated for affinity at 5-HT1A, 5-HT2A and D2 receptors. Two of the compounds (1f and 2b) can be considered as potent and selective 5-HT2A ligands. One compound (1g) demonstrated high affinity for 5-HT1A and D2 receptor binding sites and one compound (1d) proved to be a mixed 5-HT1A/5-HT2A ligand.

Synthesis and structure-activity relationships of novel arylalkyl 4-benzyl piperazine derivatives as sigma site selective ligands.

Continuing our previous work that established that some chromones substituted by an aryl alkyl piperazino alkyl side chain are potent and selective sigma ligands and could be interesting in the treatment of psychosis, we synthesized 60 new compounds, replacing the chromone moiety by various cyclic systems. Many derivatives bind to the sigma sites in the nanomolar range and are generally selective in comparison with 5HT(1A) and the D(2) receptors. One of the most potent ligands of these series, 1-(2-naphthyl methyl)-4-benzyl piperazine 29, has been studied in various pharmacological tests. Although it doesn't have potential in the treatment of psychosis, the results we obtained confirm the data which indicates that such derivatives could be interesting in the treatment of inflammatory diseases.

Antagonistic effects of S 22153, a new mt1 and MT2 receptor ligand, on the neophobia-reducing properties of melatonin in BALB/c mice.

When exposed to a free-exploratory situation, BALB/c mice are well known to exhibit strong avoidance responses toward unfamiliar places (neophobia). Because melatonin was found to significantly reduce neophobia in BALB/c mice, it seemed interesting to examine potential antagonistic effects of S 22153, a new melatonin mt1 and MT2 receptor ligand, on the neophobia-reducing properties of melatonin in BALB/c mice confronted with the free-exploratory paradigm. S 22153 was able to block, in a dose-dependent manner, the anxiolytic-like properties of melatonin when it was administered 5 min before melatonin. The antagonistic effects of S 22153 persisted when the drug was administered 2 or 4 h before melatonin, and were almost abolished when it was administered 6 h before melatonin. These results suggest that the anxiolytic-like effects of melatonin on the neophobic responses in BALB/c mice are mediated by mt1 and/or MT2 receptors.

Effects of melatonin on neophobic responses in different strains of mice.

Anxiolytic properties of melatonin in rodents had usually been examined in behavioral tests based on stressful situations, i.e., in animal models of "state" anxiety. However, no study reports effects of melatonin on emotionality of rodents submitted to situations devoid of stressful components as in the free-exploratory test, which gives to animals the opportunity to choose freely between familiar and unfamiliar places. This procedure has been proposed as a method for measuring an endogenous form of anxiety called "trait" anxiety. The present study first investigated the effects of melatonin on neophobic responses of male C57BL/6, C3H/He, and BALB/c mice submitted to a free-exploratory test. Results demonstrated that melatonin had no effect in C57BL/6 mice that presented very low neophobic responses, whereas it was effective in reducing neophobia of BALB/c and C3H/He mice that presented, respectively, strong and intermediate avoidance responses towards unfamiliarity. Indeed, mice of both latter strains treated with melatonin made fewer attempts to enter into the unfamiliar compartment, exhibited a lower latency of the first entry into the unfamiliar places, and spent more time in them. Thus, melatonin appeared to be equally effective in reducing "trait" anxiety in both BALB/c and C3H/He mice. Moreover, flumazenil was able to counteract, in a dose-dependent manner, the anxiolytic activity of melatonin in BALB/c, suggesting involvement of central GABAergic system in the pharmacological effects of melatonin.

A single oral dose of S 22153, a melatonin antagonist, blocks the phase advancing effects of melatonin in C3H mice.

Disorders of the circadian system have been associated with adverse mental and physical conditions, raising the possibility that pharmacological agents acting on the circadian system could have therapeutic benefit. Compounds acting as agonists or antagonists of melatonin, an endogenous hormone able to feed back on the circadian clock, are currently under development for possible use in modulating circadian rhythmicity. In the present study, we examined the ability of an oral dose of S 22153, a synthetic melatonin antagonist, to block the phase advancing effect of a melatonin injection at circadian time 10 in free running C3H mice. Our results show that S 22153 had no effect per se on the phase or the period of the locomotor activity rhythm but was able to block the phase advancing effect of melatonin, suggesting potent antagonist effects at melatonin receptors. Availability of a melatonin antagonist may yield new insight into the role of melatonin in physiological processes and such compounds may find widespread clinical applications.

N,N-disubstituted aminomethyl benzofuran derivatives: synthesis and preliminary binding evaluation.

A series of new N-substituted 2,3-dihydro-2-aminomethyl-2H-1-benzofuran derivatives was prepared and evaluated for affinity at 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, D2, and D3 receptors. Compound 9, 8-[4-[N-propyl-N-(7-hydroxy-2,3-dihydro -2H-1-benzofuran-2-yl)methyl]aminobutyl]-8-azaspiro[4,5]decane-7,9 -dione, bound at 5-HT1A sites with nanomolar affinity (IC50= 1.5 nM) and high selectivity over 5-HT2A, 5-HT2C, 5-HT3, D2, and D3 receptors.

Regulation of emotional behaviour by day length in mice: implication of melatonin.

Pineal melatonin secretion occurs at night in all vertebrates and the duration of its secretion is negatively correlated with day length. As short-day exposure was previously shown to decrease emotional behaviour of mice toward an unfamiliar environment, the present study was designed to determine whether such behavioural changes could be mediated by melatonin. In a first experiment, the effects of a 3-week exposure to various day lengths (18h-6h, 12h-12h and 6h-18h light-dark conditions) on neophobic behaviour (free-exploratory paradigm) were examined in both BALB/c mice, which exhibit a very transitory melatonin peak of low amplitude in a 12h light-12h dark cycle, and C3H/He mice, which present a clear melatonin rise during the night-time. A second experiment was designed to determine if the decrease of emotional reactivity induced by a short-day exposure (6h-18h light-dark cycle during 3 weeks) in C3H/He mice could be counteracted by a daily treatment with a melatonin antagonist, S 22153 (1, 5 and 25 mg/kg/day). The short-day exposure was found to decrease neophobic reactions in both C3H/He and BALB/c mice. In contrast, the long-day exposure enhanced neophobia in C3H/He mice only. S 22153 was found to counteract, in a dose-dependent manner, the anxiolytic-like effects induced by the short-day exposure in C3H/He mice. The present results provide evidence that the modulation of circulating melatonin could be involved in the emotional changes related to day-length variations. Further studies are needed to investigate whether pinealectomy could counteract the photoperiod-related changes in anxiety.

The effects of melatonin on the behavioural disturbances induced by chronic mild stress in C3H/He mice.

In rodents, exposure to chronic mild stress (CMS) is known to induce unresponsiveness to environmental stimuli, as well as sleep disturbances, suggesting some analogies between this syndrome and human depression. Furthermore, numerous studies reported a decrease in nocturnal melatonin concentration in depressed patients, compared with controls. The present study was conducted to test a possible preventative action of daily treatment with melatonin on behavioural alterations induced in C3H/He mice by CMS exposure. In addition to daily spontaneous locomotor activity and preference for sucrose solution, the emotional behaviour of mice was examined in a stressful situation (light/dark choice test), as well as in a situation devoid of constraining components (free-exploratory paradigm), after three weeks of CMS. The results showed that the behaviour of C3H/He mice was disrupted after CMS. Stressed mice exhibited blunted emotional reactivity in both the light/dark choice test and the free-exploratory situation. While unstressed mice presented no variation in their preference for a sucrose solution, stressed mice presented a decrease in such preference towards the end of the CMS exposure. Furthermore, daily spontaneous locomotor activity of the mice was reduced after CMS. Daily treatment of stressed mice with melatonin was able to prevent several CMS-induced disturbances, except in the light/dark choice test, where melatonin was ineffective. Compared to the effects of 10 mg/kg of fluoxetine, which completely prevented CMS-induced dysregulation of behaviour, melatonin was less effective. The present results support the idea that melatonin may be implicated in an homeostatic system which protects animals from disruptions induced by chronic stress.

Daily variations in pineal melatonin concentrations in inbred and outbred mice.

Melatonin was measured using a specific radioimmunoassay in 1 strain of outbred mice (OF1 Swiss) and 4 strains of inbred mice, 2 of them being known to synthesize melatonin (CBA and C3H) and the 2 others being controversial (BALB/c and C57BL/6). In this study, the 5 mouse strains were able to synthesize melatonin, but the basal levels as well as the diurnal variations were very different from one strain to another. CBA and C3H strains showed a clear-cut day-night rhythm of pineal melatonin concentration, with peak levels of 276 +/- 22 pg/pineal in CBA and 135 +/- 12 pg/pineal in C3H. In BALB/c, the authors confirmed the presence of a very short melatonin peak (15 min) in the middle of the dark period. In C57BL/6 and OF1 Swiss, a very small but significant peak was observed in the middle of the darkness. In the former, another small peak was also observed at light onset. Whether these very small peaks, which may be related to the deficience of N-acetyl transferase activity reported by others, have a physiological meaning remains to be determined.

Novel benzothiazolin-2-one and benzoxazin-3-one arylpiperazine derivatives with mixed 5HT1A/D2 affinity as potential atypical antipsychotics.

Since it was known that 5HT properties (5HT1A agonism or 5HT2A antagonism) combined with D2 antagonism may lead to atypical antipsychotic drugs, a series of 19 benzothiazolin-2-one and benzoxazin-3-one derivatives possessing the arylpiperazine moiety was prepared, and their binding profiles were investigated. All tested compounds displayed very high affinities for the 5HT1A and D2 receptors. Therefore, further pharmacological studies were carried out on selected compounds (24, 27, 30, 46, and 47). This evaluation in rats clearly revealed potent antipsychotic properties along with a decrease of extrapyramidal side effects. These derivatives are currently under preclinical development.

Effects of a daylight cycle reversal on locomotor activity in several inbred strains of mice.

There is some evidence of melatonin implication in the nycthemeral regulation of running activity rhythm in rodents. Because some inbred strains of mice such as C57BL/6 and BALB/c have been generally found to present no nocturnal melatonin peak, in contrast to others such as C3H/He and CBA mice, the aim of this study was to examine the adaptation of daily locomotor activity to a light/dark cycle phase shift in these four strains. An apparatus consisting of two boxes connected by a tunnel was used to record spontaneous locomotor activity, defined as the number of transitions between the two boxes. Locomotor activity was monitored continuously during 3 days before and 14 days after a 12-h phase delay of the light/dark cycle. Results essentially showed that the adaptation of the locomotor activity rhythm to the phase shift was faster in C57BL/6 and BALB/c mice than in C3H/He and CBA mice. This could be related, at least in part, to the differences in melatonin synthesis between the former strains and the latter ones. Although melatonin nocturnal peak is not necessary to a daylight regulation of circadian functions in rodents, it could be considered as an endocrine message that takes part in the anticipation of the following light/dark cycle.

Effects of day-length variations on emotional responses towards unfamiliarity in Swiss mice.

Pineal melatonin secretion occurs at night in all vertebrates and the duration of its secretion is negatively correlated with day length. As an anxiolytic activity of melatonin has been shown in rats and mice, this study examined possible changes of emotional reactivity in response to day length variations in Swiss mice. Three groups of mice were observed in a free-exploratory test: a group submitted to a short-day exposure (6:18 h light-dark cycle) for 2 weeks, a group submitted to a long-day exposure (18:6 h light-dark cycle) for 2 weeks and a control group which was maintained in housing 12:12 h light-dark cycle. The short-day exposed group of mice exhibited significantly fewer attempts to enter into the unfamiliar enclosure, spent significantly more time in it and presented significantly more rears than controls whereas the long-day exposed group of mice made more attempts than controls. These results suggest a decreased emotional level in short-day exposed mice and an increased level in long-day exposed mice. This could be interpreted as confirming the idea of anxiolytic-like properties of melatonin; however, the specific role of this hormone in the changes of anxiety related to day length must be assessed by further measures of potential variations of circulating melatonin.

3-amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans].

In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.