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Biomedical subjects

A Bartolini

Publications and source records attributed to A Bartolini.

At least 73 records · Page 4Linked to original sources
PubMed1996

Synthesis and enantioselectivity of the enantiomers of PG9 and SM21, new potent analgesic and cognition-enhancing drugs.

The enantiomers of two alpha-tropanyl esters, SM21 (1) and PG9 (2), derived from (+)-R-hyoscyamine, that act by increasing the central cholinergic tone, were obtained by esterification after resolution of the corresponding racemic acids [(-)-S-1, (-)-R-2 and (+)-S-2] and by stereospecific synthesis [(+)-R-1]. Their analgesic and cognition-enhancing activities were tested in mice and their ACh-releasing properties determined on rat parietal cortex. These compounds show enantioselectivity in analgesic and cognition-enhancing tests on mice, the eutomers being the isomers which possess the same spatial arrangement of the groups on the chiral atom as (+)-R hyoscyamine [(+)-R-SM21, (+)-S-PG9]. The ACh-releasing effect of the enantiomers of SM21 in rats is in agreement with the results in mice, while PG9 enantiomers do not show any appreciable enantioselectivity in this test. On the basis of the different effects of the 5-HT4 antagonist SDZ 205557 on analgesia induced by the enantiomers of 1 and 2 and by (+)-R-hyoscyamine and the alpha-tropanyl ester of 2-phenylpropionic acid 3, a mechanism of action is proposed for this class of compounds.

Acetylcholine↗
PubMed1996

Reduced flexibility analogs of analgesic and cognition enhancing alpha-tropanyl esters.

A series of semirigid analogs of compounds 1 and 2, two potent analgesics and cognition enhancers, have been synthesized and tested for antinociceptive activity (hot plate test) and for muscarinic affinity (binding in rat cerebral cortex). They were found to be in general less potent than the reference compounds; only one of them (22) shows a good affinity for the muscarinic receptor and an antinociceptive efficacy comparable with those of the reference compounds. At a dose of 30 mg/kg 22 is also able to reverse the amnesic effect of dicyclomine. Since the analgesic effect of these compounds is affected by the 5-HT4 antagonist SDZ 205557, the possible role of this receptor is discussed.

Analgesics↗
PubMed1996

S-(-)-ET 126: a potent and selective M1 antagonist in vitro and in vivo.

The pharmacological profile of the competitive muscarinic antagonist S-(-)-alpha-(hydroxymethyl)benzeneacetic acid 1-methyl-4-piperidinyl ester (S-(-)-ET 126) was evaluated on M1 (rabbit vas deferens; pA2=8.99), M2 (rat left atrium; pA2=8.21) and M3 (rat ileum; pA2=6.84) muscarinic receptors in comparison with pirenzepine. The drug shows a subtype selectivity (M1/M2=8; M1/M3=178; M2/M3=22) that proposes it as a useful pharmacological tool for receptor studies. S-(-)-ET 126, like pirenzepine, prevents the antinociception induced by M1 agonists (McN-A-343 and AF-102B). Unlike pirenzepine and spirotramine, the compound is able to cross the blood brain barrier which makes it useful for in vivo investigations.

Acetylcholine↗
PubMed1996

Central cholinergic antinociception induced by 5HT4 agonists: BIMU 1 and BIMU 8.

The antinociceptive effect of two 5-HT4 agonists, BIMU 1 and BIMU 8, were examined in mice and rats by using the hot-plate, abdominal constriction and paw-pressure tests. In both species, BIMU 1 (10-20 mg kg-1 s.c. and 40-60 mg kg-1 p.o. in mice; 20 mg kg-1 i.p. in rats) and BIMU 8 (20-30 mg kg-1 s.c. and 60 mg kg-1 p.o. in mice; 20 mg kg-1 i.p. in rats), produced significant antinociception which was prevented by atropine (5 mg kg-1 i.p.), hemicholinium-3 (1 microgram per mouse i.c.v.), SDZ 205-557 (10 mg kg-1 i.p.), GR 125487 (20 mg kg-1 i.p.) but not by naloxone (1 mg kg-1 i.p.), CGP 35348 (100 mg kg-1 i.p.) and reserpine (2 mg kg-1 i.p.). Moreover, BIMU 1 and BIMU 8 increase of pain threshold, is abolished by nucleus basalis magnocellularis (NBM) lesions in rats. SDZ 205-557 and GR 125487 which totally antagonized BIMU 1 and BIMU 8 antinociception did not modify morphine (7 mg kg-1 s.c.) or baclofen (4 mg kg-1 s.c.) antinociception. Intracerebroventricular injection in mice of BIMU 1 (3 micrograms per mouse) and BIMU 8 (10 micrograms per mouse), doses which were largely ineffective by parenteral routes, induces an antinociception whose intensity equaled that obtainable s.c., i.p. or p.o. In the antinociceptive dose-range, neither 5HT4 agonist impaired mice motor coordination evaluated by rota-rod test. On the basis of the above data, it can be postulated that BIMU 1 and BIMU 8 exerted an antinociceptive effect mediated by a central amplification of cholinergic transmission.

4-Aminobenzoic Acid↗
PubMed1996

Investigation into the role of histamine receptors in rodent antinociception.

The aim of the present study is to the elucidate the confusion that exists in the literature concerning which receptor subtype is involved in mediating histamine antinociception. To this purpose impromidine 3HCl and burimamide were used. Because both substances have been described to block histamine H3-receptor, and, at higher doses, also to act on the postsynaptic site as agonist and antagonist, respectively, they were administered in a wide range of ICV doses, to distinguish the effects due to action on different receptors. Experiments were performed in mice and rats by means of tests inducing three different kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction), and thermal (hot plate). Both substances showed, at the lowest doses tested, antinociception, which was antagonized by the selective H3-receptor agonist, (R)-alpha-methylhistamine 2HCl (RAMH) (10 mg/kg SC in mice or 0.5 microgram per rat ICV). At higher doses impromidine was antinociceptive while burimamide was hypernociceptive, in accordance with their opposite action on the H2-receptor. It is suggested that the histaminergic system modulates nociception via activation of the H2-receptor.

Animals↗
PubMed1996

Piracetam and aniracetam antagonism of centrally active drug-induced antinociception.

The effects of the nootropic drugs piracetam and aniracetam on antinociception induced by baclofen, bicuculline, and picrotoxin and on baclofen-induced muscle relaxation were studied in mice. Antinociception was investigated using both the hot plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Both behaviour inhibition and muscle relaxation were observed by using the rota-rod test. Piracetam (30 mg/kg, IP) and aniracetam (10 mg/kg, PO) reduced baclofen, bicuculline, and picrotoxin antinociception without modifying analgesia induced by non-GABAergic drugs such as morphine, physostigmine, clomipramine, and diphenhydramine. In this concentration range, piracetam, and aniracetam were also able to reduce the inhibition of rota-rod performance. At higher doses piracetam (100 mg/kg, IP) and aniracetam (100 mg/kg, PO) were able to completely prevent baclofen antinociception. However, when prevention of GABAergic antinociception was complete, piracetam and aniracetam were able to block non-GABAergic antinociception also. comparing the effects of piracetam and aniracetam with those exerted by the GABAB antagonist CGP 35348, a reduction of non-GABAergic analgesia was also observed using higher doses of CGP 35348 (2.5 micrograms per mouse ICV). The present results indicate that piracetam and aniracetam, by preventing both of the investigated effects of baclofen, have some selectivity against GABAB-mediated inhibition. The well-known activity of piracetam and aniracetam on learning and memory might, therefore, depend, at least in part, on the removal of inhibitory GABAB mechanisms that impair attention and cognitive functions.

Analgesics↗
PubMed1996

The central cholinergic system has a role in the antinociception induced in rodents and guinea pigs by the antimigraine drug sumatriptan.

The antinociceptive effect of the antimigraine drug sumatriptan was assessed in mice and rats (hot-plate, abdominal constriction and paw-pressure tests) and in guinea pigs (paw-pressure test). The ACh extracellular concentration also was detected in the hippocampus of freely moving rats by microdialysis experiments. Antinociception was induced by sumatriptan administered both parenterally (5-10 mg.kg-1 i.v.; 10-30 mg.kg-1 i.p.) and i.c.v. (50-100 micrograms per mouse). Sumatriptan antinociception was potentiated by physostigmine (0.05 mg.kg-1 i.p.) and was prevented by the muscarinic antagonist atropine (5 mg.kg-1 i.p.), the ACh depletor HC-3 (1 micrograms per mouse i.c.v.) and the 5-hydroxytryptamine1A antagonist 1-(2-methoxyphenyl)-4-[4-(2 phthalimido)butyl] piperazine (0.5 mg.kg-1 i.p.). Naloxone, 3-aminopropyl-diethoxy-methyl-phosphinc acid, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl ester and reserpine, administered in doses suitable for blocking analgesi induced by morphine, baclofen, 5-hydroxytryptamine4 agonist and clomipramine, respectively, did not modify sumatriptan antinociception. Sumatriptan, administered in the range of antinociceptive doses, was able to increase the level of ACh present in extracellular hippocampal space. On the basis of these findings we can deduce that sumatriptan was able to induce antinociception by increasing cholinergic activation in the CNS. Such activation, as indicated by the antagonism exerted by 1-(2-methoxyl-phenyl)-4-[4-(2 pethalimido)butyl]piperazine, may depend on stimulation of 5-hydroxytryptamine1A autoreceptors. It remains to be clarified whether the antimigraine activity of sumatriptan in humans is totally dependent on cranial vessel vasoconstriction of whether its central cholinergic antinociception also plays a role.

Acetylcholine↗
PubMed1995

Analgesic, antimuscarinic activity and enantioselectivity of the four isomers of 3-quinuclidinyl tropate as compared with the enantiomers of hyoscyamine.

The four stereoisomers of 3-quinuclidinyl tropate (2) were synthesized and their absolute configuration established. The analgesic activity of the four isomers on the hot-plate test and their muscarinic antagonism on rabbit vas deferens (M1), guinea-pig heart (Force, M2) and ileum (M3) and on the muscarinic receptors present in immature guinea-pig uterus were evaluated. The results were compared with those of the enantiomers of hyoscyamine (1). No apparent correlation was found between the analgesic activity and antimuscarinic activity on M1, M2 and M3 receptors, whereas striking differences exist between the affinity values of the analgesic enantiomer of hyoscyamine (R-(+)-1) and those of the inactive isomers of 2 on the muscarinic receptor present in immature guinea pig uterus. Molecular Modelling studies have shown that the only difference between 1 and 2 lies in the volumes occupied by the basic part of the molecules.

Analgesics↗
PubMed1994

Role of histamine in rodent antinociception.

1. Effects of substances which are able to alter brain histamine levels on the nociceptive threshold were investigated in mice and rats by means of tests inducing three different kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). 2. A wide range of i.c.v. doses of histamine 2HCl was studied. Relatively high dose were dose-dependently antinociceptive in all three tests: 5-100 micrograms per rat in the paw pressure test, 5-50 micrograms per mouse in the abdominal constriction test and 50-100 micrograms per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 microgram per rat in the paw pressure test and 0.1-1 microgram per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed. 3. The histamine H3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose-dependent antinociceptive effect by both parenteral (10-40 mg kg-1) and i.c.v. (1.1-10 micrograms per rat and 3.4-10 micrograms per mouse) routes. 4. The histamine H3 agonist, (R)-alpha-methylhistamine dihydrogenomaleate was hyperalgesic, with a rapid effect (15 min after treatment) following i.c.v. administration of 1 microgram per rat and 3 microgram per mouse, or i.p. administration of 100 mg kg-1 in mice. In rats 20 mg kg-1, i.p. elicited hyperalgesia only 4 h after treatment. 5. Thioperamide-induced antinociception was completely prevented by pretreatment with a non-hyperalgesic i.p. dose of (R)-alpha-methylhistamine in the mouse hot plate and abdominal constriction tests. Antagonism was also observed when both substances were administered i.c.v. in rats. 6. L-Histidine HCl dose-dependently induced a slowly occurring antinociception in all three tests. The doses of 250 and 500 mg kg-1, i.p. were effective in the rat paw pressure test, and those of 500 and 1500 mg kg-1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000 mg kg-1, i.p. showed their maximum effect 2 h after treatment. 7. The histamine N-methyltransferase inhibitor, metoprine, elicited a long-lasting, dose-dependent antinociception in all three tests by both i.p. (10-30 mg kg-1) and i.c.v. (50-100 micrograms per rat) routes. 8. To ascertain the mechanism of action of the antinociceptive effect of L-histidine and metoprine, the two substances were also studied in combination with the histamine synthesis inhibitor (S)-alpha-fluoromethylhistidine and with (R)-alpha-methylhistamine, respectively. L-Histidine antinociception was completely antagonized in all three tests by pretreatment with (S)-alpha-fluoromethylhistidine HCl (50 mg kg-1, i.p.)administered 2 h before L-histidine treatment. Similarly, metoprine antinociception was prevented by(R)-alpha-methylhistamine dihydrogenomaleate 20 mg kg-1, i.p. administered 15 min before metoprine. Both(S)-alpha-fluoromethylhistidine and (R)-alpha-methylhistamine were used at doses which did not modify the nociceptive threshold when given alone.9. The catabolism product, 1-methylhistamine, administered i.c.v. had no effect in either rat paw pressure or mouse abdominal constriction tests.10. These results indicate that the antinociceptive action of histamine may take place on the postsynaptic site, and that its hyperalgesic effect occurs with low doses acting on the presynaptic receptor. This hypothesis is supported by the fact that the H3 antagonist, thioperamide is antinociceptive and the H3 agonist, (R)-alpha-methylhistamine is hyperalgesic, probably modulating endogenous histamine release.L-Histidine and metoprine, which are both able to increase brain histamine levels, are also able to induce antinociception in mice and rats. Involvement of the histaminergic system in the modulation of nociceptive stimuli is thus proposed.

Analgesics↗
PubMed1993

Stereoselectivity in central analgesic action of tocainide and its analogs.

The antiarrhythmic drug tocainide (5a) and some related chiral alpha-amino and alpha-imino anilides (5b-e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of tocainide is due only to its (-)-(R)-enantiomer. Benzyl replacement for methyl group at the stereogenic centre of tocainide causes loss of activity while both enantiomers of the alpha-iminoxilidide 5e and of the strictly related tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [3H] quinuclidinyl benzilate ([3H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (-)-(R)-tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action.

Analgesics↗
PubMed1993

Transverse dipoles added to DNA chains by drug binding can induce inversion of the long-range chirality of DNA condensates.

The addition of poly(ethylene glycol) (PEG) to a DNA solution induces phase separation of droplets of condensed DNA. These droplets possess liquid crystalline properties and their ordering is cholesteric. It was recently proved that daunomycin, by binding to DNA chains, inverts the long-range chirality of their tertiary packing into aggregates. The present paper suggests one possible mechanism by which this inversion can take place. Daunomycin bears a cationic group in its sugar residue. Its intercalation adds a helicoidal distribution of transverse dipoles to DNA chains. By this mechanism, in favourable cases, ionic or strongly polar groups in drugs which bind DNA can induce handedness inversion of the cholesteric ordering of its condensates. This inversion mechanism was tested experimentally using several, charged and uncharged, homologues of daunomycin. All those bearing the cationic ammonium group inverted the long-range chirality of the PEG-induced DNA mesomorphic state. The effects of the uncharged desamino homologues could not be evaluated because of their lower solubility and binding affinity for DNA.

DNA↗
PubMed1993

Synthesis and biological activity of a series of aryl tropanyl esters and amides chemically related to 1H-indole-3-carboxylic acid endo 8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester. Development of a 5-HT4 agonist endowed with potent antinociceptive activity.

A series of aryl tropanyl esters and amides related to 1H-indole-3-carboxylic acid endo 8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (ICS 205930, CAS 89565-68-4) were synthesized and evaluated for antinociceptive activity using the hot-plate test. Of these, the benzofurane-3-carboxylic ester of tropine (1) was found powerfully to increase the pain threshold, with a cholinergic mechanism of action. Despite the structural similarity with ICS 205930, the analgesia induced by 1 seems not to be due to 5-HT3 receptor interaction, and there is evidence of involvement of the central 5-HT4 receptor.

Analgesics↗
PubMed1992

Desensitization of GABAB receptors and antagonism by CGP 35348, prevent bicuculline- and picrotoxin-induced antinociception.

The effect of the GABAA antagonists, bicuculline and picrotoxin, in the hot plate and writhing tests in mice and the paw-pressure test in rats was assessed. Subconvulsant doses of bicuculline (1.3-4 mumol kg-1, s.c.) or picrotoxin (0.8-2.5 mumol kg-1, s.c.) induced a dose-related increase in latency of licking in the hot plate test in mice, whereas subconvulsant doses of strychnine and thiosemicarbazide (0.9 and 6 mg kg-1, s.c. respectively), did not modify the threshold to thermal stimuli in mice. The effects of bicuculline and picrotoxin were not modified by naloxone (3 mg kg-1, i.p., a dose which inhibited the antinociceptive effect of morphine) or by atropine (5 mg kg-1, i.p., a dose which prevented oxotremorine-induced antinociception) but were antagonized by the GABAB antagonist CGP 35348 (2.5 micrograms, i.c.v., a dose which prevented (+/-)baclofen-induced antinociception). Mice, rendered tolerant to baclofen-induced antinociception by twice daily injection of increasing doses of baclofen (5-18 mg kg-1, s.c.), were unresponsive to the antinociceptive effects of bicuculline and picrotoxin but still responded to morphine. Bicuculline and picrotoxin, in the same range of doses which affected the three models of antinociception used, inhibited pentobarbital-induced hypnosis. Large doses of bicuculline and picrotoxin (4 and 2.5 mumol kg-1, s.c. respectively), reduced locomotor activity and impaired rota-rod performance in mice. The changes in response to noxious stimuli, induced by bicuculline and picrotoxin, are interpreted as an antinociceptive effect. It is then suggested that this effect might depend on an indirect activation of GABAB receptors through release of GABA.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1992

Role of muscarinic receptor subtypes in central antinociception.

1. The ability to modify the pain threshold by the two M1-muscarinic agonists: McN-A-343 and AF-102B and by the specific M2-agonist arecaidine was examined in mice and rats by using three different noxious stimuli: chemical (writhing test), thermic (hot-plate test) and mechanical (paw pressure test). 2. In the mouse hot-plate test McN-A-343 (20-50 micrograms per mouse i.c.v.) and AF-102B (1-10 mg kg-1 i.p.) produced significant antinociception which was prevented by atropine (1 microgram per mouse i.c.v.) and by the two selective M1 antagonists: pirenzepine (0.01 micrograms per mouse i.c.v.) and dicyclomine (0.08 micrograms per mouse i.c.v. or 10 mg kg-1 i.p.) but not by the specific M2-antagonist AFDX-116 (0.1 micrograms per mouse i.c.v.), naloxone (1 mg kg-1 i.p.) or by the acetylcholine (ACh) depletor hemicholinium-3 (HC-3) (1 micrograms per mouse i.c.v.). McN-A-343 and AF-102B were able to increase the pain threshold also in the mouse acetic acid writhing test and in rat paw pressure test. These antinociceptive effects were completely prevented by dicyclomine (0.08 micrograms per mouse i.c.v. or 10 mg kg-1 i.p.) but not by AFDX-116 (0.1 microgram per mouse or rat i.c.v.). 3. In contrast with the M1-agonists, the M2-agonist arecaidine (0.1-2 micrograms per mouse or rat i.c.v.) did not induce antinociception in all three analgesic tests. However, arecaidine, at the same i.c.v. doses, was able to reduce the pain threshold in the hot-plate and paw pressure tests.4. The site of muscarinic control of the pain threshold is localized in the CNS since drugs which do not cross the blood-brain barrier such as McN-A-343, pirenzepine and arecaidine exerted their effects only if injected i.c.v.5. On the basis of the above findings and existing literature we suggest that the postsynaptic muscarinic receptors involved in antinociception belong to the M1 subtype. Nevertheless, presynaptic autoreceptors (M2 subtype) may play a role in pain regulation since they are involved in modulation of endogenous ACh release.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1991

CGP 35348, a new GABAB antagonist, prevents antinociception and muscle-relaxant effect induced by baclofen.

1. CGP 35348, a new GABAB antagonist, was examined on antinociception induced by (+/-)-baclofen by use of the hot plate and writhing tests in mice and the paw pressure test in rats. CGP 35348 was also studied in mice on (+/-)-baclofen-induced impairment of rota-rod performance. 2. CGP 35348, injected either i.p. (60-100 mg kg-1 in mouse) or intracerebroventricularly (i.c.v.) (0.5-2.5 micrograms per mouse; 25 micrograms per rat) prevented (+/-)-baclofen-induced antinociception. 3. CGP 35348 did not modify oxotremorine- and morphine-induced antinociception in mice and rats. 4. CGP 35348 (2.5 micrograms i.c.v. per mouse) also prevented (+/-)-baclofen-induced impairment of the rota-rod test. 5. Two other GABAB antagonists, phaclofen (50 micrograms i.c.v. per mouse) and 2-OH-saclofen (2.5 micrograms-10 micrograms i.c.v. per mouse) did not modify (+/-)-baclofen-induced antinociception. 7. These results suggest that, at present, CGP 35348 is the only compound able to antagonize (+/-)-baclofen-induced antinociception.

Analgesics↗
PubMed1991

[Ultrasonography in diseases of lymph nodes and soft tissues of the neck].

A study of 55 patients affected by neoplasia of the head and neck or clinically evident laterocervical swellings was carried out in order to evaluate the diagnostic value of ultrasonography in the study of cervical lymph nodes and soft tissues, excluding thyroid or salivary pathologies. The analysis of results confirmed that, in line with previously published findings, ultrasonography is a reliable method of diagnosing lesions and correctly identifying the affected organ, but then it is considerably less reliable in defining the type of lesion. In view of this, it is reasonable to propose a more widespread use of ultrasonographically guided needle biopsy which, in addition to being a rapid and non-traumatic method, would allow precisely target samples to be taken from those lesions with a doubtful or unusual clinical or ultrasonic appearance.

Adolescent↗