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A Duranti

Publications and source records attributed to A Duranti.

12 recordsLinked to original sources
PubMed2005

Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis.

Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, delta9-tetrahydrocannabinol, acts by binding to brain CB1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of delta9-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.

Animals↗
PubMed2000

Homologation of mexiletine alkyl chain and stereoselective blockade of skeletal muscle sodium channels.

The optical isomers (-)-(S)- and (+)-(R)-3-(2, 6-dimethylphenoxy)-2-methyl-1-propanamine (Me2), homologues of the antiarrhythmic and antimyotonic drug mexiletine (Mex), were synthesized and assayed as new potential antimyotonic agents. As observed with Mex, Me2 exhibits an enantioselective behaviour. Tests carried out on sodium currents of single muscle fibres of Rana esculenta demonstrated that (-)-(S)- and (+)-(R)-Me2 were less potent than Mex in producing tonic block, but showed a higher use-dependent block. (-)-(S)-Me2 and (-)-(R)-Mex were also used to study the excitability of muscle fibres of myotonic ADR mice, a phenotype of a recessive form of low G(Cl) myotonia. (-)-(S)-Me2 reduced spontaneous discharges and after discharges better than (-)-(R)-Mex in agreement with the use-dependent block of sodium currents.

Animals↗
PubMed1997

Inhibition of frog skeletal muscle sodium channels by newly synthesized chiral derivatives of mexiletine and tocainide.

To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthesized chiral analogs of mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by vaseline-gap voltage clamp method. The effect of each drug on the maximal peak Na+ transient (I(Na) max) was evaluated as both tonic and use-dependent block by using infrequent depolarizing stimulation and trains of pulses at 2-10 Hz frequency, respectively. The mexiletine analog 3-(2,6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent than mexiletine in producing a tonic block but produced a remarkable use-dependent block. In fact, the half-maximal concentration (IC50) for tonic block of S(-)-Me2 was 108 microM vs. 54.5 microM of R(-)-mexiletine, but the IC50 was 6.2 times lowered by the 10 Hz stimulation with respect to the 2.4 fold decrease observed with mexiletine. The R(-)-mexiletine and the S(-)-Me2 were about twofold more potent than the corresponding enantiomers in producing a tonic block, but the stereoselectivity attenuated during use-dependent blockade. The more lipophilic 2-(4-chloro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as raceme, produced a potent and irreversible tonic block of the sodium currents with an IC50 of 29 microM, but had a less pronounced use-dependent inhibition, with a 1.9 fold decrease of the IC50 at 10 Hz. The R(-) isomer of 2',6'-valinoxylidide (To1), a tocainide derivative with an increased hindrance on the chiral carbon atom, was twofold (IC50 = 209 microM) and tenfold (IC50 = 27.4 microM) more potent than R(-)-tocainide in tonic and use-dependent block, respectively. Tocainide was almost devoid of stereoselectivity, whereas the eudismic ratio of To1 [(IC50 S(+)-To1/IC50 R(-)-To1] was 1.7. As for mexiletine and Me2, the stereoselectivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 microM, and 1 min stimulation at 10 Hz was needed to show up a 50% block of I(Na) max. All the compounds produced a left-shift of the steady-state inactivation curve correlated positively with the extent of use-dependent inhibition, with the exception of the cyclic To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and To1 might be promising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomitantly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skeletal muscle sodium channels.

Animals↗
PubMed1997

Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse.

To search for use-dependent sodium channel blockers to selectively solve skeletal muscle hyperexcitability in hereditary myotonias, mexiletine (MEX; compound I) and its newly synthetized analogs, 2-(4-chloro-2-methylphenoxy)-benzenethanamine (compound II) and (-)-S-3-(2,6-dimethylphenoxy)-2-methylpropanamine (compound III), were tested on intercostal muscle fibers from the myotonic ADR mouse through use of the standard current-clamp microelectrode technique. In parallel, the effects of these compounds on the sodium channels were measured on frog muscle fibers under voltage-clamp conditions. The tonic and use-dependent blocks of peak sodium currents (I(Namax)) produced by each compound were evaluated by using a single depolarizing pulse and a pulse train at 10 Hz frequency, respectively. At 10 and 50 microM, MEX decreased the occurrence of spontaneous excitability in myotonic muscle fibers; 100 microM was required to decrease the amplitude of the action potential and the stimulus-induced firing of the membrane as well as to increase the threshold for generation of action potential. At 300 microM, MEX decreased the latency of the action potential and increased the threshold current to elicit a single action potential. MEX produced a tonic block of I(Namax) with an half-maximal concentration (IC50) of 83 microM, but the IC50 value for use-dependent block was 3-fold lower. Compound III, which differs from MEX in that it has a longer alkyl chain, similarly blocked first the spontaneous and then the stimulus-evoked excitability of myotonic muscle fibers but at 2-fold lower concentrations than MEX. Compound III was less potent than MEX in producing a tonic block of I(Namax) (IC50 = 108 microM) but was a strong use-dependent blocker with an IC50 close to 15 microM. The more lipophylic compound II irreversibly blocked both spontaneous and stimulus-evoked membrane excitability at concentrations as low as 10 microM and shortened the latency of the action potential in a concentration-dependent fashion. Compound II produced a potent tonic block of I(Namax) (IC50 = 30 microM), and its potency increased 2-fold during high-frequency stimulation. Both of the new analogs (compound II in particular), but not MEX, were less effective on the excitability parameters of striated fibers of healthy vs. ADR mice, a characteristic that increases their interest as potential antimyotonic agents.

Animals↗
PubMed1993

2-Substituted 5-methoxy-N-acyltryptamines: synthesis, binding affinity for the melatonin receptor, and evaluation of the biological activity.

A series of 2-substituted 5-methoxy-N-acyltryptamines was synthesized and their affinity for the melatonin receptor, isolated from whole quail brains, was tested in a succession of in vitro ligand-receptor binding experiments, using 2-[125I]iodomelatonin as a labeled ligand. Optimization of the C2 substituent and the N-acyl group resulted in compounds having picomolar affinity for the receptor (vs nanomolar affinity for melatonin). In two tests for evaluation of the biological activity (effects on the spontaneous firing activity of single neurons in the rabbit parietal cortex in situ, and the Syrian hamster gonadal regression model in vivo) most of the analogs behaved as agonists. Isopropyl substitution at C2 alone, or concomitantly with cyclopropyl substitution at the N-acyl position, resulted in much lower affinity and weaker biological effect, or lack of activity in the latter case. Of interest are the compounds 4d (R = phenyl, R1 = CH3) and 4g (R = phenyl, R1 = cyclopropyl), which expressed high affinity for the receptor and apparent antagonistic activity under the conditions of the experimental models employed, though the analog 4g (R = phenyl, (R1 = cyclopropyl) seemingly was a weak antagonist and in situ expressed mixed activity in the higher concentration range. Cyclopropyl substitution at the N-acyl position inevitably resulted in lower affinity for the receptor and weaker biological activity. These data demonstrate that the N-acetyl group is important for both affinity and agonist biological activity. The substituents at C2 are crucial for the affinity of the compound for the receptor and can be utilized to create putative high-affinity agonists or antagonists.

Animals↗
PubMed1992

2-Bromomelatonin: synthesis and characterization of a potent melatonin agonist.

A practical synthesis of N-[2-(2-bromo-5-methoxy-1H-indol-3-yl)ethyl]- acetamide (2-bromomelatonin) was achieved by direct bromination of melatonin with N-bromosuccinimide (NBS) in anhydrous acetic acid at room temperature under nitrogen, followed by flash-chromatography. 1H-NMR and mass spectra showed the bromine to be incorporated at the C-2 position of the indole moiety. Tests performed in vitro with isolated melatonin receptors from rabbit parietal cortex demonstrated that the relative binding affinity of 2-bromomelatonin was about ten times higher than that of melatonin and close to that of 2-iodomelatonin. 2-Bromomelatonin behaved as a potent agonist in the physiological studies. It showed enhanced activity in inhibiting the spontaneous firing activity of cortical neurons and similarly to melatonin and 2-iodomelatonin potentiated significantly the inhibitory effect of GABA. 2-Bromomelatonin was also an extremely effective agonist in the tests performed in vivo in the Syrian hamster gonadal regression model.

Animals↗
PubMed1987

Coronary reconnection in emergency "conduit operation" for acute type-a aortic dissection with aortic insufficiency: experience with 24 cases.

Twenty-four cases of acute type-A aortic dissection with aortic valvular insufficiency were treated in our institution by means of an emergency operation in which the aortic valve, ascending aorta, and aortic arch were resected and replaced with a valved conduit that had been lengthened with a tubular Dacron graft. The procedure included the use of deep hypothermia for cerebral protection, as well as extracorporeal circulation. Aortic resection was performed from the aortic valve to the origin of the descending thoracic aorta; the aortic graft was anastomosed proximally to the valve annulus and distally to the descending aorta. The carotid orifices were connected to the side of the graft in a single tissue button. The coronary arteries were then reconnected by means of double venous bypass grafts to the innominate artery, to allow for inclusion of the graft. Within 1 month after operation, four patients died of the consequences of dissection. Six months postoperatively, one patient succumbed to an infarction. Six months to 5 years after operation, the remaining 19 patients are still alive. On the basis of this experience, we believe that acute type-A aortic dissection with aortic valvular insufficiency should be treated during the first hours after the onset of symptoms. The above-described procedure proved effective in the control of bleeding, which is the major risk in emergency operations of this type.

Journal Article↗
PubMed1986

Simultaneous total aortic replacement from arch to bifurcation: experience with six cases.

Simultaneous total aortic replacement, including the arch and extending to bifurcation, has been performed in six cases at our institution. The cases presented were (1) acute dissection, including the intimal tear in the arch (one case); (2) chronic Type-I dissection, with both visceral and inferior limb ischemia (three cases); and (3) multiple aneurysms (two cases). The broad outline of the surgical technique employed consists of inducing general hypothermia with extracorporeal circulation. At core temperature of 20 degrees C, circulation is stopped and the aortic arch is replaced. Afterward, cerebral perfusion and total body perfusion are resumed at low flow, keeping body temperature between 20 and 24 degrees C. The intercostal orifices are attached to the side of the aortic graft, and the spinal cord is reperfused. Finally, during a period of hypothermic abdominal ischemia, the abdominal aorta is replaced, and subsequently, rewarming is started. This result is achieved by instituting extracorporeal circulation with two arterial return cannulae (in the ascending aorta and in a femoral artery), making it possible to continue the perfusion of both the upper and lower body during the stages of aortic occlusion. Two patients died from bleeding 3 to 6 hours after operation, and medullary injury was not ascertained; one patient died after 1 month without neurologic disturbances; three patients are alive and in good functional condition 6 to 27 months after operation. We believe that total simultaneous aortic replacement is feasible with the hypothermic technique.

Journal Article↗
PubMedDate not supplied

[Temporary caval filters. Our experience. Preliminary analysis of 24 cases].

The AA. utilized temporary vena cava filters (16 Filcard and 8 Lysofilters) in 24 patients affected by deep venous thrombosis (DVT) of the lower limbs for the prevention of primary and recurrent pulmonary embolism (PE). The diagnosis of thromboembolic disease was always achieved by means of Ultrasounds (echo-color doppler) and was punctually confirmed by a retrograde cavagram during the insertion of the device. 19 patients presented large free-floating thrombi at inferior caval, iliac or common femoral vein level whereas 5 patients presented thrombi mostly of occlusive aspect. There was clinical or scintigraphic evidence of PE in 6 of the patients enrolled. 20 patients, without contraindications, were treated by fibrinolysis (F) with Urokinase (2-10 days) whereas 4 patients underwent surgical thrombectomy (T) because of short time relation with surgical intervention or trauma. All of them were protected by temporary vena cava filters and heparinized. All the filters were removed within 10 days. The results were considered "very good" (complete regression of floating thrombi) in 16 cases (14 F + 2 T), "good" (nearly complete regression of floating thrombi) in 3 cases (2 F + 1 T) and "poor" (unchanged) in the remaining 5 cases (4 F + 1 T). We didn't observe any new case or relapse of PE in the whole group and, furtherly, in 2 cases (1 F and 1 T) we demonstrated the capture of big emboli by the filter's basket. These clots were subsequently dissolved by fibrinolysis. To achieve the diagnosis of thromboembolic disease the following methods were used: 1--Screening: echo-color doppler of lower limbs extended to iliac and inferiora cava veins for detection of DVT and echocardio-color doppler for the detection of cardiac signs of PE. 2--DIAGNOSIS: pulmonary scintigram, retrograde cavogram and, rarely, angioCT scan. 3--FOLLOW-UP: echo-color doppler of lower limbs and pulmonary scintigram. The percutaneous insertion sites were the basilic vein (Filcard) and the right jugular vein (Lysofilter). Left jugular vein was used in 1 case with a big thyroid goitre. In the present experience we had no accidents during filters introduction or removal and no thrombosis at the insertion site (1 case of phlebitis of basilic vein). Indications and effectiveness: our results seem to be favorable to the use of inferior vena cava temporary filters for primary and recurrent pulmonary embolism prevention in the cases with floating thrombi both on fibrinolysis and embolectomy. In the cases of occlusive thrombotic diseases they proved to be effective to prevent PE during surgical embolectomy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMedDate not supplied

[Indications for hepatic resection: personal experience].

The Authors, before examining their case history, which includes 103 major and minor hepatic resections performed during the last decade, briefly show the surgical technique concerning hepatic ischaemia and the new technologies proposed to reduce the hematic loss during hepatic resections. The constant adoption of these techniques and the careful evaluation of some parameters concerning hepatic functionality allowed to decrease postoperative complications and mortality, which currently is around 5-10%. These data are confirmed by the Authors experience.

Animals↗