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Biomedical subjects

R Silvestri

Publications and source records attributed to R Silvestri.

At least 19 recordsLinked to original sources
PubMed2001

SSRI treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects.

Clinical lore and a small number of published studies report that the selective serotonin reuptake inhibitors (SSRIs) intensify dreaming. This study examines the dream effects of paroxetine and fluvoxamine in order to both increase clinical knowledge of these agents and to test an important potential method for probing the relationship between REM sleep neurobiology and dreaming in humans. Fourteen normal, paid volunteers (4 males, 10 females; mean age 27.4 year, range 22--39) free of medical or neuropsychiatric symptoms as well as of psychotropic or sleep affecting drugs completed a 31-day home-based study consisting of: 7 days drug-free baseline; 19 days on either 100 mg fluvoxamine (7 Ss) or 20 mg paroxetine (7 Ss) in divided morning and evening doses; and 5 days acute discontinuation. Upon awakening, subjects wrote dream reports, self-scored specific emotions in their reports and rated seven general dream characteristics using 5-point Likert scales. Dream reports were independently scored for bizarreness, movement and number of visual nouns by three judges. REM sleep-related measures were obtained using the Nightcap ambulatory sleep monitor. Mean dream recall frequency decreased during treatment compared with baseline. Dream report length and judge-rated bizarreness were greater during acute discontinuation compared with both baseline and treatment and this effect was a result of the fluvoxamine-treated subjects. The subjective intensity of dreaming increased during both treatment and acute discontinuation compared with baseline. Propensity to enter REM sleep was decreased during treatment compared with baseline and acute discontinuation and the intensity of REM sleep increased during acute discontinuation compared with baseline and treatment. The decrease in dream frequency during SSRI treatment may reflect serotonergic REM suppression while the augmented report length and bizarreness during acute SSRI discontinuation may reflect cholinergic rebound from serotonergic suppression.

Adult↗
PubMed2001

Effects of fluvoxamine and paroxetine on sleep structure in normal subjects: a home-based Nightcap evaluation during drug administration and withdrawal.

BACKGROUND: Acute and chronic administration of the selective serotonin reuptake inhibitors (SSRIs) have been widely reported to disrupt sleep in laboratory studies. This study examines the naturalistic, longitudinal effects of paroxetine and fluvoxamine on sleep quality in the home setting. METHOD: Fourteen healthy volunteers free of medical and neuropsychiatric symptoms entered a 31-day protocol: 7 days of drug-free baseline (days 1-7), 19 days of drug treatment (steady state during days 18-26), and 5 days of acute withdrawal (days 27-31). On day 8, the subjects were randomly assigned to receive either 100 mg/day of fluvoxamine or 20 mg/day of paroxetine (half receiving each drug) in divided morning and evening oral doses. Investigators remained blinded to drug assignment until all sleep data had been analyzed. Sleep was monitored using the Nightcap ambulatory sleep monitor. Four standard and 3 novel measures were computed and compared using multivariate analysis of variance, analysis of variance, and Bonferroni-corrected comparison of means. RESULTS: Sleep disruption was most clearly demonstrated using the novel measures eyelid quiescence index, rhythmicity, and eyelid movements per minute in non-rapid eye movement sleep, but was also apparent as determined by standard measures of sleep efficiency, number of awakenings, and sleep onset latency. Paroxetine disrupted sleep more than fluvoxamine, and paroxetine-induced sleep disruption persisted into the withdrawal phase. Rapid eye movement sleep was suppressed during treatment (especially for fluvoxamine) and rebounded during withdrawal (especially for paroxetine). CONCLUSION: We confirm laboratory polysomnographic findings of SSRI-induced sleep quality changes and demonstrate the Nightcap's efficacy as an inexpensive longitudinal monitor for objective sleep changes induced by psychotropic medication.

Adult↗
PubMed2000

Structure-based design, synthesis, and biological evaluation of novel pyrrolyl aryl sulfones: HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations.

Pyrrolyl aryl sulfones (PASs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors acting at the non-nucleoside binding site of this enzyme (Artico, M.; et al. J. Med. Chem. 1996, 39, 522-530). Compound 3, the most potent inhibitor within the series (EC(50) = 0.14 microM, IC(50) = 0.4 microM, and SI > 1429), was then selected as a lead compound for a synthetic project based on molecular modeling studies. Using the three-dimensional structure of RT cocrystallized with the alpha-APA derivative R95845, we derived a model of the RT/3 complex by taking into account previously developed structure-activity relationships. Inspection of this model and docking calculations on virtual compounds prompted the design of novel PAS derivatives and related analogues. Our computational approach proved to be effective in making qualitative predictions, that is in discriminating active versus inactive compounds. Among the compounds synthesized and tested, 20 was the most active one, with EC(50) = 0.045 microM, IC(50) = 0.05 microM, and SI = 5333. Compared with the lead 3, these values represent a 3- and 8-fold improvement in the cell-based and enzyme assays, respectively, together with the highest selectivity achieved so far in the PAS series.

Cell Survival↗
PubMed2000

1-[2-(Diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole: a potent lead for the design of novel NNRTIs.

A novel family of non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentrations was discovered. The new derivatives are 1-[2-(diarylmethoxy)ethyl]imidazoles bearing substituents both at benzene and imidazole rings. The most potent derivatives were those having nitro and methyl groups as substituents in the imidazole ring. Among 10 test derivatives compound 6d was found to be as potent as nevirapine and was selected as a lead for further studies.

Anti-HIV Agents↗
PubMed2000

Computer-assisted design, synthesis and biological evaluation of novel pyrrolyl heteroaryl sulfones targeted at HIV-1 reverse transcriptase as non-nucleoside inhibitors.

Three pyrrolyl heteroaryl sulfones (ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxyla te, ethyl 1-[(1H-benzimidazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate and ethyl 1-[(1H-benzotriazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate) were designed as novel HIV-1 reverse transcriptase non-nucleoside inhibitors using structure-based computational methods. Although these compounds were inactive in the cell-based assay, they inhibited the target enzyme with micromolar potency (IC50s = 2 microM, 3 microM and 9 microM, respectively).

Anti-HIV Agents↗
PubMed1998

Synthesis and biological evaluation of 5H-indolo [3,2-b][1,5]benzothiazepine derivatives, designed as conformationally constrained analogues of the human immunodeficiency virus type 1 reverse transcriptase inhibitor L-737,126.

In the presence of sodium hydride, reaction of aryl-disulphides with ethyl esters of indole-2-carboxylic acids furnished ethyl 3-arylthioindole-2-carboxylates, which were cyclized intramolecularly to afford 5H-indolo[3,2-b][1,5]benzothiazepin-6(7H)-ones or hydrolysed in alkaline medium to give 3-arylthioindole-2-carboxylic acids. These acids, also obtained by the action of aryldisulphides on indole-2-carboxylic acids, afforded tetracyclic 5H-indolo [3,2-b][1,5]benzothiazepin-6(7H)-ones upon treatment with EDCI-DMAP. Transformation of cyclic sulphides into the required sulphones was achieved by treatment with hydrogen peroxide or with m-chloroperbenzoic acid. The title derivatives are conformationally constrained analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor 3-benzene-sulphonyl-5-chloroindole-2-carboxamide (L-737, 126). Although the indolobenzothiazepine derivatives, as well as the indolyl aryl sulphones used for their synthesis, were endowed with anti-HIV-1 activities in the submicromolar and micromolar range, none of them proved more potent than L-737,126.

Anti-HIV Agents↗
PubMed1997

Sulfone derivatives with anti-HIV activity.

Following the discovery of anti-HIV properties of suramin great efforts were devoted to design novel NNRT agents with the aims to find novel drugs for the clinical therapeutic management of AIDS. Sulfone and sulfonamide derivatives were studied by NCI at Bethesda as potential anti-HIV-1 agents and nitrophenyl phenyl sulfone (NPPS) was selected as lead compound for further investigations. At the same time Merck Laboratories discovered L-737,126, a potent indolyl aryl sulfone with inhibitory activity against reverse transcriptase. These studies stimulated novel search in the sulfone series and both diarylsulfones and cyclic sulfone derivatives were investigated. Our decennial interest in chemotherapeutic agents containing a pyrrole ring pulsed us to synthesize and test as anti-HIV-1 agents a number of pyrryl aryl sulfones (PASs), pyrrolobenzothiadiazepine (PBTDs) and pyrrolobenzothiazepine related sulfones. The new sulfone derivatives inhibit selectively HIV-1 and were inactive against HIV-2. Most of them were as active as, if not more active than, nevirapine.

Anti-HIV Agents↗
PubMed1996

2-Sulfonyl-4-chloroanilino moiety: a potent pharmacophore for the anti-human immunodeficiency virus type 1 activity of pyrrolyl aryl sulfones.

The synthesis and the evaluation of cytotoxicity and anti-HIV-1 activity of new aryl pyrrolyl (8) and aryl indolyl (9) sulfones are reported. Preparation of above sulfones was achieved by reacting arylsulfonyl chlorides with substituted pyrroles and indoles or by condensing sulfonamides with 2,5-dimethoxytetrahydrofuran in glacial acetic acid according to the Clauson-Kaas method. Chemical requisites relevant to the anti-HIV-1 activity of these compounds are both a 2-sulfonyl-4-chloroanilino moiety and an alkoxycarbonyl group at position 2 of the pyrrole ring. The best activity and selectivity were obtained with ethoxycarbonyl and isopropoxycarbonyl substituents. Substitutions at the amino group of the pharmacophore moiety led to inactive products (alkylation) or weakened (acylation) anti-HIV-1 activity. Among test derivatives, 16 compounds showed EC50 values ranging between 10 and 1 microM, and five (8b',d',f',h'j') showed EC50S in the sub-micromolar range. The compounds were active against HIV-1, both wild type and AZT-resistant strains, but not against HIV-2. Moreover, in enzyme assays they potently inhibited the HIV-1 recombinant reverse transcriptase, were 10 times less active against enzymes from nevirapine- and TIBO-resistant strains, and were totally inactive against the HIV-2 recombinant enzyme. Interestingly, some compounds (8r'-y') were inactive against the recombinant reverse transcriptase while being active in tissue culture.

Antiviral Agents↗
PubMed1996

5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepines (PBTDs): a novel class of non-nucleoside reverse transcriptase inhibitors.

With the aim of developing novel inhibitors of human immunodeficiency virus, various derivatives (10-17) related to 5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepine (PBTD) were prepared and tested in vitro. The title tricyclic derivatives were obtained by intramolecular cyclization of the open-chain intermediate arylpyrrylsulfones, followed by N-alkylation at position 10. Among test derivatives some 10-alkyl-5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepin-11(10H)-one-5,5-dioxides were found to exert potent and specific activity against HIV-1. In particular, 7-chloro derivatives 11i and j showed a potency comparable to that of nevirapine. However, when the chloro atom was shifted to the 8 position, the related products were scarcely active or totally inactive. Replacement of the pyrrole with pyrrolidine led to inactive products and the reduction of SO2 to S strongly diminished the antiviral potency. PBTD derivatives active in cell cultures were also inhibitory to the recombinant HIV-1 RT in enzyme assays, thus allowing the conclusion that PBTDs are a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Anti-HIV Agents↗
PubMed1996

Synthesis and anti-HIV activity of 10,11-dihydropyrrolo [1,2-b][1,2,5]benzothiadiazepine-11-acetic acid 5,5-dioxide derivatives and related compounds.

The synthesis and the in vitro anti-HIV-1 activity of novel pyrrolo annulated benzothiadiazepine acetic acids and some related derivatives are reported. The new compounds share chemical features with pyrrolo[1,2-d][1,4]benzodiazepin-6-one 1 and Ro 5-3335 pyrrylbenzodiazepinone 4, two inhibitors of HIV-replication at the level of reverse transcriptase (RT) and transcriptional transactivation by Tat, respectively. Two derivatives, namely methyl 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic-5,5 -dioxide (5a) and 1,12b-dihydro-2H-azeto[2,1-d]pyrrolo[1,2-b][1,2,5]benzoth iadiazepin-2-one 8,8-dioxide (7a), were found to exhibit a significant, although not very potent, activity against human immunodeficiency virus Type 1 (HIV-1).

Antiviral Agents↗
PubMed1995

Synthesis of pyrryl aryl sulfones targeted at the HIV-1 reverse transcriptase.

Various aryl 1-pyrryl sulfones were synthesized and tested as inhibitors of HIV-1. 2-Nitrophenyl-2-ethoxycarbonyl-1-pyrryl sulfone, the most active among test derivatives, was selected as lead compound of the aryl pyrryl sulfone series. The in vitro anti-HIV-1 activity and cytotoxicity of 41 compounds is reported. Some structure-activity relationships are discussed also in comparison with the known NPPS (2-nitrophenyl phenyl sulfone).

Cell Survival↗
PubMed1995

Epileptic seizures in subjects previously affected by disorders of arousal.

Six patients (3M, 3F, mean age 17.3 yrs) presenting different types of evolution from disorders of arousal to epilepsy are described. All subjects during their childhood had been diagnosed in a sleep center as affected by sleep-walking (three cases) and night terrors (the other three). Successively they developed nocturnal events different from those previously exhibited and consisting of clear epileptic seizures, generalized tonic-clonic in one case and complex partial in five cases. Nocturnal monitoring allowed recognition of clear interictal paroxysmal activity in three patients, while ictal events were recorded in the remaining three. Anticonvulsant treatment (carbamazepine in five patients, phenytoin in one patient) led to the resolution of the ictal events in all cases. The fact that both disorders of arousal and epilepsy are strictly related to sleep and often share common features such as age range of onset and precipitating factors, suggests the existence of common functional substrates identifiable in constitutional maturative and biologic factors. The possible occurrence of seizures in subjects exhibiting parasomnia during their childhood has to be considered in patients with familial history of epilepsy and in all doubtful cases.

Adolescent↗
PubMed1995

Sleep features in Tourette's syndrome, neuroacanthocytosis and Huntington's chorea.

Twenty-one patients affected by extrapyramidal disorders were polygraphically recorded during spontaneous nocturnal sleep for two consecutive nights to assess their sleep and movement patterns. The patients (pts) sample included: Gilles de La Tourette syndrome (TS, nine pts), neuroacanthocytosis (NA, six pts) and Hungtington's chorea (HC, six pts). Sleep recording included C3/A2, 01/A2, ROC/LOC, submental EMG, EKG, nasal airflow thoracoabdominal respirogram, bilateral anterior tibialis and other EMGs, in relation to the individual distribution of the abnormal movements. According to our observations, abnormal movements always decreased but never ceased completely during sleep. Sleep efficiency (SE) was nearly always poor with a high percentage of wakefulness after sleep onset (WASO) and increased number of arousals. REM sleep was often reduced and in some cases (3 TS pts) incompletely defined as far as its microstructural aspects. Slow wave sleep (SWS) was reduced in HC, normal in NA, and increased in all TS patients with the exception of the two adult subjects more severely affected, while the percentage of stage 2 was not affected. Spindling was increased in NA, HC and in the two most severely affected adult TS patients.

Acanthocytes↗
PubMed1995

Sleep structure in essential hypertensive patients: differences between dippers and non-dippers.

The objective of this study was to determine whether the macrostructure and microstructure of sleep were altered in non-dipper essential hypertensive patients. Patients included 9 non-dipper essential hypertensive patients and 10 dippers. We measured blood pressure beat-to-beat by Finapres and all stages of sleep by polysomnografically recording simultaneously during spontaneous nocturnal sleep. We analysed blood pressure pattern for 4-min long random periods while the patients were awake and during all stages of sleep; sleep-efficiency (SE), sleep-latency (SL), delta sleep-latency (delta-SL), REM sleep-latency (REM-SL), St. 1, St.2, St.3, St.4 and REM duration and percentage (%) values, and microstructural aspects of sleep (arousal and microarousal temporisation and features). Dipper patients showed a fall in blood pressure (BP) greater than 10% in all stages of NREM sleep; in the non-dipper patients BP fell by less than 10% of waking values in all NREM stages. REM sleep as well as HR were similar in both groups during all stages of sleep. Non-dippers showed the same number of arousals but more microarousals than dippers (p < 0.001). During and after microarousals BP and HR increased in non-dippers, but showed light variation in dippers. Microarousals induced several stage shifts towards lighter sleep. For this reason non-dippers spent less time in stage 4 than dippers (p < 0.001). In conclusion, non-dipper essential hypertensive patients are a subset of patients with central sympathetic hyperactivity responsible for quantitative and qualitative alteration of sleep.

Adult↗
PubMed1995

Antifungal agents. 10. Synthesis and antifungal activities of aryl-(1H-imidazol-1-yl)-(isoquinolin-1-yl) methane derivatives.

Various aryl-(1H-imidazol-1-yl)-(isoquinolin-1-yl)methane derivatives have been synthesized and tested as antifungal agents. The new imidazoles have been obtained by the action of 1,1'-sulfinyldiimidazole on aryl-(isoquinolin-1-yl)carbinols, which have been prepared by standard procedures starting from isoquinoline. Among 44 test derivatives only a few have exhibited some antifungal activity, the most active compound (4e) being twofold less potent than miconazole, ketoconazole and bifonazole, used as standard drugs.

Antifungal Agents↗
PubMed1994

Sleep spindles in the initial stages of the vegetative state.

The aim of this study was to look for the presence of spindling in the different stages of remission of the vegetative state to underline all possible correlations with lesional sites, severity of coma and final outcome. The nocturnal polygraphic recordings from 30 patients were examined: 20 (15M, 5F, mean age 31.7 years, range 16-41) had originally suffered a traumatic brain injury, 10 (4M, 6F, mean age 40.5 years, range 24-48) had hypoxic brain lesions. Evidence of spindling, always reduced in density and duration, was found in 44% of these patients, prevalently in the traumatic patients (53.3% versus 30% of hypoxic patients). No subjects in the full stage 0, 0-1 of the vegetative state (apallic syndrome) presented spindling. No significant correlation was found between spindling and the following parameters: gender, the time between the onset of coma and the polygraphic recording, or the site of the lesion.

Adolescent↗