Search PubMed⌕ Search

Biomedical subjects

F Giuliano

Publications and source records attributed to F Giuliano.

At least 55 records · Page 3Linked to original sources

Quality of life in patients with spinal cord injury receiving Viagra (sildenafil citrate) for the treatment of erectile dysfunction.

STUDY DESIGN: A multicenter, randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover study conducted June 1996 through January 1997. OBJECTIVES: To evaluate the effect of sildenafil citrate (VIAGRA(R)) on the quality of life (QoL) of men with erectile dysfunction (ED) caused by spinal cord injury (SCI). SETTING: Study centers in Australia, Belgium, France, Germany, Norway, Sweden and the United Kingdom. METHODS: Questions 13 and 14 of the 15-item International Index of Erectile Function (IIEF) addressed QoL issues directly related to ED in 178 men with SCI. A 5-item questionnaire addressing concerns that men had about their erection problems was also used to evaluate the impact of ED on QoL. Several commonly used psychometric instruments, including the Medical Outcomes Survey (MOS) Short Form-12, Psychological General Well-Being Index, and MOS Family Survey, assessed general QoL issues. RESULTS: Significant improvements were seen for overall satisfaction with sex life (IIEF Q13), sexual relationship with partner (IIEF Q14), and concerns about erectile problems (P<0.0001). Improvements were reported in scores for the generic QoL parameters of mental health, well-being, depression, and anxiety (P<0.05 sildenafil versus placebo). CONCLUSION: Treatment with sildenafil can significantly improve key QoL parameters in men with ED caused by SCI. SPONSORSHIP: This study was funded by Pfizer Inc. Spinal Cord (2000) 38, 363 - 370.

Adult↗

Switching from intracavernous prostaglandin E1 injections to oral sildenafil citrate in patients with erectile dysfunction: results of a multicenter European study. The Sildenafil Multicenter Study Group.

PURPOSE: Intracavernous injection is a well established medical therapy for erectile dysfunction. We assessed the rate of success when patients with erectile dysfunction who were effectively treated with intracavernous injections of prostaglandin E1 were changed to oral therapy with sildenafil citrate. MATERIALS AND METHODS: Only patients effectively managing erectile dysfunction by the intracavernous injection of 20 microg. or less prostaglandin E1 for more than 6 months were eligible for study enrollment. After a 4-week run-in phase while intracavernous prostaglandin E1 therapy continued and a 48-hour washout period 176 patients with erectile dysfunction received open label sildenafil orally for 12 weeks. Satisfaction with treatment was evaluated by the 11-item erectile dysfunction index of treatment satisfaction questionnaire. A successful change to sildenafil was prospectively defined as a questionnaire score of 0 to 100 after sildenafil that was greater than or equal to the score after intracavernous prostaglandin E1. RESULTS: Of the 176 patients 69% (95% confidence limit 62 to 76) successfully changed from intracavernous prostaglandin E1 injections to oral sildenafil and elected to continue oral treatment. Mean satisfaction score after sildenafil and prostaglandin E1 was 73.8 and 63.9, respectively (p <0.001). Only 3 patients (1.7%) discontinued therapy because of treatment related adverse events. CONCLUSIONS: More than two-thirds of the men with erectile dysfunction who were stable on intracavernous injections of 20 microg. or less prostaglandin E1 successfully changed to oral sildenafil, as determined by maintained or enhanced treatment satisfaction.

3',5'-Cyclic-GMP Phosphodiesterases↗

Central control of erection and its pharmacological modification.

Advances in our understanding of the local mechanisms of penile erection have paralleled the use of pharmacological treatments of erectile dysfunction. In contrast, the spinal and supraspinal mechanisms that control penile erection are less well understood. Although the role of hypothalamic areas (medial preoptic area, paraventricular nucleus) and brainstem nuclei (raphe nuclei) in penile erection has been evaluated, as has the role of an association between neuromediators and receptors (serotonin, dopamine, noradrenalin, glutamate, gamma-aminobutyric acid, nitric oxide), an integrative view of the central mechanisms of penile erection is lacking. New strategies to treat erectile dysfunction employ oral agents, some of which target central brain nuclei. The future of such treatments largely depends on a better understanding of the central mechanisms of penile erection.

Animals↗

Effects of intracavernous administration of selective antagonists of alpha(1)-adrenoceptor subtypes on erection in anesthetized rats and dogs.

The proerectile properties of three novel alpha(1)-adrenoceptor (alpha(1)-ADR) antagonists with different profiles of selectivity for the alpha(1)-ADR subtypes have been evaluated in anesthetized rats and dogs on intracavernous (IC) injection, in comparison with prazosin and phentolamine. In rats, the tested compounds decreased blood pressure (BP) and increased IC pressure (ICP), as well as the ratio ICP/BP. Rec 15/2841 (alpha(1a)- plus alpha(1L)-ADR-selective antagonist) and Rec 15/2615 (alpha(1b)-ADR selective) were the most potent compounds. The ICP/BP ratios calculated after injection of Rec 15/3039 (alpha(1d)-ADR selective) were not markedly different from those observed after vehicle injection. Prazosin and phentolamine proved poorly active, their main effect being hypotension. Approximate ED(25) values (dose of compound in micrograms inducing 25% increase of ICP/BP ratio) were Rec 15/2615 (22 microgram/kg)>= Rec 15/2841 (29 microgram/kg) > prazosin (136 microgram/kg) > phentolamine (1298 microgram/kg) > Rec 15/3039 (9600 microgram/kg). Submaximal stimulation of the cavernous nerve elicited an ICP rise whose amplitude was not altered by Rec compounds. In contrast, prazosin and phentolamine decreased this ICP rise. All compounds but 15/3039 induced significant increase of the ICP/BP ratio in dogs. Rec 15/2615 proved to be the most interesting compound, inducing significant increases of ICP/BP at doses practically devoid of effects on BP. The rank order of potency in dog in increasing the ICP/BP ratio was similar to that observed in rats. Only at the highest doses tested, all compounds, except Rec 15/3039, decreased the ICP rise elicited by submaximal stimulation of the cavernous nerve. Our data demonstrate that the alpha(1b)- and alpha(1L)-ADR subtypes are functionally relevant for the erectile function in these models, and that alpha(1b)- and/or alpha(1L)-ADR subtypes selective antagonists could represent a real advantage in erectile dysfunction therapy.

Adrenergic alpha-1 Receptor Antagonists↗

Central noradrenergic control of penile erection.

Penile erection is completely dependent on commands from the central nervous system. Spinal centers controlling penile erection are located in the thoracolumbar and lumbosacral spinal cord. These centers are activated by information from the periphery and supraspinal nuclei so as to elicit penile erection in a variety of physiological contexts. A small number of nuclei including the locus coeruleus located in the pons sends noradrenergic fibers to the forebrain and spinal cord, including those areas controlling penile erection. Recent morphological techniques such as in situ hybridization and autoradiography using radioligand binding permit investigation of the brain and spinal pathways utilizing alpha adrenoceptor subtypes. Furthermore, pharmacological experiments suggest a modulatory role for noradrenaline in the control of penile erection either in the brain or in the spinal cord. The most robust evidence is that central inhibition of alpha-2 adrenoceptors facilitates sexual function. Taken together, the data propose new directions in the physiological exploration of penile erection and the therapeutic approach of erectile dysfunction.

Animals↗

Central noradrenergic control of penile erection.

Penile erection is completely dependent on commands from the central nervous system. Spinal centers controlling penile erection are located in the thoracolumbar and lumbosacral spinal cord. These centers are activated by information from the periphery and supraspinal nuclei so as to elicit penile erection in a variety of physiological contexts. A small number of nuclei including the locus coeruleus located in the pons sends noradrenergic fibers to the forebrain and spinal cord, including those areas controlling penile erection. Recent morphological techniques such as in situ hybridization and autoradiography using radioligand binding permit investigation of the brain and spinal pathways utilizing alpha adrenoceptor subtypes. Furthermore, pharmacological experiments suggest a modulatory role for noradrenaline in the control of penile erection either in the brain or in the spinal cord. The most robust evidence is that central inhibition of alpha-2 adrenoceptors facilitates sexual function. Taken together, the data propose new directions in the physiological exploration of penile erection and the therapeutic approach of erectile dysfunction. International Journal of Impotence Research (2000) 12, Suppl 1, S13-S19

Journal Article↗

Sildenafil citrate (Viagra) is effective and well tolerated for treating erectile dysfunction of psychogenic or mixed aetiology.

Sildenafil citrate (Viagra) has been shown to be an effective treatment for erectile dysfunction (ED) of organic aetiology. This study assessed the efficacy and tolerability of sildenafil for treating ED of psychogenic and mixed psychogenic/organic aetiology. Men with ED of psychogenic and mixed aetiology were randomised in a double-blind, fixed-dose study to placebo (n = 95) or sildenafil 10 mg (n = 90), 25 mg (n = 85), or 50 mg (n = 81) once daily for 28 days. Efficacy was evaluated with two global efficacy questions, a patient log of erectile activity, a sexual function questionnaire and a partner questionnaire. Patients receiving sildenafil had significantly more grade 3 (hard enough for penetration) or grade 4 (fully hard) erections per week than patients receiving placebo, and a greater proportion of patients receiving sildenafil reported that treatment had improved their erections (p < 0.001). Results of the sexual function questionnaire demonstrated significant improvement for patients with ED receiving sildenafil compared with patients receiving placebo for frequency, hardness and duration of erections (p < 0.01), and for enjoyment of sexual intercourse and satisfaction with sex life (p < 0.05). The results of the partner questionnaire were consistent with the results reported by patients and showed that treatment with sildenafil was associated with significant improvement in the partners' own sex lives (p < 0.001). Adverse events were mostly mild to moderate in nature. The commonest adverse events were headache, dyspepsia, flushing, myalgia, arthralgia and flu syndrome. Discontinuations due to treatment-related adverse events were few, ranging from 1.1% to 6.2% for patients receiving different doses of sildenafil and 4.2% for patients receiving placebo. Sildenafil is an effective and well-tolerated treatment for ED of psychogenic or mixed aetiology with once-daily dosing.

Adolescent↗

Spinal and brain circuits to motoneurons of the bulbospongiosus muscle: retrograde transneuronal tracing with rabies virus.

Retrograde transneuronal tracing with rabies virus from the left bulbospongiosus muscle (BS) was used to identify the neural circuits underlying its peripheral and central activation. Rats were killed at 2, 3, 4, and 5 days post-inoculation (p.i.). Rabies immunolabelling was combined with immunohistochemical detection of choline acetyltransferase and oxytocin. Virus uptake was restricted to ipsilateral BS motoneurons (2 days p.i.). The onset of transfer (3 days p.i.) visualized interneurons in the dorsal grey commissure (DGC), intermediate zone, and sacral parasympathetic nucleus (SPN), mainly in DGC at L5-S1, and revealed synaptic connections between BS and external urethral sphincter motoneurons. At 4 and 5 days p.i., higher-order interneurons were labelled in other spinal areas and segments. Supraspinal labelling initially involved only Barrington's nucleus, nucleus reticularis magnocellularis, and paragigantocellularis lateralis (4 days p.i.). Later, labelling extended to other populations traditionally associated with control of sexual activity and micturition (periaqueductal grey, paraventricular nucleus, medial preoptic area, prefrontal cortex), but also indicated the intervention of somatic descending motor pathways (vestibulospinal and reticulospinal neurons, "hindlimb" regions of sensorimotor cortex and red nucleus) and cerebellar nuclei in multisynaptic innervation of the labelled motoneurons. Dual color immunofluorescence disclosed multisynaptic links between these motoneurons and thoracolumbar medial sympathetic (choline acetyltransferase-immunoreactive) neurons. In contrast, preganglionic neurons in SPN and most oxytocinergic neurons in paraventricular hypothalamic nucleus remained unlabelled, suggesting that parasympathetic and somatic outflow to pelvic organs are probably controlled by separate interneuronal populations and that oxytocinergic spinal projections are more likely to influence sacral autonomic rather than somatic outflow.

Animals↗

Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.

Anti-Inflammatory Agents, Non-Steroidal↗

Randomized trial of sildenafil for the treatment of erectile dysfunction in spinal cord injury. Sildenafil Study Group.

Erectile dysfunction is a common complication of spinal cord injury. This double-blind, placebo-controlled, two-way crossover study assessed the efficacy and safety of oral sildenafil in men with erectile dysfunction caused by traumatic spinal cord injury. A total of 178 men (mean age, 38 years) received placebo or sildenafil 1 hour before sexual activity for 6 weeks; after a 2-week washout period, the men received the alternate treatment for 6 weeks. The 50-mg starting dose could be adjusted to 100 or 25 mg based on efficacy and tolerability. Efficacy was assessed by using global efficacy questions, the International Index of Erectile Function (IIEF), and a patient log of erectile activity. Of 143 men with residual erectile function at baseline, 111 (78%) reported improved erections and preferred sildenafil to placebo. For all men (including those who reported no residual erectile function at baseline), 127 of 168 (76%) reported improved erections and preferred sildenafil to placebo. For all men, 132 of 166 (80%) reported that sildenafil improved sexual intercourse compared with 17 of 166 men (10%) reporting improvement with placebo. IIEF questions assessing the ability to achieve and maintain erections and satisfaction with sexual intercourse demonstrated significant improvement with sildenafil. Sildenafil was well tolerated, with a low rate of discontinuation because of treatment-related adverse events (2% vs 1% for placebo). Oral sildenafil is an effective and well-tolerated treatment for erectile dysfunction caused by spinal cord injury.

Administration, Oral↗

Assessment of the functional role of accessory pudendal arteries in erection by transrectal color Doppler ultrasound.

PURPOSE: Anatomical studies have demonstrated accessory pudendal arteries originating from supralevator vessels in about two-thirds of men. Injury to accessory pudendal arteries derived from inferior vesical and obturator arteries has been reported to be responsible for vasculogenic impotence after nerve sparing radical prostatectomy. We performed transrectal and perineal color Doppler ultrasound in patients before radical pelvic surgery to identify accessory pudendal arteries and assess their functional role during erection. MATERIALS AND METHODS: A total of 12 patients with a mean age of 60 years were examined before radical prostatectomy (10) or cystoprostatectomy (2). Transrectal and perineal color Doppler flow imaging and spectral waveform analysis were performed. Peak systolic velocity, end diastolic velocity, resistive index and arterial diameter were measured before and during pharmacologically induced erection. Transrectal color Doppler ultrasound data were compared with intraoperative findings. RESULTS: Transrectal color Doppler ultrasound visualized accessory pudendal arteries derived from supralevator arteries in 9, and prostatic and seminal vesicle arteries in all patients. Perineal color Doppler ultrasound visualized internal pudendal arteries in all patients. After intracavernosal injection of papaverine accessory and internal pudendal arteries displayed similar significant hemodynamic changes. Diameter as well as peak systolic and end diastolic velocities increased, and resistive index decreased. Prostatic and seminal vesicle arteries showed no significant change. Presence and location of accessory pudendal arteries demonstrated by transrectal color Doppler ultrasound were confirmed by intraoperative findings. CONCLUSIONS: During pharmacologically induced erection hemodynamic changes in accessory and internal pudendal arteries are similar to those described in cavernous arteries, thus demonstrating the functional role of accessory pudendal arteries in penile erection. Color Doppler ultrasound appears to be reliable to examine internal and accessory pudendal arteries based on morphological and functional criteria.

Aged↗

5-Hydroxytryptamine2C receptors on spinal neurons controlling penile erection in the rat.

The localization of 5-hydroxytryptamine2C receptors in the lumbosacral spinal cord of the rat was investigated using selective antibodies raised against the carboxyl-terminal part of the rat receptor. The distribution of immunoperoxidase labelling at the light microscope level revealed numerous labelled neurons in the gray matter, with a higher intensity in the sacral parasympathetic nucleus, the dorsal gray commissure and particularly the motoneurons of the ventral horn. Confocal microscope analysis showed that immunostaining was mainly intracellular (motoneurons), but could also be associated with the membrane of cell bodies and dendrites. Actually, electron microscope immunogold experiments demonstrated an exclusive staining of the cis-Golgi apparatus. Following pseudo-rabies virus transsynaptic retrograde labelling from the corpus cavernosum, labelled neurons were found in the sacral parasympathetic nucleus and the dorsal gray commissure of the L6-S1 segments. All virus-labelled neurons exhibited 5-hydroxytryptamine2C receptor immunoreactivity. These results indicate that all parasympathetic preganglionic neurons and their related interneurons which contribute to the innervation of cavernosal tissue bear 5-hydroxytryptamine2C receptors. In the sacral parasympathetic nucleus, most neurons which were retrogradely-labelled from the pelvic ganglion with Fast Blue also showed 5-hydroxytryptamine2C receptor immunoreactivity. In the ventral horn, motoneurons retrogradely labelled from the ischiocavernosus muscle and the bulbospongiosus muscle, both of which are involved in erection and ejaculation, were also 5-hydroxytryptamine2C receptor-immunopositive. The supraspinal serotoninergic control of erection at the lumbosacral level therefore appears to be strongly associated with the activation of 5-hydroxytryptamine2C receptors, consistent with the proerectile properties of 5-hydroxytryptamine2C agonists.

Amidines↗

Oxytocinergic innervation of autonomic nuclei controlling penile erection in the rat.

In the rat, spinal autonomic neurons controlling penile erection receive descending pathways that modulate their activity. The paraventricular nucleus of the hypothalamus contributes oxytocinergic fibers to the dorsal horn and preganglionic sympathetic and parasympathetic cell columns. We used retrograde tracing techniques with pseudorabies virus combined with immunohistochemistry against oxytocin and radioligand binding detection of oxytocinergic receptors to evidence the oxytocinergic innervation of thoracolumbar and lumbosacral spinal neurons controlling penile erection. Spinal neurons labelled with pseudo-rabies virus transsynaptically transported from the corpus cavernosum were present in the intermediolateral cell column and the dorsal gray commissure of the thoracolumbar and lumbosacral spinal cord. Confocal laser scanning microscopic observation of the same preparations revealed close appositions between oxytocinergic varicosities and pseudorabies virus-infected neurons, suggesting strongly the presence of synaptic contacts. Electron microscopy confirmed this hypothesis. Oxytocin binding sites were present in the superficial layers of the dorsal horn, the dorsal gray commissure and the intermediolateral cell column in both the thoracolumbar and lumbosacral segments. In rats, stimulation of the paraventricular nucleus induces penile erection, but the link between the nucleus and penile innervation remains unknown. Our findings support the hypothesis that oxytocin, released by descending paraventriculo-spinal pathways, activates proerectile spinal neurons.

Animals↗

Ex vivo assay to determine the cyclooxygenase selectivity of non-steroidal anti-inflammatory drugs.

1. In this study we describe experiments to establish ex vivo the selectivity of non-steroidal anti-inflammatory drugs (NSAIDs) given in vivo. 2. Anaesthetised (Inactin, 120 mg kg(-1)) male Wistar rats (220-250 g) received an i.v. dose of one of the following compounds (dose mg kg(-1)): aspirin (20), diclofenac (3), L-745,337 (30), nimesulide (15), salicylate (20), sulindac (10). Blood samples were taken before and up to 6 h after dosing and the plasma obtained from it was tested for its ability to inhibit prostanoid formation in IL-1beta-treated A549 cells (COX-2 system) and human washed platelets (COX-1 system). For control the same compounds were also added directly to the assay systems. 3. All drugs, except sodium salicylate, inhibited COX-1 and COX-2 when added directly to the test systems. Plasma from aspirin-treated rats was without effect on either COX-1 or COX-2, consistent with the rapid in vivo metabolism to salicylate. Conversely, plasma from sulindac-treated rats inhibited COX-1 and COX-2 with potencies according with in vivo metabolism to sulindac sulphide. Diclofenac was COX-1/2 non-selective when tested in vitro, but a slightly preferential inhibitor of COX-2 when tested ex vivo. Nimesulide was confirmed as preferential inhibitor of COX-2 both in vitro and ex vivo. L-745,337 was a selective COX-2 inhibitor when tested in vitro or ex vivo. 4. In conclusion, our experiments show clearly (a) NSAIDs inactivation, (b) activation of prodrugs, and (c) NSAIDs selectivity. Our assay provides useful information about the selectivity of NSAIDs that could be extended by the analysis of plasma samples taken from humans similarly treated with test drugs.

Analgesics↗

Supra and infralevator neurovascular pathways to the penile corpora cavernosa.

The aim of this study was to provide a comprehensive description of both penile innervation and vascularisation. Eighty-five male cadavers were examined through gross and microscopic anatomical analysis. The pelvic nerve plexus had both parasympathetic and sympathetic roots. It was distributed to the external urethral sphincter giving rise to cavernous nerves which anastomosed in 70% of the cases with the pudendal nerve in the penile root. Accessory pudendal arteries were present in the pelvis in 70% of the cases, anastomosing in 70% of the cases with the cavernous arteries that originated from the pudendal arteries. Transalbugineal anastomoses were always seen between the cavernous artery and the spongiosal arterial network. There were 2 venous pathways, 1 in the pelvis and 1 in the perineum with a common origin from the deep dorsal penile vein. It is concluded that there are 2 neurovascular pathways destined for the penis that are topographically distinct. One is located in the pelvis and the other in the perineum. We were unable to determine the functional balance between these 2 anastomosing pathways but experimental data have shown that they are both involved in penile erection. These 2 neurovascular pathways, above and below the levator ani, together with their anastomoses, form a neurovascular loop around the levator ani.

Aged↗

Intracavernous pressure during erection in rats: an integrative approach based on telemetric recording.

To better understand the similarities and differences in the neural control of penile erection occurring in different contexts, we recorded intracavernous pressure (ICP) in conscious rats using a miniaturized telemetric device. ICP changes during reflexive, noncontact, and apomorphine-induced erections were characterized by a plateau increase surmounted by peaks. Plateaus were also elicited by cavernous nerve stimulation in anesthetized rats, suggesting that the cavernous nerve represents the final common proerectile autonomic pathway in these contexts and that it responds similarly to information originating in the periphery or in supraspinal nuclei. During reflexive, noncontact, and apomorphine-induced erections, activation of spinal autonomic nuclei, considered the spinal generators of erection, would take place first, representing a prerequisite for the occurrence of peaks. Suprasystolic peaks would result from the addition of pudendal motoneuron activity. In contrast, only peaks were recorded during copulation. In this context, the convergence of peripheral and supraspinal information apparently elicits the best temporal arrangement of autonomic and somatic outflows, reflecting a highly organized and integrated spinal activity.

Animals↗

Cavernospongious shunts: anatomical study of intrapenile vascular pathways.

OBJECTIVES: The reality of cavernospongious shunts has never been confirmed and their role in penile erection remains undetermined. We aim to describe the intrapenile vascular anatomy as the precise nature of the connections between the corpus spongiosum, the glans and the corpora cavernosa remains unknown. METHODS: Ten human penises were removed from adult male cadavers 8 days after arterial casting with latex. In four specimens coloured latex was injected into the corpus spongiosum. Ex situ microdissection was performed to analyse the origin and distribution of the penile arteries. The anastomotic arterial pathways were dissected. RESULTS: In all the specimens, 6-10 anastomoses were found between the cavernous arteries (a. profundae penis) and the spongious arterial network. These arteries arose at regular intervals from the cavernous arteries and perforated the tunica albuginea vertically to anastomose with urethral arteries (a. urethralis). No arteriovenous shunts were found between the corpus spongiosum and the corpora cavernosa, nor was there any venous drainage from the corpus spongiosum entering the corpora cavernosa. CONCLUSION: These shunts are arteries connecting the urethral and cavernous arteries. Cavernospongious arterial anastomoses were found in all the cadavers dissected. Further studies are needed to determine their role in penile erection.

Aged↗