[Tadalafil versus sildenafil citrate in the treatment of ED:Italian patients' preferences and explanatory notes].

This is an open, multicentre, randomized, crossover study having the aim to evaluate the preference for sildenafil citrate or tadalafil in a population of Italian patients affected by ED, and to compare the efficacy and safety of these two drugs. MATERIAL AND METHODS. From October 2003 to November 2004, thirteen Italian centers enrolled ED patients (age >18) being in steady and naïve relation to ED treatment, both through PDE5 inhibitors and any other treatment option. These patients were randomized to sildenafil or tadalafil for 12 weeks, after which they were switched to the alternative treatment for a further 12 weeks. The preference was evaluated through the Treatment Preference Question (TPQ): "During this clinical trial you have taken tadalafil and sildenafil for the treatment of erectile dysfunction. Which medication do you prefer to take for the next 8 weeks of treatment?". Moreover, patients were asked to express their preference as "strong" or "moderate" and to answer some questions to clarify the reasons behind their preference. SEP and IIEF-EF questionnaires were used for a comparison of efficacy. RESULTS. 167 patients were enrolled, 144 of whom completed both treatment periods. On being asked the TPQ, 75% of patients (n=108) decided to continue treatment with tadalafil, in particular because it made it possible to have an erection many hours after taking the medication (first or second preference reason for 64.8% of patients), while 25% (n=36) preferred sildenafil (p=0.001). Both drugs improved the IIEF-EF and SEP scores compared to baseline, with a slightly but significantly greater improvement with tadalafil for both parameters. CONCLUSIONS. Tadalafil and sildenafil are both effective and well tolerated. Most of the patients prefer tadalafil thanks to the possibility of having sexual intercourse many hours after taking the medication.

[An alternative dosing regimen with tadalafil 3 times/week in the treatment of erectile dysfunction:italian data from the SURE study]. / Un regime alternativo di somministrazione di tadalafil, 3 volte a settimana, nel trattamento della disfunzione erettile: dati italiani dello studio SURE

To evaluate the preference for 2 dosing regimens of tadalafil 20 mg, on demand or 3 times/week, in Italian men affected by erectile dysfunction (ED). MATERIALS AND METHODS. SURE is a multicenter, crossover, open-label study, involving 94 urology centers in Italy. Patients aged 18 or more, affected by ED for at least 3 months were enrolled into the study and randomized to a tadalafil 20 mg treatment on demand or 3 times/week for 5-6 weeks. After a 1-week washout period, patients were crossed over to the alternate regimen for 5-6 weeks. A treatment preference question (TPQ) was used to determine the preferred treatment regimen. IIEF and SEP questionnaires were used as efficacy measures. RESULTS. 1058 men, mean age 54.8 years, were randomized to treatment. Overall, 59.1% of patients preferred the on-demand regimen and 41.9% preferred the 3 times/week dosing regimen. Both regimens were efficacious and well tolerated. CONCLUSIONS. Tadalafil is effective and well tolerated whether used both on demand and three times/week. Patients should be given the possibility to choose the best treatment regimen according to personal needs and preferences.

Early dysfunction of iris sensory fibres in diabetic patients.

BACKGROUND: The present study was designed to propose transcutaneous electrical nerve stimulation (TENS) of the infratrochlear nerve as a noninvasive test useful in the detection of early iris small nerve fibre dysfunction in patients with diabetes mellitus. METHODS: A total of 32 diabetic patients with no symptoms or signs of diabetic neuropathy were enrolled from a clinical practice. Sixteen of them, 6 women and 10 men, ranging in age from 19 to 53 years, had been affected by IDDM for 13 +/- 2 years. The remainder, 6 women and 10 men, age range 32 to 58 years, were suffering from NIDDM (duration of manifestation 5 +/- 1 years). Twenty-six healthy individuals, 11 women and 15 men, ranging in age from 21 to 47 years, served as controls. Pupil area changes induced by TENS of the infratrochlear nerve were investigated. The electrical stimulus was not painful and consisted of a single square wave pulse of 40 mA intensity and 0.8 ms duration. Measurements were carried out by means of a TV monocular electronic pupillometer. RESULTS: A clear-cut miosis was provoked in controls (p < 0.01 versus basal values 100 sec to 220 sec from stimulation). NIDDM patients also showed a miotic response, but it was slower in onset (p < 0.05 versus basal values 140 sec after stimulation) and shorter (p < 0.01 at 180 sec from stimulation) in duration. No pupillary changes were registered in IDDM patients. CONCLUSIONS: An abnormality of iris sensory nerve fibres in inducing pupillary constriction was detected in both diabetic groups. The differences in the severity of the dysfunction could be related to the differences in duration of the disease among the diabetic patients in the two groups. In conclusion, TENS of the infratrochlear nerve could represent an original noninvasive method in detecting early iris sensory alterations in diabetic patients.

Differential activation of the epithelial and smooth muscle NK1 receptors by synthetic tachykinin agonists in guinea-pig trachea.

1. The presence of tachykinin NK1 receptors have been shown in the epithelium and smooth muscle of guinea-pig airways. Previous data showed that substance P (SP), and the NK1 receptor agonist, [Sar9, Met (O2)11]-SP, relax guinea-pig tracheal tube preparations by stimulation of epithelial NK1 receptors and via nitric oxide (NO) release. However, the selective tachykinin NK1 receptor agonist, septide, was unable to produce this effect. The aim of the present study was to investigate the ability of a series of SP analogues to stimulate NK1 receptors of guinea-pig airway epithelium. 2. Isometric tension was recorded in isolated tracheal tube preparations in which compounds were administered intraluminally in the presence of phosphoramidon, indomethacin (both 1 microM) and the tachykinin NK2 receptor antagonist, SR 48,968 ((S)-N-methyl N-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl)benzam ide) (0.1 microM). Cumulative concentration-response curves were obtained in preparations under resting tone or in preparations precontracted with acetylcholine (ACh, 10 microM). 3. Contractile responses to low concentrations (0.1-10 nM) of substance P (SP) and the selective agonist of NK1 receptors, [Pro9]-SP. in non precontracted tracheae were higher in preparations pretreated with the NO-synthase inhibitor, NG-monomethyl L-arginine (L-NMMA, 100 microM) than in preparations pretreated with its inactive enantiomer D-NMMA (100 microM). Tracheal tube preparations precontracted with ACh and pretreated with D-NMMA were relaxed by low concentrations of SP and [Pro9]-SP (0.1-10 nM). In contrast, after pretreatment with L-NMMA, SP and [Pro9]-SP contracted tracheae at all the concentrations tested. 4. Concentration-response curves to the NK1 receptor agonists, SP methyl ester, [Apa9-10]-SP and [pGlu6] SP (6-11) obtained in non-precontracted tracheae were similar in the presence of either D-NMMA or L-NMMA. SP methyl ester, [Apa9-10]-SP and [pGlu6] SP (6-11) did not produce any relaxation, but instead, cause contractions in tracheal tube preparations precontracted with ACh and pretreated with D-NMMA. Concentration-response curves produced by all these agonists were similar in preparations precontracted with ACh and pretreated with L-NMMA or D-NMMA. 5. In guinea-pig tracheal tube preparations two groups of NK1 receptor agonists can be distinguished: one group, including [Pro9]-SP, stimulator epithelial NK1 receptors, the other group, including SP methyl ester, [Apa9-10]-SP and [pGlu6] SP (6-11), does not. One possible explanation for these findings and for the existence of compounds with a peculiar 'septide-like' pharmacological profile in the guinea-pig trachea could be the recently proposed phenomenon referred to as 'agonist-directed receptor trafficking'.

Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients.

Nitroglycerine is known to induce a headache attack in cluster headache patients, which is indistinguishable from a spontaneous attack. It has recently been suggested that a release of calcitonin gene-related peptide (CGRP) from peripheral terminals of trigeminal nociceptive neurons, which supply cephalic blood vessels, underlies symptoms of cluster headache. The aim of this study was to investigate whether the provocative action of nitroglycerine in cluster headache is due, at least in part, to activation of the trigeminovascular system. Nineteen subjects suffering from episodic cluster headache participated in the study. Eleven of them were in an active period, whilst the others were in remission at the time of the study. CGRP-like immunoreactivity (CGRP-LI) was measured in blood samples from the extracerebral circulation before and after the sublingual administration of nitroglycerine. Baseline CGRP-LI plasma levels were higher (P < 0.05) in the patients who were in an active period. Only in these patients did nitroglycerine induce an attack, which was preceded by a latent period with a mean duration of 27 +/- 3 min. When compared with the baseline, a significant (P < 0.01) increase in plasma CGRP-LI was detected at the peak of the provoked attack; no such increase was detected during the latent period, or at the onset of the attack. The results of this study suggests that the provocative action of nitroglycerine in cluster headache is due, at least in part, to activation of the trigeminovascular system. This mechanism seems to be slow and unrelated to the well-known rapidly occurring vasodilator effects of the drug. Finally, activation of the trigeminovascular system only occurs in those patients already in an active cluster headache period who also have high basal CGRP-LI plasma levels. This suggests that a hyperactivity of trigeminal nociceptive fibres could make the trigeminovascular system of these patients sensitive to the triggering action of nitroglycerine.

Headache induced by serotonergic agonists--a key to the interpretation of migraine pathogenesis?

Serotonergic agonists such as m-chlorophenylpiperazine (m-CPP) and fenfluramine may induce migraine attacks. This has led to opposing theories concerning the role of 5-hydroxytryptamine (5HT) in triggering migraine attacks; is there hyperfunction or hypofunction of the central serotonergic system. Our review of the literature strongly suggests that m-CPP and fenfluramine provoke migraine attacks by stimulating, directly or indirectly, the 5HT2C/5HT2B receptors, although there is no total agreement with this interpretation. Central 5HT hypersensitivity in migraine patients, probably due to 5HT neuronal depletion, is proposed on the basis of review of electrophysiological tests and neuroendocrine challenge paradigms.

Buspirone, but not sumatriptan, induces miosis in humans: relevance for a serotoninergic pupil control.

BACKGROUND AND OBJECTIVE: Drugs that act on the serotoninergic system have been shown to influence the pupil size. However, the 5-hydroxytryptamine (5-HT) receptor type or subtype that affects pupil diameter has not been defined in humans. With a placebo-controlled, double-blind randomized design, we investigated in healthy volunteers the effect on pupil size of buspirone and sumatriptan, which mainly act on 5-HT1A- and the 5-HT1-like receptors, respectively. METHODS: The pupil area was measured by means of a videopupillometer before and after a single oral administration of placebo or of three different doses of active drugs. Heart rate and arterial blood pressure were recorded after pupil area measurement. RESULTS: Buspirone (5, 10, and 20 mg) caused a dose-dependent miosis. Sumatriptan (50, 100, and 200 mg) did not affect the pupil size. Twenty milligrams of buspirone reduced the mydriasis induced by pretreatment with homatropine eyedrops. A 20 mg dose of buspirone reduced blood pressure without change in heart rate, whereas buspirone, at doses lower than 20 mg, and sumatriptan did not affect heart rate and blood pressure. CONCLUSIONS: This study suggests that buspirone, but not sumatriptan, the selective agonist of 5-HT1-like receptors, causes miosis in humans by activation of 5-HT1A receptors, possibly located in the central nervous system where they inhibit iris sympathetic pathways. Measurement of pupil size seems to provide a valuable and sensitive index of 5-HT1A receptor function in humans.

Visceral pain threshold is deeply lowered far from the head in migraine.

A short-lasting over-distension of the hand-forearm veins, obtained through a non-invasive original maneuver (Hand Arm Vein Distension test) induces local pain when applied to migraine sufferers in inter-critical period. Conversely, subjects with an absolutely negative personal and family history for any type of idiopathic headache do not report any pain or only an uncertain, slight one. The injection of 1 mL of 2% to 8% (i.e. 0.34 mol/L to 1.36 mol/L) hypertonic saline into the antecubital vein during an extemporary short (1 minute) circulatory blockage (ischemia induced to guarantee a strictly local action of the chemical stimulus) provokes moderate, strong or unbearable local (arm vein) pain in migraine sufferers but not in subjects with a personal and family history absolutely free from any type of headache. These results show for the first time that migraineurs show a proneness to visceral pain in viscera (veins) distant from the head (arm-hand). Such a finding is consistent with the theory that migraine pain is due to a central derangement of the viscerosensory system.

[Noci-autonomic-affective automatism, the physiopathological essence of hemicrania. The serotonin theory as a guiding principle in the labyrinth of interpretations]. / Automatismo noci-vegeto-affettivo, essenza fisiopatologica dell'emicrania. La teoria serotoninica come filo conduttore nel labirinto delle interpretazioni.

After thousands of painful long-lasting migraine or extremely violent cluster headache attacks no one has yet traced histological inflammatory or degenerative alterations of the interested tissues able to explain such dreadful pain. Therefore it has seemed logical to include these pains among the unjustified aimless, non finalized types of pain. Furthermore, clinical characteristics of automatism, explosiveness and the course of these pains resemble other aimless pains like those of organic deafferentation (phantom pain) which appear in a desensitized limb after denervation or even in amputated subjects. Intense and long lasting pains in opioid abstinence, mainly located in the chest and in the hip, also have all the characteristics of aimless pain. Idiopathic cephalic pain, together with deafferentation or opioid-abstinence pain, seems to be due to a dysafferentation which, through different channels, follows an analogous mechanism. This mechanism seems to be due to a deficit of autoanalgesia which in both organic deafferentation (phantom limb) and in opioid-abstinence can be related to the disuse of afferences' modulation. In idiopathic headache such a failure of autoanalgesia is likely to be due to a genetic, idiopathic mechanism. Headaches are characterized by a clear deficiency of autoanalgesia which may manifest itself not only at the level of the cephalic segment, which is so rich in afferences, but it may even involve the whole body. Even if pain is the compulsory phenomenon to diagnose headache, one must consider that migraine is a symptomatic triad in which vegetative and emotional phenomena also emerge. These phenomena are interindependent and not interdependent as each of them may appear as a first manifestation of an attack; one must therefore consider the possibility of a "unicum movens". Serotonin was taken into consideration because of its action which interests all or nearly all vegetative-emotional pain transmitting pathways. Today's identification of four types and various sub-types of 5-HT receptors has revealed the extraordinary eclecticism of this transmitter which within migraine's clinical expression underscores that migraine sufferers are characterized by a marked sensitivity to all the drugs capable of acutely or chronically interacting with serotonin metabolism and binding with many serotonin receptor types and sub-types. So even if the migraine sphinx still proposes its enigma, researchers--with their incurable curiosity--may not only find more and more accurate and effective medication for many human beings but also start penetrating a mystery, a great challenge to human imagination.