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.

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.

The immediate objective of phosphodiesterase type 5 (PDE5) inhibitor treatment is to restore the ability of a man to achieve and/or maintain an erection adequate for sexual intercourse. As erectile dysfunction (ED) generally develops in the second half of life, the ultimate objective generally is not procreation, but quality of sexual life. Indeed, ED is known to impair quality of life considerably; two-thirds of men report that ED has impaired their self-esteem and nearly a third claim that it has damaged the relationship with their partner. It follows that the therapeutic success of PDE5 inhibition has an important subjective component, which is compounded by the subjective nature and complexity of sexual life in humans. This makes it very difficult for physicians to be certain that they have selected the optimal therapy for a couple, even after a thorough evaluation. The 2007 European Association of Urology Guidelines stress the importance of educating the patient and claim that 'the patient will choose the final drug after his own experience'. However, PDE5 inhibitors are typically used twice a week, so a patient would have to spend approximately 3 months trying the various compounds and dosages to achieve adequate exposure to all three PDE5 inhibitors; this would seem an unrealistic strategy in normal clinical practice. The acknowledgement that the patient has an important role in therapeutic decisions for ED has fuelled interest in the concept of patient preference. It has been established that patient preference depends on three factors, i.e. personal characteristics, e.g. age, duration of ED, frequency and dynamics of sexual relations, and the characteristics of their partners, e.g. age, menopausal status and level of interest in sexual activity and medication profile. Medication features of interest include efficacy in terms of quality of erection, consistency of effects, rapid onset of action, long duration of action, side-effect profile and route of administration; drug costs must also be considered if the medicinal product is not reimbursed.

As efficacy and tolerability of current therapy for PDPN are not ideal, the need for a better approach in management further exists. Novel compounds should be developed for the treatment of PDPN.

1 The presence of tachykinin NK 1 receptors have been shown in the epithelium and smooth muscle of guinea-pig airways. Previous data showed that substance P (SP), and the NK 1 receptor agonist, [Sar 9 , Met (O 2 ) 11 ]-SP, relax guinea-pig tracheal tube preparations by stimulation of epithelial NK 1 receptors and via nitric oxide (NO) release. However, the selective tachykinin NK 1 receptor agonist, septide, was unable to produce this eect. The aim of the present study was to investigate the ability of a series of SP analogues to stimulate NK 1 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 mM) and the tachykinin NK 2 receptor antagonist, SR 48,968 ((S)-N-methyl N-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl)benzamide) (0.1 mM). Cumulative concentration-response curves were obtained in preparations under resting tone or in preparations precontracted with acetylcholine (ACh, 10 mM). ]-SP and [pGlu 6 ] SP (6 ± 11), does not. One possible explanation for these ®ndings and for the existence of compounds with a peculiar`septide-like' pharmacological pro®le in the guinea-pig trachea could be the recently proposed phenomenon referred to as`agonist-directed receptor tracking'.