Increased urinary excretion of nitric oxide metabolites in longitudinally monitored migraine patients.

This study evaluated a relationship between nitric oxide (NO) and migraine attacks in order to gain insight into migraine pathomechanism. The study groups consisted of 12 migraineurs and eight controls. All subjects collected morning urine samples for 40 consecutive days. Urinary NO metabolites, nitrite/nitrate (NO(x)) levels were measured with the vanadium-based assay, whilst creatinine (Cr) and neopterin were determined with high-performance liquid chromatography. The mean urinary NO(x)/Cr ratio and number of NO(x) peaks was significantly greater in the migraine group compared with controls (P = 0.01 and P = 0.007, respectively). In the second approach, high NO(x) values were re-assessed in relation to raised neopterin, a marker of systemic infection or inflammation, and were excluded. The excretion of NO(x) persisted being pulsatile, and migraineurs had more peaks compared with controls (P = 0.01). In seven patients, NO(x) peaks coincided with headache days. This was more frequent than expected by random association in four patients (Monte-Carlo simulation; odds ratios: 2.16-7.77; no overlap of 95% CI). In four patients, NO(x) peaks preceded or followed headache days. Although there is a difference in the pattern of urinary NO(x) excretion between control and migraine populations, the variable temporal association of NO(x) peaks and headaches suggests a complex role of NO in this condition.

Greater occipital nerve injection in primary headache syndromes--prolonged effects from a single injection.

Most patients with primary headache syndromes who have frequent attacks of pain have tenderness in the sub-occipital region. Injection of the greater occipital nerve (GON) with local anesthetic and corticosteroids has been widely used in clinical practice for many years, yet there is no clear understanding of its mechanisms of action. Moreover, there is no current gold-standard of practice regarding GON injections in the management of headache. We audited of our practice to generate hypotheses about the range of primary headaches that might benefit, to determine response rates to power future studies, and to assess whether we should continue to do this procedure. Twenty-six of fifty-seven injections in 54 migraineurs yielded a complete or partial response that lasted for the partial response a median of 30 days. For cluster headache 13 of 22 injections yielded a complete or partial response lasting for a median of 21 days for the partial response. Tenderness over the GON was strongly predictive of outcome, although local anesthesia after the injection was not. The presence or absence of medication overuse did not predict outcome. Apart from two patients with a small patch of alopecia the injection was well tolerated. GON injection is a useful tool in some patients that provides interim relief while other approaches are explored. It is remarkable that in all conditions in which an effect is observed the response time so much exceeds the local anesthetic effect that the mechanism of action may well be through changes in brain nociceptive pathways.

A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate.

Migraine is a common disabling condition likely to be associated with dysfunction of brain pathways involved in pain and other sensory modalities. A cardinal, indeed signature, feature of the disorder that led to its name is that the pain may be lateralized. H(2)15O-labelled PET was used to study 24 migraineurs and eight healthy controls. The migraineurs were divided into three groups according to the site of their headache: right, left or bilateral. In each group, a migraine was induced using a glyceryl trinitrate (GTN) infusion. The subjects were scanned at predefined points: pre-infusion, during GTN, during migraine and post-migraine. SPM99 software was used to analyse the data. Significant brainstem activation was seen in the dorsal lateral pons (P < 0.05 after small volume correction) during the migraine state versus the pain-free state when comparing migraineurs with controls. When each group was analysed separately, to investigate laterality, it was found that the dorsal pontine activation was ipsilateral in the right-sided and left-sided groups and bilateral in the bilateral headache group with a left-sided preponderance. Consistent with previous work, the activation persisted after pain was controlled by sumatriptan. These results suggest that lateralization of pain in migraine is due to lateralized brain dysfunction.

Transcutaneous delivery of prostaglandin E1: in vitro and laser doppler flowmetry study.

The aim of this study was to assess the rate and extent of transcutaneous delivery of prostaglandin E1 (PGE1) from various formulations [liposomal, novel biphasic, and nonliposomal (oil/water cream) delivery systems] in vitro using diffusion cells and in vivo using laser doppler flowmetry, to aid in the development of a topically active preparation for the treatment of male sexual dysfunction. Percutaneous absorption through adult human foreskin was tested in flow-through diffusion cells using [3H]PGE1. Nine healthy volunteers participated in the crossover, randomized, double-blind, placebo-controlled study, where 0.1 g of each preparation was applied to a 4 cm2 area on the forearm. Laserflo BPM2 blood perfusion monitor with Model P-430 skin probe was used for evaluating skin blood perfusion. Encapsulation of PGE1 into novel biphasic delivery systems resulted in significantly increased skin blood perfusion relative to traditional liposomal, nonliposomal, and placebo formulations (6.25 +/- 1.58 vs 2.72 +/- 0.79, 0.53 +/- 0.64, and 0.58 +/- 0.06 mLLD/min/100 g, respectively, n = 9). The in vitro absorption of PGE1 through foreskin correlated well with the in vivo data (respective permeability coefficients 3.33, 1.57, and 1. 40 x 10(-4) cm/h). Formulation parameters greatly influence the absorption of PGE1 through skin as measured by laser doppler flowmetry, but by the application of a novel topical delivery technology, a significant enhancement of PGE1 delivery can be achieved.

Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study.

OBJECTIVE: To evaluate the efficacy and safety of 2 years' treatment of moderate benign prostatic hyperplasia (BPH) with finasteride. DESIGN: Double-blind, parallel-group, placebo-controlled, multicentre, prospective randomized study. SETTING: Outpatient care in 28 centres across Canada. PARTICIPANTS: Men aged 45 to 80, in good health, with moderate BPH and no evidence of prostate cancer. A total of 613 men were entered into the study; 472 completed the 2 years of treatment. INTERVENTION: After 1 month of receiving a placebo (run-in period), patients were given either finasteride (5 mg/d) or a placebo for 2 years. EFFICACY: changes from baseline in BPH symptom scores, maximum urinary flow rates and prostate volume. SAFETY: onset, course and resolution of all adverse events during the treatment period. RESULTS: In the efficacy analyses the mean BPH symptom scores decreased 2.1 points (from 15.8 to 13.7) in the finasteride group, as compared with a decrease of 0.7 points (from 16.6 to 15.9) in the placebo group (P < or = 0.01). The maximum urinary flow rate increased by a mean of 1.4 mL/s (from 11.1 to 12.5 mL/s) in the finasteride group, as compared with an increase of 0.3 mL/s (from 10.9 to 11.2 mL/s) in the placebo group (p < or = 0.01). The mean prostate volume decreased by 21% (from a mean volume of 44.1 cm3 at baseline) in the treatment group; it increased by 8.4% (from a mean volume of 45.8 cm3 at baseline) in the placebo group (p < or = 0.01). In the safety analysis, the proportion of patients who experienced any adverse event was similar in the two groups (81.0% in the treatment group and 81.2% in the placebo group). However, the incidence of adverse events related to sexual dysfunction were significantly higher in the finasteride group than in the placebo group (ejaculation disorder 7.7% v. 1.7% and impotence 15.8% v. 6.3%; p < or = 0.01 for both parameters). CONCLUSION: Finasteride is a well-tolerated and effective alternative to watchful waiting in the treatment of moderate BPH.