Vasopressin and catecholamine secretion during apomorphine-induced nausea mediate acute changes in haemostatic function in man

Seven male volunteers were given apomorphine (14-20 micrograms/kg) subcutaneously on a total of ten occasions. Nausea was experienced on six occasions and on four occasions there was no effect. Venous samples were taken before injection, at peak nausea and 20 min later for assay of factor VIII coagulant activity (FVIIIC), von Willebrand factor antigen (vWFAg), the ristocetin cofactor (FVIIIRiCof), euglobulin clot lysis time (ECLT), fibrinopeptide A (FPA), FPA generation time, activated partial thromboplastin time (APTT), vasopressin (aVP) and adrenaline. During nausea plasma aVP concentrations rose from median values of 0.4 pg/ml (at time 0) to 76 pg/ml at peak nausea and fell to 32 pg/ml 20 min later. Adrenaline rose from 0.36 to 0.91 nmol/l (P less than 0.05) before falling to 0.55 nmol/l. During nausea, FVIIIC rose from 100% to 143% (P less than 0.05) and to 214% (P less than 0.05) 20 min later. FVIIIRiCof and vWFAg showed similar changes. Plasminogen activator activity (10(6)/ECLT2) rose from 23 units at time 0 to 592 units during nausea and 1135 units (P less than 0.05) after 20 min. The APTT fell from 49 s to 44 s during the study, plasma FPA levels and the FPA generation time both remained unchanged. On the four occasions nausea was not experienced, there were no changes in vasopressin and catecholamine concentrations nor in haemostatic function. During the study, plasma aVP concentrations rose to levels previously shown to influence haemostatic function. This provides further support for the view that aVP has a secondary role as a mediator of acute changes in haemostasis, and during nausea contributes with adrenaline to an abrupt change in factor VIII and fibrinolytic activator activity.     

Effects of physiological concentrations of vasopressin on haemostatic function in man

Plasma concentrations of vasopressin (aVP) attained under conditions of stress were simulated by infusing four volunteers with 0.25, 0.5, 1.0 and 2.0 pressor units of aVP over 1 h (units/h). Three subjects had all four infusions and one received only 1.0 unit/h. Blood samples were taken for assay of factor VIII coagulant activity (FVIIIC), factor VIII related antigen (FVIIIRAg), the ristocetin cofactor (FVIIIRiCof), euglobulin lysis time (ELT) and aVP concentrations before infusion (time 0) and every 20 min for 80 min. Fibrinopeptide A (FPA) generation time was measured at time 0, 60 and 80 min. At infusion rates of 0.25 unit/h median aVP levels peaked at 6.5 pg/ml and there was no change in FVIII or FPA generation time, and plasminogen activator activity (10(6)/ELT2) rose from 100 to 400 units. At 1.0 unit/h, aVP levels rose to 25.4 pg/ml, FVIIIC rose by 160% and activator activity from 87 to 360 units. At 2.0 units/h, aVP concentrations reached 83 pg/ml, there was an increase in all modalities of FVIII and activator activity rose from 251 to 452 units. FPA generation time shortened and circulating plasma levels of FPA were increased. There was a highly significant correlation between the percentage increases in all three components of FVIII and plasma aVP levels (FVIIIC: r = 0.87, P less than 0.0001; FVIIIRAg: r = 0.61, P less than 0.0001; FVIIIRiCof: r = 0.80, P less than 0.0001) and between the increase in plasminogen activator activity and aVP levels (r = 0.56, P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)     

311C90 (Zolmitriptan*), a novel centrally and peripheral acting oral 5-hydroxytryptamine-1D agonist: a comparison of its absorption during a migraine attack and in a migraine-free period

The oral absorption of a 10-m. oral dose of the novel 5-hydroxytryptamine (5HT_1D) agonist, 311C90, was compared during a moderate or severe migraine headache and in a migraine-free period in an open, two-period study. The safety and efficacy of 311C90 in acute migraine were also assessed. Twenty patients attended the clinics during a moderate or severe migraine attack and 18 patients returned for a second dose in a migraine-free period 311C90 was less rapidly absorbed during a migraine attack compared to the migraine-free period, cons stent with gastric stasis during a migraine attack. The median area under the curve (AUC) was 15.7 ng/mlh lower during a migraine (median AUC: 18.4ng/ml.h, range: 0–60.8 ng/ml.h) compared to the migraine-free period (median AUC: 33.4 ng/ml.h, range 9.4–79.5 ng/ml.h) (95% confidence interval: 6.9,25.3) and the time to reach maximum plasma concentration was delayed ( n = 18). Eleven out of 20 patients experienced a significant improvement in migraine headache intensity at 2 h post-dose. Plasma 311C90 concentrations were generally higher in those patients who responded to treatment with 311C90 in the plasma, but there was one patient with no quantifiable 311C90 in the plasma whose headache improved. Minor adverse experiences were reported in 11 out of 20 patients during a migraine attack and in 11 out of 18 patients outside an attack. They occurred shortly following drug administration and were of short duration, but their occurrence did not appear to be related to plasma 311C90 concentration. There were no clinically significant changes in blood pressure or 12-lead ECG during the assessment period.     

Plasma calcitonin gene-related peptide in diagnosing and predicting paediatric migraine

To investigate the role of plasma calcitonin gene-related peptide (CGRP) in paediatric migraine, we prospectively collected 134 blood samples during or between attacks from 66 migraine, 33 non-migraine headache (non-migraine) and 22 non-headache patients, aged 4–18 years. Plasma CGRP concentrations were measured by enzyme-linked immunosorbent assay and disability by Pediatric MIgraine Disability ASsessment (PedMIDAS) questionnaire. Migraineurs had higher plasma CGRP levels than non-migraine patients ( P  = 0.007). The attack level was higher than the non-attack level in migraine ( P  = 0.036), but not in non-migraine, patients. This was also revealed in paired comparison ( n  = 9, P  = 0.015 vs. n  = 4, P  = 0.47). Using a threshold of 55.1 pg/ml, the sensitivity of the attack level in predicting migraine was 0.81, and specificity 0.75. The PedMIDAS score tended to be higher in the high CGRP (> 200 pg/ml, n  = 7) group than in the low (< 200 pg/ml, n  = 33) group (26.07 vs. 19.32, P  = 0.16) using Mann–Whitney test. Plasma CGRP is useful for diagnosis in paediatric migraine.     

Plasma changes of calcitonin gene-related peptide and substance P in patients with dialysis headache

Little is known of mechanism of dialysis headache (DH). As suggested for migraine, a role for neuropeptides has been investigated. Twenty-four patients under haemodialysis were studied. Twelve of them suffered from DH. The remaining patients were headache free. Blood samples for radioimmunoassay of calcitonin gene-related peptide (CGRP) and substance P (SP) were collected from the arteriovenous fistula before and after dialysis treatment. Basal plasma concentrations of CGRP were found to be higher in headache patients. Dialysis significantly decreased CGRP concentrations in both groups. No difference in basal plasma concentrations of SP was observed between groups. At the end of the treatment plasma SP concentrations were reduced in headache-free patients but increased in headache patients. Elevated plasma concentrations of CGRP in patients with DH could represent a biochemical factor contributing to susceptibility to headache. Because of the disputable role of SP in migraine, the significance of the increase of the peptide in plasma during DH remains to be elucidated.     

Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache

OBJECTIVE: To determine the effectiveness and tolerability of intravenous valproate for the acute treatment of migraine headache with or without aura (International Headache Society diagnostic criteria 1.1 and 1.2) compared with intramuscular metoclopramide 10 mg followed 10 minutes later by intramuscular dihydroergotamine 1 mg. BACKGROUND: Divalproex sodium is approved for prophylaxis of migraine headache. We studied the possible effectiveness of intravenous sodium valproate for the treatment of acute migraine headache. Valproate offers a treatment option for patients with migraine who recently have used a triptan or dihydroergotamine, theoretically avoiding the risk of drug interactions or cardiovascular complications. DESIGN/METHODS: In an open-label randomization, patients with an established diagnosis of migraine with or without aura were administered either intravenous valproate or intramuscular dihydroergotamine with metoclopramide to treat moderate-to-severe migraine headache of 24 to 96 hours' duration. Forty patients alternately received either 500 mg intravenous valproate or 10 mg metoclopramide intramuscularly followed by 1 mg dihydro- ergotamine. Patients rated severity of headache and the presence or absence of nausea, photophobia, or phonophobia at baseline, and at 1, 2, 4, and 24 hours. RESULTS: With intravenous valproate, 50% of patients reported headache improvement from moderate or severe to none or mild at 1 hour following treatment, 60% reported such improvement at 2 hours, 60% at 4 hours, and 60% at 24 hours. Corresponding improvement rates for dihydroergotamine were 45% at 1 hour, 50% at 2 hours, 60% at 4 hours, and 90% at 24 hours. Intravenous valproate and intramuscular dihydroergotamine provided similar relief from associated migrainous symptoms (nausea, photophobia, and phonophobia) during the first 4 hours following treatment. While none of the patients who received intravenous valproate experienced drug-related side effects during treatment, 15% of patients who took dihydroergotamine experienced one or more episodes of nausea and diarrhea during the first 4 hours of treatment. CONCLUSIONS: Intravenous valproate is similar in effectiveness to dihydroergotamine/metoclopramide as abortive therapy for prolonged moderate-to-severe acute migraine headache. Although the results were not statistically significant (P =.3635), intravenous valproate appears to offer a safe, effective, and well-tolerated treatment for patients with acute migraine. Relative to dihydroergotamine/metoclopramide, however, headache relief was not as likely to be sustained at 24 hours as with intravenous valproate.     

Endothelin in migraine patients

Endothelins (ETs) are the most potent vasoconstrictors known, and may be the mediators of the vasoconstrictive phase in migraine attacks. We studied 31 previously selected migraine patients with (9) and without (22) aura ictally and interictally to determine their plasma ET-1 values, The mean interictal and ictal values were 5.3 pg/ml (SD 1.8) and 6.4 pg/ml (SD 3.9), respectively. The ictal values were markedly elevated at the beginning of the migraine attack (<2 h) and declined to interictal or even lower level later (4 to 6 h) in the course of an attack. The local vasoconstriction at the beginning of a migraine attack might be ET-mediated secondarily to serotonin activation.     

Treatment of migraine attacks with intranasal alniditan:an open study

In this open phase-II clinical tolerability trial 17 neurologists enrolled a total of 112 patients and instructed them to administer a maximum of two doses of intranasal alniditan, a 5-HT1B/D receptor agonist, for the treatment of three consecutive migraine attacks of moderate to severe intensity. A second dose of the trial medication was allowed within 1-24 h after the first administration. At 1 h after intranasal administration, 70/103 (68%) patients had responded to treatment (reduction from severe or moderate headache before treatment to mild or no headache) after their first migraine attack, 65/94 (69%) after their second and 52/75 (71%) after their third. In 187/270 (69%) of all attacks, patients were considered responders at 1 h. The median time to onset of effect was 30 min. The migraine headache recurred in 44% (attack 1), 55% (attack 2) and 44% (attack 3) after 4-5 h. Sixty-eight per cent of the patients reported nasal irritation, 19% taste disturbance and 44% throat irritation. Alniditan 2 mg, administered via the intranasal route, was effective in relieving migraine headaches in over two-thirds of the patients at 1 h.     

Rizatriptan combined with rofecoxib vs. rizatriptan for the acute treatment of migraine: an open label pilot study

Rizatriptan is an effective and fast acting drug for the acute treatment of migraine. As with any other acute treatment for migraine, headache recurrence may occur in up to one-third of responders. Combination with non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the incidence of headache recurrence in clinical practice. Rofecoxib is a member of a new class of NSAIDs, which selectively inhibits the COX-2 enzyme and therefore is associated with a lower risk of gastrointestinal side-effects; the drug has a long plasma half-life (17 h). This open label study compared rizatriptan with rizatriptan plus rofecoxib in the acute treatment of migraine. Fifty-six triptan naive patients from a tertiary centre (37 women and 19 men, ages 16-55 years, mean 35 years) with International Headache Society migraine were randomized into two groups. They were instructed to treat three consecutive moderate or severe attacks with either 10 mg rizatriptan (group 1: 18 women and 10 men) or with 10 mg rizatriptan plus 25 mg rofecoxib (group 2: 19 women and 9 men). The presence of headache and nausea at 1, 2 and 4 h, and of side-effects, use of rescue medication and recurrence were compared. Fifty-four patients completed the study. Group 1 treated 76 attacks and group 2 treated 81 attacks. Absence of headache at 1 h was seen in 19 attacks (25%) in group 1 and in 34 attacks (42%) in group 2 (P=0.082); at 2 h absence of headache was seen in 60% of group 1 attacks and in 76% of group 2 attacks (P=0.115). At 4 h, 75% of group 1 attacks and 88% of group 2 attacks were pain free (P=0.122). With regard to nausea, of those who had nausea at baseline, 31% and 49% of attacks in groups 1 and 2, respectively, were nausea free at 1 h (P=0.091), 75% and 79% at 2 h (P=0.736) and 82% and 91% (P=0.479) at 4 h. Recurrence, based on all attacks of those patients who achieved pain free at 4 h, was observed in 53% of group 1 and 20% of group 2 attacks (P<0.001). Sustained pain-free rates (for the 4-h time point) were 45.6% of group 1 and 78.9% of group 2 attacks. There were no significant differences with regard to rescue medication consumption after 4 h and side-effects in both groups. There was a non-significant trend for the combination group to have a higher response rate. The group treated with rizatriptan and rofecoxib had a lower recurrence rate than the group treated with rizatriptan. This study demonstrated that combining a fast acting triptan such as rizatriptan with rofecoxib reduced headache recurrence rates, was well tolerated and may be more effective than the use of rizatriptan alone. Double-blind, placebo-controlled studies are necessary to confirm these observations.     

Meta-analysis of rizatriptan efficacy in randomized controlled clinical trials

Data from seven randomized, placebo-controlled, double-blind phase III clinical trials were analysed to further evaluate the efficacy of rizatriptan 10 mg (n = 2068) in comparison with placebo (n = 1260) and rizatriptan 5 mg (n = 1486) for the acute treatment of a migraine attack. Migraine was diagnosed according to International Headache Society criteria. Headache severity, associated migraine symptoms and functional disability were measured immediately before dosing and at 0.5, 1, 1.5 and 2 h. Headache recurrence (return of moderate or severe headache after an initial response) was also recorded. In addition to conventional pain relief (reduction of moderate or severe headache to mild or none) and pain free measures, the analysis looked at the elimination of associated migraine symptoms and disability in patients who had symptoms or disability at baseline. Maintenance of pain relief or pain-free status over 24 h was also analysed. At 2 h, rizatriptan 10 mg was significantly more effective than placebo for pain relief (71% vs. 38%, P < 0.001), and for elimination of pain, nausea, photophobia, phonophobia and functional disability. The benefit was maintained over 24 h; 37% of patients on rizatriptan 10 mg had sustained pain relief vs. 18% for placebo (P < 0.001). Rizatriptan 10 mg was also more effective than rizatriptan 5 mg, with a significant superiority at 2 h on all measures except for elimination of nausea. The benefit was maintained over 24 h; 38% of patients on rizatriptan 10 mg had sustained pain relief vs. 32% for rizatriptan 5 mg (P = 0.001).     

Oral sumatriptan in the acute treatment of migraine and migraine recurrence in general practice

We investigated the efficacy, safety and tolerability compared with placebo of a second dose of oral sumatriptan 100 mg in 1349 general practice patients who had already treated a moderate or severe migraine headache with 100 mg sumatriptan 4 h earlier. Headache was relieved by the first sumatriptan dose in about 70% of patients, but the second dose did not produce significantly more relief than placebo, either in nonresponders or in the group as a whole, nor did it reduce other symptoms (photophobia, nausea, vomiting, etc,) at 8 h, or influence the incidence of headache recurrence. The drug was well-tolerated, and a further single dose was effective in treating recurrence after initial relief. A single 100 mg dose of sumatriptan is an effective acute treatment for migraine. A second dose should be reserved for treating headache recurrence.      

Clinical use of copeptin in migraine patients admitted to the emergency department

PurposeThe purpose of this study was to investigate the clinical use of copeptin to evaluate migraine attacks in the Emergency Department. An additional aim was to detect changes in serum copeptin levels in migraine patients during attack and attack-free periods.MethodsThis prospective case–control study included 52 migraine patients and 51 healthy individuals with similar demographic characteristics. Blood samples were collected from migraine patients both in attack and attack-free periods.ResultsThe mean copeptin levels in the patients group in the attack and attack-free periods were 689.28 and 576.68 pg/ml, respectively, whereas they were 608.68 pg/ml in the control group. There was a significant difference in the mean copeptin level in the attack period and attack-free periods (p = 0.026). The sensitivity and specificity of copeptin in detecting headache episodes in migraine patients were 58.8% and 60.7%, respectively, at a cut-off value of 388.67 pg/ml.ConclusionThis is the first study to investigate the diagnostic efficacy of serum copeptin levels in migraine patients. Although the diagnostic efficacy of serum copeptin levels for migraines was unsatisfactory, it could be helpful at management of migraine patients in ED.     

Self-treatment of acute migraine with subcutaneous sumatriptan using an auto-injector device: comparison with customary treatment in an open, longitudinal study

In a multicenter open longitudinal clinical trial where 479 patients suffering from migraine with or without aura were recruited, patients treated at home one to three migraine attacks with their customary treatment, and subsequently, over a 3-month period, one to three migraine attacks with (5 mg sumatriptan sc using an auto-injector. The headache response to customary treatment was 19% at 1 h and 30.5% at 2 h, and was not significantly different when only attacks treated "adequately" according to accepted treatment recommendations were considered: 16% at 1 h and 35% at 2 h. In contrast, 69% and 82% of patients treated with 6 mg sumatriptan sc had mild headache or no headache at 1 and 2 h respectively, regardless of migraine type or duration of symptoms prior to treatment. Other migraine symptoms (nausea, vomiting, photo- and phonophobia) were effectively treated with sumatriptan. Recurrence of migraine was observed in 31% of patients and was well controlled by a second injection of sumatriptan. It is concluded that 6 mg sumatriptan sc, self-administered using an auto-injector, is well tolerated and more effective than most currently used acute treatments for migraine in a population of severely affected patients consulting a neurologist.     

Interleukin-6, gamma interferon, and tumor necrosis factor receptors in typhoid fever related to outcome of antimicrobial therapy.

To study mechanisms of antibiotic effects in typhoid fever, levels of interleukin-6 (IL-6), gamma interferon (IFN-gamma), and cytokine receptors (tumor necrosis factor receptor [TNF-R] p55 and TNF-R p75) were measured in the plasma of 29 adult Nepalese with culture-positive typhoid fever before therapy and on days 4 and 15 after start of therapy with either ceftriaxone at 2 g/day for 3 days or chloramphenicol at 50 mg/kg of body weight per day for 14 days. Bacteriologic cure was defined as blood cultures testing negative on days 4 and 15 after start of therapy; clinical cure was defined as symptomatic improvement within 5 days after start of therapy and absence of relapse. Clinical and bacteriologic cures occurred in 24 patients. There were two clinical failures, two patients who failed to complete therapy because of leukopenia, and one relapse. Mean levels before therapy were elevated compared with those in healthy controls (IL-6, 11.4 pg/ml; IFN-gamma, 1.3 ng/ml; TNF-R p55, 3.8 ng/ml; and TNF-R p75, 6.1 ng/ml) and fell progressively during and after therapy. For six patients (three in each treatment group) who showed prolonged fever (> 5 days) or relapse, mean levels of IL-6 and TNF-R p55 before therapy (29.5 pg/ml and 6.1 ng/ml, respectively) and on day 4 (17.7 pg/ml and 4.0 ng/ml) were significantly greater than corresponding means for 23 patients who showed early defervescence (on admission, 6.7 pg/ml and 3.3 ng/ml, and on day 4, 1.8 pg/ml and 2.7 ng/ml, P < .05). These results indicate that the concentrations of plasma cytokines and their receptors are elevated in typhoid fever and that these concentrations can be useful in predicting outcome.     

Tonabersat, a gap-junction modulator: efficacy and safety in two randomized, placebo-controlled, dose-ranging studies of acute migraine

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.     

Platelet activation in muscle contraction headache and migraine

In migraine, the role of platelets is regarded as an important factor. We investigated plasma beta-thromboglobulin (BTG), platelet factor 4 (PF4), and 5-hydroxytryptamine (5-HT) in migraine patients and muscle contraction headache (MCH) patients during headache-free periods. The mean values of the plasma BTG, PF4, and 5-HT concentrations in the migraine group and the MCH group were significantly higher than those in healthy controls. The mean value of the plasma BTG concentration was significantly higher in the migraine group than in the MCH group, but the differences in the mean plasma PF4 and 5-HT concentrations between the two groups were not significant. Continuous platelet activation exists in both MCH patients and migraine patients. From the biochemical point of view, we have provided evidence for a similarity between migraine and MCH.     

A chronobiological study of melatonin, cortisol growth hormone and prolactin secretion in cluster headache

The temporal organization of plasma melatonin. cortisol. growth hormone (GH) and prolactin secretion was examined in healthy rested controls and in patients suffering from episodic cluster headache. Eleven patients with typical cluster headache (10 men, 1 female) and 8 male controls were studied over a 24-h period: blood was collected at 2-h intervals during the day and at l-h intervals at night. Plasma melatonin. cortisol, GH and prolactin levels were determined by radioimmunoassay. Most of the cluster headache patients showed a decrease in nocturnal melatonin secretion and the melatonin rhythm was even completely abolished in one patient. Chronobiological analysis of the cluster headache patients' 24-h plasma melatonin profile showed a significant decrease in amplitude and mesor: these were 58.7 pg/ml and 34.4 pg/ml respectively in control subjects, versus 18.7 pg/ml and 17.6 pg/ml for the patients. In addition. patients showed a significant phase-advance in their melatonin rhythm For cortisol, the rhythm appeared slightly blunted in the cluster headache group and was significantly phase-advanced. The plasma prolactin profile showed no significant alteration, but for plasma GH the nocturnal peak was advanced in some patients: in the absence of sleep recording, however, no conclusion could be drawn. Results from this study suggest a neuroendocrine dysregulation in cluster headache in the endogenous clock which controls the pineal rhythmicity.     

Effectiveness of Subcutaneous Dihydroergotamine by Home Injection for Migraine

The effectiveness of dihydroergotamine administered by home subcutaneous injection by the patient or family for severe headache attacks was assessed retrospectively in 51 patients. Average follow-up was 21 weeks. Twenty-one patients had intermittent migraine attacks, 27 had transformed migraine with chronic daily headache, and 3 had chronic tension-type headache. Of the 51 patients taught home injection, 35% had an excellent overall response 18% had a good response, 12% had a poor response but continued to use dihydroergotamine, and 35% had discontinued dihydroergotamine use. Side effects were the main reason for stopping dihydroergotamine. These included nausea or vomiting or both, limb pain or numbness or both, chest or throat tightness or both, and soreness at the injection site. Thirty-three patients (65%) continued to use dihydroergotamine at the end of the follow-up period. In patients who previously required injections from medical personnel for headache crises and in whom home injection of dihydroergotamine was effective, a dramatic reduction occurred in hospital emergency room and physician office utilization. Dihydroergotamine use by home injection can be an effective treatment for a significant proportion of patients with severe migraine including patients with transformed migraine and medication overuse.     

Increased plasma histamine levels in uraemic pruritus

1. We determined plasma levels of histamine in uraemic patients and examined their correlation with the presence of pruritus. 2. In 27 patients with chronic renal failure, plasma histamine levels were analysed by radioimmunoassay and were compared with those of 40 healthy adult subjects. The control population showed plasma histamine concentrations of 185 +/- 33 pg/ml, which were significantly lower than those of the patients with renal insufficiency. The highest levels (552 +/- 116 pg of histamine/ml) were found in 16 patients with chronic renal failure (mean serum creatinine 5.1 +/- 1.0 mg/dl) and severe itching. 3. Twelve patients with pronounced pruritus who were on maintenance haemodialysis (serum creatinine 9.2 +/- 1.2 mg/dl) had a mean plasma histamine concentration of 515 +/- 81 pg/ml. Fifteen patients on regular haemodialysis (serum creatinine 9.0 +/- 1.5 mg/dl) and who experienced itching had plasma histamine levels (322 +/- 40 pg/ml) which were significantly lower (P less than 0.01) than those of the patients with pruritus but which were elevated compared with those of the control population (P less than 0.01). 4. No correlation could be found between increased plasma histamine levels and the type of dialysis membrane used or the method of sterilization of the membrane. 5. Haemodialysis alone did not reduce plasma histamine concentrations, although high concentrations could be detected in the ultrafiltrate. In six patients a rapid decrease in plasma histamine concentration from 565 +/- 134 pg/ml to within the normal range could be detected after 60 min of combined haemodialysis and haemoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Twelve-month tolerability and efficacy study of NP101, the sumatriptan iontophoretic transdermal system

Objective.— To assess the long‐term tolerability and efficacy of NP101, a novel transdermal sumatriptan patch being developed for the acute treatment of migraine. Background.— Nausea (with or without vomiting) and gastroparesis have been characterized as being among the most problematic challenges affecting migraine care today. Migraine‐associated nausea can cause patients to delay or avoid taking oral medication with a resultant loss or reduction of therapeutic efficacy. Migraine‐associated gastroparesis can impair absorption and reduce bioavailability of oral migraine medications and thereby reduce and delay therapeutic efficacy. The non‐oral triptan formulations that have been used to overcome these challenges are associated with other shortcomings that can limit their use. Designed to overcome these shortcomings and treatment limitations imposed by gastrointestinal signs and symptoms, the NP101 patch avoids the need for oral administration, does not depend upon gastrointestinal absorption, and provides more consistent, predictable plasma concentrations than oral and intranasal formulations of sumatriptan and a lower maximum plasma concentration than sumatriptan injection. Methods.— Patients diagnosed with migraine who had participated in a randomized, double‐blind, Phase III study of the NP101 patch were given the option to use NP101 to treat migraine episodes with moderate or severe headache pain for up to 12 months in this open‐label trial. Results.— One hundred eighty‐three patients applied 2089 study patches. The most common adverse events involved the patch application site (45% of patients). The only non‐application‐site adverse events reported in >2% of patients were nausea (n = 6, 3.3%), upper respiratory tract infection (n = 6, 3.3%), and nasopharyngitis (n = 4, 2.2%). The incidence of triptan‐associated adverse events was 1.6%. Across all visits for investigator assessments, the majority of patients (ranging from 74.7% at Month 1 to 92.2% at Month 9) were scored as having no erythema at patch application sites. For patient assessments, the percentage of patch placement sites scored as having no or minimal redness was 38.2% at the time of patch removal and 65.4% 24 hours after patch activation. Two hours after patch activation across all patch treatments over the 12‐month study, 23.8% of initial acute migraine episodes were scored as being free from headache pain, 58.2% as having headache pain relief,78.9% as nausea free, 60.1% as phonophobia free, 53.4% as photophobia free, and 20.7% as migraine free. No evidence of waning tolerability or efficacy was observed over the 12‐month study period. Conclusion.— NP101, a transdermal sumatriptan formulation in development for the acute treatment of migraine, demonstrated tolerability and efficacy with successive uses over 12 months in this clinical trial.