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Purpose To compare the efficacy of intravenous (IV) iron (ferric derisomaltose) with oral iron (ferrous fumarate) in women 14–21 weeks pregnant with persistent iron deficiency (ferritin Methods In a single-centre, open-label, randomised controlled trial at a Danish hospital, women with persistent iron deficiency after routine oral iron treatment were allocated to receive 1000 mg IV iron (single-dose) or 100 mg elemental oral iron daily. Outcomes were assessed during an 18-week follow-up period. The primary endpoint was the proportion of non-anaemic (haemoglobin [Hb] ≥ 11 g/dL) women throughout follow-up. Other outcomes included changes in haematological parameters, patient-reported fatigue, and quality of life (QoL). Safety was assessed by recording adverse events. Results From July 2017 to February 2020, 100 women were randomised to IV iron and 101 to oral iron. Throughout follow-up, 91% of women were non-anaemic in the IV iron group compared with 73% in the oral iron group (18% difference [95% confidence interval 0.10–0.25]; p p p p = 0.01). Improvements in fatigue and QoL were greater with IV iron versus oral iron at Weeks 3 and 6. The incidence of treatment-related adverse events was comparable between treatment groups. Conclusion IV iron was superior in preventing anaemia compared with oral iron in pregnant women with persistent iron deficiency; biochemical superiority was accompanied by improved fatigue and QoL. Clinical trial registration European Clinical Trials Database: EudraCT no.: 2017-000776-29 (3 May 2017); ClinicalTrials.gov: NCT03188445 (13 June 2017). The trial protocol has been published: https://dx.doi.org/10.1186%2Fs13063-020-04637-z.

BACKGROUND This trial evaluated the efficacy and safety of intravenous (IV) iron isomaltoside (Monofer) in comparison with placebo in first-time female blood donors. STUDY DESIGN AND METHODS The trial was a prospective, double blind, placebo-controlled, randomized, comparative, single-center trial of 85 first-time female blood donors. The subjects were randomly assigned 1:1 to either 1000 mg IV iron isomaltoside infusion or placebo. The primary endpoint of the trial was change in hemoglobin (Hb) from baseline to right before the third blood donation. RESULTS The increase in Hb was significantly higher for iron isomaltoside compared with placebo right before both the second blood donation (p = 0.0327) and the third blood donation (primary endpoint, p < 0.0001). Improvements in other iron-related variables (plasma iron, plasma ferritin, transferrin saturation, and reticulocyte count) in favor of iron isomaltoside were also observed. The trial was not powered on patient-reported outcomes. However, improvements in iron stores and Hb levels after iron isomaltoside administration were supported by the fact that several of the fatigue symptoms scores showed numerical differences in favor of iron isomaltoside. There were no differences in side effects between the groups. CONCLUSION In iron-deficient female blood donors a single IV iron isomaltoside administration resulted in an improvement in Hb concentration and iron stores and demonstrated a favorable safety profile comparable to placebo.

Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In early embryonic life, iron is already needed for proper development of the brain with the proliferation, migration, and differentiation of neuro-progenitor cells. This is underpinned by the widespread expression of transferrin receptors in the developing brain, which, in later life, is restricted to cells of the blood–brain and blood–cerebrospinal fluid barriers and neuronal cells, hence ensuring a sustained iron supply to the brain, even in the fully developed brain. In embryonic human life, iron deficiency is thought to result in a lower brain weight, with the impaired formation of myelin. Studies of fully developed infants that have experienced iron deficiency during development reveal the chronic and irreversible impairment of cognitive, memory, and motor skills, indicating widespread effects on the human brain. This review highlights the major findings of recent decades on the effects of gestational and lactational iron deficiency on the developing human brain. The findings are correlated to findings of experimental animals ranging from rodents to domestic pigs and non-human primates. The results point towards significant effects of iron deficiency on the developing brain. Evidence would be stronger with more studies addressing the human brain in real-time and the development of blood biomarkers of cerebral disturbance in iron deficiency. Cerebral iron deficiency is expected to be curable with iron substitution therapy, as the brain, privileged by the cerebral vascular transferrin receptor expression, is expected to facilitate iron extraction from the circulation and enable transport further into the brain.

Aim We compared the iron concentration in breast milk after a single high dose of intravenous iron isomaltoside or daily oral iron for postpartum haemorrhage. Methods In this randomised controlled trial, the women were allocated a single dose of intravenous 1200 mg iron isomaltoside or oral iron at a mean daily dose of 70.5 mg. We included 65 women with sufficient breast milk three days after inclusion – 30 from the intravenous iron group and 35 from the oral iron group – and collected breast milk and maternal blood samples three days and one week after allocation. Results The mean (±SD) iron concentration in breast milk in the intravenous and oral groups was 0.72 ± 0.27 and 0.40 ± 0.18 mg/L at three days (p < 0.001) and 0.47 ± 0.17 and 0.44 ± 0.25 mg/L after one week (p = 0.64). Baseline samples were not available that soon after birth. Conclusion A single high dose of intravenous iron isomaltoside for postpartum haemorrhage led to a transient increase in the iron concentration in breast milk three days after treatment compared with oral iron. The difference disappeared one week after treatment, and mean iron concentrations were within the normal range in all samples.

Background Iron deficiency is especially common in women during the reproductive age and it is estimated that 52% of pregnant women have iron deficiency anemia. Maternal iron deficiency with or without anemia in pregnancy may have consequences for the fetus, where it may have an impact on the cerebral development of the brain. Both animals and adult human studies support that iron deficiency affects psychomotor development, behavioral traits, and cognitive functions in the offspring. However, it has not yet been established whether the availability of sufficient iron is particularly important in certain phases during brain development, and whether possible damages are reversible if iron supplementation is provided during pregnancy. Here we report results from a pilot study in an experimental rat model suitable for introducing iron deficiency in the fetal rat brain. Methods The model was utilized for examination of the potential to reverse changes in fetal brain iron by maternal parenteral iron administration. Fertilized females subjected to iron deficiency without anemia were subcutaneously injected with iron isomaltoside at the day of mating (E0), 14 days into pregnancy (E14), or at the day of birth (Postnatal (P) 0). Blood, brain and liver in the offspring were examined on P0 or in adulthood on postnatal day P70. Results Maternal iron restriction during pregnancy led to significantly lower levels of iron in the brains of newborn rats compared to levels in pups of iron sufficient mothers. Females fed ID diet (5.2 mg/kg Fe) had offspring with significantly lower cerebral iron compared to a control group fed a standard diet (158 mg/kg Fe). Injection of IIM to pregnant ID females on E0 or E14 yielded normalization of Fe in the developing brain known to express elevated levels of capillary transferrin receptors, indicating that the administered iron passed the placenta and fetal blood brain barrier. Conclusions In future studies, this translational model may be applied to examine morphological and biochemical consequences of iron deficiency and iron deficiency treatment in the developing fetal brain.

Background and objectives: To explore if intravenous iron isomaltoside (Monofer®) leads to a better relief of fatigue than current treatment practice with oral iron in women suffering from severe f...

Cyclic nucleotides are important hemodynamic regulators in many tissues. Glyceryl trinitrate markedly dilates large cerebral arteries and increases cGMP. Here, the authors study the effect of sildenafil, a selective inhibitor of cGMP-hydrolyzing phosphodiesterase 5 on cerebral hemodynamics and headache induction. Ten healthy subjects were included in a double-blind, placebo-controlled crossover study where placebo or sildenafil 100 mg (highest therapeutic dose) were administered on two separate days. Blood velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler, and regional cerebral blood flow in the perfusion area of the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133xenon inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasound. Blood pressure and heart rate were recorded repeatedly. Headache responses and tenderness of pericranial muscles were scored verbally. Sildenafil caused no significant changes in rCBFmca, Vmca, or in temporal or radial artery diameter, but heart rate increased and diastolic blood pressure decreased significantly compared to placebo. Despite the lack of cerebral arterial dilatation, sildenafil caused significantly more headache than placebo. The present results show that sildenafil 100 mg does not dilate cerebral or extracerebral arteries but nevertheless causes headache, which may be attributed to nonvascular mechanisms.

Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine with aura. The clinical characteristics of FHM have been described previously in selected materials or case studies, but population-based studies are important in order to analyse the full spectrum of the disorder. The aim of the present study was to perform a systematic search for familial cases of migraine with an aura that included motor weakness in order to generate non-selected material of as many FHM cases as possible in the Danish population of 5.2 million inhabitants, and to compare this material with already available population-based clinical descriptions of migraine with typical aura (MA). Due to the rarity of FHM, traditional population-based methods were not feasible. Therefore, the search strategy employed a computer search of the National Patient Register, screening >27 000 case records from headache clinics and private neurologists, and advertisements. A total of 147 affected FHM patients from 44 families were identified. FHM patients most often had all four 'typical' aura symptoms (visual, sensory, aphasic and motor symptoms) and all had at least two of these aura symptoms during FHM attacks. The motor, sensory and visual aura symptoms were all similar in type to the motor, sensory and visual aura symptoms in MA, but FHM had a statistically significantly longer duration of the visual and sensory aura symptoms, and these and other aura symptoms often fulfilled the criteria of the International Headache Society for prolonged aura. In addition, 69% had basilar migraine (BM) symptoms during FHM attacks. The order of the aura symptoms was usually visual, followed by sensory, aphasic, motor and, lastly, basilar-type migraine symptoms. Headache was present in 99% of FHM patients during FHM attacks, whereas the aura symptoms more often occurred without headache in MA. Headache duration was significantly longer in FHM compared with MA. Based on these data, we suggest more precise diagnostic criteria for FHM and a more clear clinical distinction between FHM and BM. Our results have significant implications for case finding in genetic studies and for clinical migraine differential diagnosis.

The molecular mechanisms that underlie the primary headaches-migraine, cluster headache and tension-type headache-have not yet been clarified. On the basis of studies in headache induced by intravenous infusions of glyceryl trinitrate (an exogenous nitric oxide donor) and histamine (which liberates nitric oxide from vascular endothelium), it has been suggested that nitric oxide is a likely candidate responsible molecule. The present review deals with the biology of this small messenger molecule, and the updated scientific evidence that suggests a key role for this molecule in primary headaches. This evidence suggests that the release of nitric oxide from blood vessels, perivascular nerve endings or from brain tissue is an important molecular trigger mechanism in spontaneous headache pain. Pilot trials have shown efficacy of a nitric oxide synthase inhibitor in both migraine attacks and chronic tension-type headache. These observations suggest new approaches to the pharmacological treatment of headache.

Previous studies suggest that nitric oxide (NO) is involved in headaches induced by i.v. infusion of the vasodilator and NO donor glyceryl trinitrate (GTN) in healthy subjects. Extending these studies to sufferers of migraine without aura, it was found that migraineurs experienced a stronger headache than non-migraineurs. In addition, most migraineurs experienced a delayed migraine attack at variable times (mean 5.5 h) after GTN provocation. This biphasic headache response in migraineurs may be linked to hypersensitivity in the NO-cGMP pathway. Thus, compared to controls, migraineurs were found to be more sensitive to GTN-induced intracranial arterial dilatation, which is known to be mediated via liberation of NO and subsequent synthesis of cGMP Furthermore, histamine infusions in migraineurs induced headache responses and intracranial arterial responses resembling those induced by GTN in migraineurs. Histamine is known to liberate NO from the endothelium via stimulation of the H1 receptor, which is present in the large intracranial arteries in man. Because both immediate histamine-induced headache and intracranial arterial dilatation and delayed histamine-induced migraine are blocked by H1-receptor blockade, a likely common pathway for GTN and histamine-induced headaches/migraines and intracranial arterial responses may be via activation of the NO-cGMP pathway. The delay in the development of these experimental migraines may reflect activation of multiple physiological processes. The intracranial arteries of migraineurs were found supersensitive to the vasodilating effect of GTN (exogenous NO). This relates to clinical findings suggesting dilatation of the large intracranial arteries on the headache side during spontaneous migraine attacks. The function of arterial regulatory mechanisms involving NO in migraine was therefore studied. In peripheral arteries, no endothelial dysfunction of NO was found and cardiovascular and intracranial arterial sympathetic function was normal. A mild parasympathetic dysfunction may be involved and may, via denervation supersensitivity, be responsible for the observed supersensitivity to NO. Another possibility is that NO initiates a perivascular neurogenic inflammation with liberation of vasoactive peptides. NO also mediates a variety of other physiological phenomena. One of these, the pain-modulating effect observed in animals, was evaluated in a human study using GTN infusion and measurements of pain thresholds. No definite effects of GTN were demonstrated. The precise mechanisms involved in NO-triggered migraines and which part of the NO-activated cascade that is involved remain to be determined. The possibilities for pharmacological stimulation and/or inhibition of several steps of the NO-activated cascade increase rapidly and soon may be available for human studies.

Cerebrovascular reactivity during hypocapnia was tested in 20 migraineurs (8 with aura, 12 without aura) and 30 sexand age-matched healthy subjects, and during nitroglycerin-induced headache in 12 healthy subjects. Before and during hyperventilation, mean blood-flow velocity (Vmean) in the middle cerebral artery was measured with transcranial Doppler. In each subject a pCO2 reactivity index (RI) was calculated as DVmean/baseline Vmean)/ DpCO2. Interictally, patients with migraine with aura showed higher RI ( p < 0.05 ANOVA and multiple range test) than controls, whereas migraineurs without aura did not differ from healthy subjects. Ictal and interictal RIs were similar in 9 patients suffering from migraine without aura. No side-to-side differences were detected in RI. During nitroglycerin-induced headache, the RIs were no different from those recorded during migraine attacks and in non-nitroglycerin-provoked healthy controls (p < 0.05, ANOVA and multiple range test). The exaggerated response in migraine with aura might predispose for the characteristic changes in rCBF seen during attacks.

The molecular mechanisms of migraine pain remain to be determined. Our studies of glyceryl trinitrate (GTN)-induced and histamine-induced headaches have led us to propose that nitric oxide (NO) may be the causative molecule in migraine pain. We also propose that substances capable of inducing experimental vascular headache do so with NO as the common mediator. Finally, we suggest that drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. We believe these observations provide new insight into the mechanisms of vascular headache. The importance of NO as a potential initiator of the migraine attack indicates new directions for the pharmacological treatment of migraine and other vascular headaches.

The transcranial Doppler (TCD) and cardiovascular responses to established tests of autonomic function were studied in 50 migraineurs (23 of whom experienced aura and 27 who did not) and 30 healthy control subjects. In addition to the measurements outside attacks, 10 migraineurs were also tested during unilateral attacks of migraine without aura. Transcranial Doppler examinations of middle cerebral artery (MCA) blood velocity showed no differences between migraineurs and healthy subjects and no difference between migraineurs experiencing an attack and outside an attack when examined in response to a head-up tilt test, a cold-pressor test and a Valsalva manoeuvre. The cardiovascular reflexes in response to the Valsalva manoeuvre suggested a mild parasympathetic hypofunction in migraineurs, both those with and those without aura. On the basis of the present results and previous findings by others, we conclude that mild parasympathetic hypofunctioning with preserved sympathetic functioning is an established finding in migraine both with and without aura.

In recent years, an increasing volume of evidence has suggested that the small messenger molecule nitric oxide (NO) plays a pivotal role in migraine pain. This evidence is mainly based on experimental studies using 2 different human headache models — intravenous infusion of nitroglycerin (glyceryl trinitrate) [a donor of NO] and intravenous infusion of histamine (which probably activates endothelial NO formation). These models offer unique possibilities for the study of NO mechanisms in migraine. Data suggest that NO is involved in the aetiology of migraine, a finding that may open up a number of possibilities for future drug treatments of the disorder.

Nitric oxide (NO) may play a key role in migraine and other vascular headaches since glyceryl trinitrate (a donor of NO) and histamine (which probably activates endothelial NO formation) both cause a pulsating dose-dependent headache with several migrainous characteristics. At relatively high doses of glyceryl trinitrate, migraine sufferers develop stronger and more migraine-like headaches and more pronounced cerebral arterial dilatation than controls. After the infusion of glyceryl trinitrate, non-migraineurs remain headache-free while migraineurs develop a migraine-like attack. In this review, Jes Olesen, Lars Thomsen and Helle Iversen suggest that migraine may be caused by increased amounts and/or affinity of an enzyme in the NO-triggered cascade of reactions. NO may also be involved in the pathogenesis of other vascular headaches.

Migraine is considered a neurovascular disease involving dilatation of cerebral arteries. Nitric oxide (NO) donors induce dilatation of cerebral and extracranial arteries and migraine, but NO has several mechanisms of action in addition to its cyclic guanosine monophosphate (cGMP)‐mediated vasodilatation. We examined whether sildenafil (Viagra®), a selective inhibitor of cGMP‐hydrolysing phosphodiesterase 5 (PDE5), which acts exclusively by increasing cGMP, can induce migraine and dilatation of cerebral arteries. We included 12 patients with migraine without aura in this double‐blind, placebo‐controlled crossover study, in which placebo or sildenafil 100 mg was administered orally on two separate days. Blood flow velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler ultrasonography and regional cerebral blood flow in the territory of the middle cerebral artery (rCBFmca) was measured using SPECT (single photon emission computed tomography) and xenon 133 inhalation. Radial and temporal artery diameters were studied using high‐frequency ultrasonography. Headache response, tenderness of pericranial muscles, blood pressure and heart rate were measured repeatedly. We found that migraine attack was induced by sildenafil in 10 of 12 migraine patients and by placebo in two of 12 patients ( P = 0.01). Vmca ( P = 0.1) and rCBFmca ( P = 0.93) remained unchanged after sildenafil. Temporal ( P = 0.47) and radial ( P = 0.87) artery diameter and pericranial tenderness ( P = 0.16) were unaffected by sildenafil. Systolic and diastolic blood pressures were unchanged but heart rate increased from a mean of 62 ± 2 to 74 ± 3 beats/min ( P = 0.01) after sildenafil. Our results demonstrate that migraine may be induced via a cGMP‐dependent mechanism, and we show for the first time that this occurs without initial dilatation of the middle cerebral artery. We propose that triggering mechanisms may reside within the perivascular sensory nerve terminals or the brainstem. However, other sites of action may also be possible and future studies are needed to elucidate this. In the clinical use of sildenafil, patients who have migraine should be informed about the risk of migraine attacks.

Dipyridamole is used for secondary prophylaxis in ischemic stroke and as a vasodilator agent in myocardial scintigraphy. An important side effect to administering dipyridamole is headache. The aim of the current study was to investigate the effects of dipyridamole on cerebral blood flow, large artery diameter, and headache induction. Twelve healthy subjects were included in this single-blind placebo-controlled study in which placebo (0.9% NaCl) and dipyridamole 0.142 mg/kg·min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler and regional cerebral blood flow in the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133Xenon-inhalation. Blood pressure, heart rate, and pCO2 were measured repeatedly. Headache response was scored every 10 minutes on a verbal scale from 0 to 10 (10 = worst). Dipyridamole caused a decrease in pCO2 ( P < 0.001). pCO2 corrected rCBFmca was 41.7 ± 6.9 mL/100 g ·min after placebo versus 41.2 ± 6.9 after dipyridamole ( P ≥ 0.05). pCO2 corrected Vmca decreased 8.4% ± 11.7 ( P < 0.001) after dipyridamole, indicating a mean 5.6% ± 6.7 ( P = 0.005) relative increase of the arterial diameter. After dipyridamole the median peak headache score was 2 (range 0 to 7) compared with 0 (range 0 to 3) after placebo ( P = 0.02). Dilatation of the middle cerebral artery outlasted the headache response. In conclusion, dipyridamole causes a modest pCO2 independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.

Migraine attacks are known to involve alterations or even dysfunction in the regulation of tone in intra-and/or extra-cranial blood vessels (Iversen et al., 1990; Friberg et al., 1991; Olesen 1991; Thomsen et al., 1995). The nature of these alterations is not clearly established, and a number of candidate neurotransmitters have been discussed (Edvinsson et al. 1988). Some of these candidates have their origin in sympathetic, parasympathetic, or sensory neurons; endothelial cells; mast cells; or on blood-borne cells. An increasing number of perivascular neurotransmitters have been detected, and their receptor mechanisms and effects have been elucidated during the last decades (Jansen-Olesen and Edvinsson, 1999). In addition, endothelium-derived relaxing factors (EDRFs) have been demonstrated; today these include nitric oxide (NO) prostaglandin I2 (PGI2) and endothelium-derived hyperpolarizing factor (EDHF).These agents are released following the stimulation of receptors located on endothelial cells or following shear-stress phenomena causing relaxation. Thus, a number of mechanisms exist for regulation of tone in cranial blood vessels. Neurogenic inflammation has been suggested as a mechanism of migraine (Moskowitz, 1993). It involves the liberation of several neuropeptides, primarily substance P (SP) and calcitonin-gene-related peptide (CGRP) (Buzzi and Moskowitz 1990). Unfortunately, neurogenic inflammation has never been shown to occur around cranial blood vessels during migraine attacks and the concentration of SP in external and internal jugular venous blood remains normal during migraine attacks (Goadsby et al., 1990; Friberg et al., 1994).

Evidence for the involvement of the cranial arterial system in migraine is plentiful, but it is unclear whether the cranial venous system may be involved in the mechanism of migraine pain. Venules are the preferentially involved vessels in the neurogenic inflammation animal model of migraine. The cranial and cerebral veins and sinuses are pain sensitive and receive sensory innervation from the trigeminal nerve. If the veins are involved in migraine pathogenesis, a venous dilatation would presumably be painful. The effect of a short lasting cranial venous dilatation, induced by applying pressure on the internal jugular veins (Queckenstedt's manoeuvre), was therefore compared with a placebo procedure, consisting of an equal pressure applied on to the lateral aspect of the neck. In each procedure pressure was applied for 10 seconds. The study used a single blind, randomised, cross over design, and 20 patients with an acute attack of migraine without aura participated. After each procedure, headache intensity was rated on a standardised five point scale. After Queckenstedt's manoeuvre 40% of the patients reported no change in headache intensity, 25% a worsening, and 35% an improvement of their headache. No significant difference between the headache intensity ratings during Queckenstedt's manoeuvre and the placebo manoeuvre was found (p=0.22). The findings make it unlikely that the cephalic venous system is of major importance in migraine pain mechanisms and, therefore, also less likely that neurogenic inflammation plays a significant part in humans during attacks of migraine without aura.

Kim Nordfjeld, Hans Andreasen, Lars L ThomsenPharmacosmos A/S, Holbaek, DenmarkBackground: Iron isomaltoside 1000 is a novel injectable iron compound which offers potential advantages in the treatment of subjects with iron-deficiency anemia. We studied the pharmacokinetics (PK) of this novel compound in subjects with mild-to-moderate inflammatory bowel disease (IBD).Methods: This open-label, crossover, single-center trial was conducted in 12 subjects with IBD who were allocated to one of the two single intravenous (IV) bolus sequences of iron isomaltoside 1000: 100 mg followed by 200 mg, or vice-versa. PK variables were analyzed according to a single-compartment model.Results: The concentration-versus-time relationship for isomaltoside-bound iron (IBI) and total iron (TI) showed first-order kinetics with small deviations from dose-linearity. The area under the concentration-time curve (AUC) values in h * µg/mL for IBI following 100 mg and 200 mg doses were 888 and 2141 respectively, and for TI following 100 mg and 200 mg doses, the AUC values were 1010 and 2319 respectively. The corresponding maximum serum concentration (Cmax) values in µg/mL were 35.6 and 68.6 for IBI, and 37.3 and 71.1 for TI. The half-life (T½) values for IBI and TI were between 20.8–23.5 hours. The apparent volume of distribution (VD) ranged from 3.0–3.5 L. Only approximately 1% of the doses administered were excreted in the urine. No serious adverse event (SAE) was reported. One subject was withdrawn after the 100 mg dose due to abdominal pain and flushing.Conclusion: At the administered doses, iron isomaltoside 1000 showed first-order PK, and did not raise safety concerns in patients with IBD. The PK parameters for IBI were close to those of TI.Keywords: inflammatory bowel disease, iron deficiency anemia, iron treatment, iron isomaltoside, pharmacokinetics

The sensitivity to nitroglycerin-induced dilatation of large intracranial arteries was studied in 17 patients with migraine without aura, 17 age and sex-matched healthy subjects and 9 patients with episodic tension-type headache. Nitroglycerin in the doses of 0.015, 0.03, 0.25 and 0.5 μg/kg/min was successively infused for 15 min per dose. Blood velocity (Vmean) in the middle cerebral artery (MCA) was recorded with transcranial Doppler before and at the end of every infusion period, and 30 and 60 min after end of the last infusion. In all three groups Vmean decreased with increasing doses ( p < 0.001). The response was more pronounced in migraine patients at the two higher doses ( p < 0.05). Since nitroglycerin acts as an exogenous source of nitric oxide (NO), these data support that NO supersensitivity may be an important molecular mechanism of migraine pain.

A new transcranial Doppler system (3-D Transscan, Eden Medizinische Elektronik) was evaluated in relation to sex, age, intersubject, interobserver, side-to-side, and day-to-day variation. Fifty-eight healthy volunteers participated (aged 18–80 yr). Mean velocity was higher in females than in males and decreased with age. The coefficient of variation in the middle cerebral artery was 26% between subjects, 20% between sides, 16% between days, 13% between observers, and 7% during 5 min. The coefficient of variation was higher in the anterior and posterior cerebral arteries. Bruits were heard in 35 subjects, 24 females and 11 males (P = 0.002). When middle cerebral artery velocity was monitored, high- and low-frequency oscillations were found, with a mean frequency of 5 and 1.6/min, respectively. These variations underline the necessity of standardized conditions and very carefully matched control groups in studies using transcranial Doppler. This is especially important when expected changes are small and easy to overlook, as in studies of normal physiological responses and migraine.

In primates, histamine activates cerebral endothelial H1-receptors leading to formation of nitric oxide (NO). Twenty migraine patients received pretreatment with placebo or the histamine-H1-receptor antagonist, mepyramine, in a randomized, double blind fashion, followed in both groups by i.v. histamine (0.5 microgram kg-1 min-1 for 20 min). Headache characteristics were subsequently observed for 12 h. In patients given placebo histamine caused immediate headache during the infusion followed by a delayed migraine attack fulfilling IHS criteria for migraine without aura. The temporal profile of induced headache was exactly the same as after glyceryl trinitrate. Mepyramine pretreatment abolished both immediate headache and delayed migraine attacks. Our results suggest that a migraine attack can be caused by NO formation in the endothelium of cerebral arteries.

Nitroglycerin, which may be regarded as a prodrug for nitric oxide, induces a mild to moderate headache in healthy subjects. In order to study whether migraine patients are more sensitive to nitric oxide than non-migrainous subjects, four different doses of intravenous nitroglycerin were given in a double blind design to 17 migraine patients, 17 age and sex matched healthy controls and 9 subjects with tension-type headache. The nitroglycerin-induced headache was significantly more severe in migraine sufferers, lasted longer and fulfilled diagnostic criteria for migraine more often. We have previously shown a similar supersensitivity to histamine which in human cerebral arteries activates endothelial H1 receptors and causes endothelial production of nitric oxide. Migraine patients are thus supersensitive to exogenous nitric oxide from nitroglycerin as well as to endothelially produced nitric oxide. It is suggested that nitric oxide may be partially or completely responsible for migraine pain.

Inhalation of hyperbaric oxygen has been used as an experimental treatment for migraine and pure oxygen is an established treatment for cluster headache. Intravenous glyceryl trinitrate (GTN) is an established headache model. In the present study the possibility of decreasing the headache by inhalation of pure oxygen was explored in a double-blind crossover design in 18 healthy subjects. Inhalation of air served as placebo. The subjects received intravenous GTN (0.25 microg/kg/min) for 20 min. Headache was scored for 85 min. Sixteen of 18 (89%) subjects experienced GTN-induced headache after O(2)-inhalation and 17/18 (94%) experienced GTN-induced headache after air. The mean peak headache scores were 1.9 and 2.4, respectively, on a numerical scale of 0-10. Oxygen inhalation did not have effect on GTN-induced headache, most likely because the theoretical decrease in NO levels, due to faster metabolism of NO, is too small to be detected in the GTN headache model.

Background Postpartum haemorrhage can lead to iron deficiency with and without anaemia, the clinical consequences of which include physical fatigue. Although oral iron is the standard treatment, it is often associated with gastrointestinal side effects and poor compliance. To date, no published randomised controlled studies have compared the clinical efficacy and safety of standard medical care with intravenous administration of iron supplementation after postpartum haemorrhage. The primary objective of this study is to compare the efficacy of an intravenous high single-dose of iron isomaltoside 1000 with standard medical care on physical fatigue in women with postpartum haemorrhage. Methods/Design In a single centre, open-labelled, randomised trial, women with postpartum haemorrhage exceeding 700 mL will be allocated to either a single dose of 1,200 mg of iron isomaltoside 1000 or standard medical care. Healthy parturients with a singleton pregnancy will be included within 48 hours after delivery. Participants will complete structured questionnaires that focus on several dimensions of fatigue and mental health (Multidimensional Fatigue Inventory, Edinburgh Postnatal Depression Scale and the Postpartum Questionnaire), at inclusion and at follow-up visits after three days, one week, three weeks, eight weeks, and 12 weeks postpartum. The primary endpoint is the aggregated change in physical fatigue score within 12 weeks postpartum, as measured by a subscale of the Multidimensional Fatigue Inventory. The primary objective will be considered to have been met if an intravenous high single dose of iron isomaltoside 1000 is shown to be superior to standard medical care in women after postpartum haemorrhage regarding physical fatigue. For claiming superiority, we set the minimal clinically relevant difference between the mean scores at 1.8, and the assumed standard deviation at 4.2. Hence, 87 participants per treatment group are needed in order to demonstrate superiority; to provide an extra margin for missing data and dropouts, 200 women will be included. Discussion The study will provide evidence on relevant clinical outcomes beyond biochemical parameters for intravenous iron isomaltoside 1000 compared to standard medical care in women after postpartum haemorrhage. Trial registration This trial is registered with Clinicaltrials.gov (identifier: NCT01895218) on 26 June 2013. Electronic supplementary material The online version of this article (doi:10.1186/1745-6215-16-5) contains supplementary material, which is available to authorized users.