Is oral absorption of vigabatrin carrier-mediated?

The aim of the study was to investigate the intestinal transport mechanisms responsible for vigabatrin absorption in rats by developing a population pharmacokinetic (PK) model of vigabatrin oral absorption. The PK model was used to investigate whether vigabatrin absorption was carrier-mediated and if the proton-coupled amino acid transporter 1 (PAT1) was involved in the absorption processes. Vigabatrin (0.3-300mg/kg) was administered orally or intravenously to Sprague Dawley rats in the absence or presence of PAT1-ligands l-proline, l-tryptophan or sarcosine. The PK profiles of vigabatrin were described by mechanistic non-linear mixed effects modelling, evaluating PAT1-ligands as covariates on the PK parameters with a full covariate modelling approach. The oral absorption of vigabatrin was adequately described by a Michaelis-Menten type saturable absorption. Using a Michaelis constant of 32.8mM, the model estimated a maximal oral absorption rate (Vmax) of 64.6mmol/min and dose-dependent bioavailability with a maximum of 60.9%. Bioavailability was 58.5-60.8% at 0.3-30mg/kg doses, but decreased to 46.8% at 300mg/kg. Changes in oral vigabatrin PK after co-administration with PAT1-ligands was explained by significant increases in the apparent Michaelis constant. Based on the mechanistic model, a high capacity low affinity carrier is proposed to be involved in intestinal vigabatrin absorption. PAT1-ligands increased the Michaelis constant of vigabatrin after oral co-administration indicating that this carrier could be PAT1.

Flow estimation using ultrasound imaging (color M-mode) and computer postprocessing.

We have developed a method to calculate flow noninvasively in blood vessels using color Motion-mode (M-mode) and computer postprocessing. The velocity of each point in the cross-sectional area of the vessel was found from the color M-mode recording by correcting for angle both distances and velocities and by assuming a symmetrical circular velocity field. Volume flow was then found by integrating the velocity field at 5-ms intervals through the cardiac cycle. In a cardiovascular hydromechanical model, a correlation of 0.99 and p value of less than 0.001 were found between estimated and measured flow in the model (n = 8). In 20 healthy individuals, we made 31 investigations in the common carotid (CCA), internal carotid (ICA), and external carotid (ECA) artery, comparing flow in the CCA with the added flow in the ICA and ECA. The values (CCA versus ICA + ECA) correlated with r = 0.91 and p less than 0.01. Repeated investigations (n = 8) in one individual gave flow estimates of 495 +/- 50 ml/min in the CCA, 304 +/- 45 ml/min in the ICA, and 165 +/- 37 ml/min in the ECA (means +/- SD). This article shows that this system can make accurate estimation of blood flow to the brain noninvasively.

Relaxation of human temporal artery by endothelin ETB receptors.

Endothelin receptors have been characterized in human temporal artery by molecular biological methods and in vitro pharmacology. Reverse transcriptase-polymerase chain reaction was used to detect mRNA encoding ETA and ETB receptors in normal and endothelium-denuded arteries. Vasomotor response experiments with a specific ETA antagonist (FR 139317) suggested the presence of ETA subtypes. Marked ETB-mediated relaxation was obtained with ET-3 when ETA activity was blocked in precontracted arteries. Relaxation was significantly reduced by bosentan, indomethacin, and a nitric oxide synthase inhibitor. It may be speculated that the relaxant activity is mediated through ETB1 receptors.

Interleukin-1beta potentiates endothelin ET(B) receptor-mediated contraction in cultured segments of human temporal artery.

Segments of human temporal artery were placed in organ culture for up to 4 days and examined for endothelin ET(B) receptor activity in the presence and absence of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) by in vitro pharmacology and reverse transcriptase-polymerase chain reaction (RT-PCR). The contractile effect of prostaglandin F2alpha (used as a reference), was not significantly altered by culture or IL-1beta. However, the selective ET(B) agonist sarafotoxin S6c induced no contraction in fresh arteries, but marked contraction after culture. Both maximal contraction and potency to sarafotoxin S6c were increased in segments incubated with IL-1beta . The contraction was sensitive to BQ 788 (ET(B) antagonist), but not FR 139317 (ET(A) antagonist). Actinomycin D abolished the contraction, whereas only the cytokine-induced increase in contraction was inhibited by cycloheximide. ET(A) and ET(B) receptor mRNAs were detected in all arteries; predominantly for the ET(A) receptor in fresh arteries, and for the ET(B) receptor after culture. However, there was no change in the ET(A)/ET(B) receptor mRNA ratio after treatment with IL-1beta. This suggests de novo synthesis of contractile ET(B) receptors after organ culture and that IL- 1beta may further stimulate translation of the mRNA to active receptors. The results raise the possibility that contractile ET(B) receptors may be implicated in disease states with inflammatory processes.

Mutual modification of vasoactivity by calcitonin gene-related peptide and endothelin-1 in isolated porcine ophthalmic artery.

Vasodilation has been implicated in the pathophysiology of some headaches, but the mechanisms behind such abnormalities remain unknown. Calcitonin gene related peptide (CGRP), a peptide present in sensory trigeminal fibres, induces strong and long lasting vasodilation in cranial vessels, and has been found to be increased in jugular blood during migraine attacks. Endothelin (ET) is a recently identified potent vasoconstrictor peptide, which also induces long-lasting responses. ET-CGRP interactions may be of importance in vascular beds putatively involved in pain development in the head, and were therefore studied in isolated porcine ophthalmic arteries. Both peptides were found to induce strong and long-lasting reactions in this artery. CGRP decreased ET-induced contractions and ET decreased CGRP-induced relaxations. These effects were additive rather than synergistic.

Cytokine enhancement of endothelin ET(B) receptor-mediated contraction in human temporal artery.

Segments of human temporal artery were incubated in organ culture for 2 days in the absence or presence of cytokines. Thereafter, contractions were induced by the selective endothelin ET(B) receptor agonist sarafotoxin S6c, a peptide that does not induce contraction in fresh human temporal artery. Interleukin-1beta was most potent in increasing the sarafotoxin-induced contraction in cultured segments. Tumour necrosis factor (TNF)-alpha increased the magnitude of contraction to a similar degree, but at a higher dose. A significant increase was also induced by interferon-gamma, but not by interleukin-6 at the concentrations used. The results suggest that endothelin ET(B) receptor-mediated contraction can be enhanced by pro-inflammatory cytokines in a concentration-dependent manner, and this may have relevance for pathophysiological conditions where inflammation and vasoactivity are important.

Calcitonin gene-related peptide (human alpha-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage.

Calcitonin gene-related peptide (CGRP) is a neuropeptide co-stored with tachykinins (substance P, neurokinin A) in cerebrovascular sensory fibers in the trigeminal ganglion. Preceding studies on subarachnoid hemorrhage (SAH) revealed that an enhanced release of CGRP resulted in the selective loss of perivascular CGRP. Therefore, the present study was designed to evaluate the effects of intravenous administration of human alpha-CGRP on cerebral vasoconstriction in the postoperative course after SAH in 5 patients (8 infusions). Cerebral vasoconstriction was evaluated with transcranial Doppler sonography. The increase in the relationship between middle cerebral artery (MCA) velocity and internal carotid artery (ICA) velocity (the hemodynamic index) was used as an indicator of vasoconstriction and compared to the contralateral side. A significant reduction was found in the hemodynamic index during the CGRP infusion (4.3 +/- 0.5, P < 0.05) as to compared to before infusion (6.2 +/- 0.5). There was no measurable change in the hemodynamic index on the contralateral side. No significant change was observed in pulsatility index, blood pressure or consciousness during the peptide infusion. A significant increase in heart rate was observed during the infusion as compared to before and after infusion (90 +/- 4 vs. 76 +/- 5). Cardiac ultrasound data indicated a mean cardiac output increase of 1.9 liter/min, and a mean decrease in total peripheral resistance of 538 dynes s/cm5. The results obtained show that infusion of human alpha-CGRP may induce normalisation of cerebrovascular tone in SAH.

Proton magnetic resonance spectroscopy of brain biopsies from patients with intractable epilepsy.

In the present study metabolite concentrations were determined by proton magnetic resonance spectroscopy (MRS) in biopsies obtained from patients suffering intractable epilepsy from several different causes. Seven patients had gliosis, four had mild cortical dysplasia, three had tuberous sclerosis, two had astrocytomas, and one had a cavernous angioma. No significant differences were found in gliotic tissue in comparison with controls except for an increase in lactate. However, in the subgroup with tuberous sclerosis an increase was found in GABA and a dramatic decrease in N-acetyl aspartate (NAA). The most marked changes were found in the group with mild cortical dysplasia. There was a considerable decrease in NAA as well as large increases in GABA, alanine, tyrosine, acetate, inositol, glucose and lactate. The GABA content did not appear to correlate with antiepileptic therapy. Moreover, since all these patients required surgery, an elevated GABA level does not necessarily provide protection from seizures. The results indicate that use of proton MRS could become a useful presurgical predictor of underlying pathology.

Prognosis in subarachnoid hemorrhage of unknown etiology.

Thirty-two patients with subarachnoid hemorrhage of unknown etiology were followed for periods from 1 to 6 1/2 years. Two more patients had normal initial angiograms, but were excluded when repeat angiography revealed an aneurysm. The mortality rate in this series was 6%. There was one possible early and no late episode of rebleeding. One patient developed epilepsy. Five patients developed communicating hydrocephalus and underwent a shunting procedure. A complete recovery was observed in 12 patients. An additional eight had minimal disability, seven were more severely disabled, and three patients were totally disabled. Antifibrinolytic treatment (tranexamic acid) was given in a nonstandardized regimen to 14 patients who showed a poorer result than did the 18 untreated patients.

Microdialysis in cisterna magna during cerebral air embolism in swine.

Arterial gas embolism may occur as a consequence of lung rupture, decompression sickness, following operative procedures or as accidental infusion of gas during various diagnostic procedures. It can lead to severe morbidity or even death. Microdialysis is a technique that has been extensively used for evaluating localized changes in the brain. The microdialysis probe is only capable of measuring changes in the immediate adjacent tissue. In arterial gas embolism the changes are multifocal. Thus a probe located in the cerebral cortex will not detect the total amount of damage. We used microdialysis in the cisterna magna of 9 anaesthetized pigs to study the diffuse injury following arterial gas embolism. After injection of 5.0 mL of air in the internal carotid artery, we found a significantly increased lactate-pyruvate ratio in the cerebrospinal fluid, lasting for 2 hours. This indicates anaerobic metabolism. Mean levels of glycerol were significantly increased, indicating membrane disruption. Glutamate levels were also elevated, although not significantly. The injection of air affected carotid flow. Flow in the carotid artery of the side of injection decreased significantly, but returned to baseline in 1 hour. Flow in the contralateral carotid was increased, but not significantly. We conclude that massive air embolism causes ischemia and reduced blood flow in the brain that can be detected in the cisterna magna.

Peptidergic innervation of the cerebral circulation. Role in subarachnoid hemorrhage in man.

The present paper reviews recent studies in monkey and man adding further to understanding of the role of perivascular peptides in the pathophysiology of subarachnoid haemorrhage. 1. The perivascular fibers, sympathetic fibers (storing noradrenaline, neuropeptide Y), parasympathetic fibers (storing acetylcholine, vasoactive intestinal peptide, peptide histidine methionine and neuropeptide Y) and sensory fibers (storing tachykinins, calcitonin gene-related peptide) were traced using True Blue in monkey. 2. Tracing studies of the monkey middle-cerebral artery (MCA) innervation confirmed earlier studies in rats and cats, with superior cervical and trigeminal ganglia as main immunostaining areas, and contralateral involvement in the superior cervical and trigeminal ganglia. Sphenopalatine immunostaining was scarce. 3. The release of neuropeptides in the external jugular vein in humans in the postoperative course after subarachnoid hemorrhage, using radioimmunoassay, was correlated to hemodynamical changes (vasoconstriction) monitored with Doppler ultrasound on middle cerebral (MCA) and internal carotid arteries (ICA)). 4. Neuropeptide Y-like immunoreactivity (NPY-LI) levels were increased compared to controls in patients with hemodynamic changes, and in some patients a relationship was found between velocities and NPY-LI. 5. Calcitonin gene-related peptide-LI levels were also increased in connection with vasospasm. In patients with MCA lesions a correlation of 0.61, p = 0.0002 was found between hemodynamic index (V MCA/V ICA) and CGRP-LI. The possible sympathetic and trigemino-cerebrovascular activation are discussed.

Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage.

INTRODUCTION--Cerebral blood vessels are innervated by sympathetic nerve fibres storing neuropeptide Y (NPY), parasympathetic nerves storing acetylcholine, vasoactive intestinal peptide (VIP) and sensory afferent fibres containing calcitonin gene-related peptide (CGRP), substance P (SP) and neurokinin A. In experimental studies on subarachnoid haemorrhage (SAH) there are indications that perivascular peptides are involved. In the present study we have in man measured the levels of NPY, VIP, SP and CGRP in brain vessels of patients that have suffered a fatal SAH and compared this with the levels encountered in subjects that died of an extracerebral cause. MATERIAL AND METHODS--Vessels from patients who have died from SAH or nonSAH were obtained during autopsy performed within 24 hrs after death. The peptides were extracted and fractionated with reversed phase liquid chromatography (HPLC). The levels of NPY, VIP, SP, and CGRP were measured with radioimmunoassay. Vasomotor responses of human cerebral arteries were performed using a sensitive in vitro system. RESULTS--Human cerebral vessels contained NPY, VIP, CGRP and SP which eluted at the same positions as the authentic peptides. The level of CGRP was significantly lower (p < 0.01) in arteries removed from SAH patients as compared to control subjects. The level of SP was not changed, if anything it tended to be increased after SAH. The levels of NPY and VIP were not significantly altered after SAH. In isolated brain vessels alpha-CGRP was a potent vasodilator of arteries precontracted with whole blood, prostaglandin F2 alpha or endothelin. It had a poor effect on vessels precontracted with 60 mM potassium. CONCLUSION--The evidence suggest that the trigemino-cerebrovascular system, storing CGRP and SP, is to a differential degree involved in the pathophysiology of SAH in man and supports the hypothesis of an exhaustion of CGRP as one important factor in the development of late spasm occurring after SAH.

Cluster headache: transcranial Doppler assessment of dynamic cerebral circulatory changes during hypocapnia and attack.

Transcranial Doppler ultrasound (TCD) investigations have been carried out in cluster headache patients (8 during remission and 6 during bout) and 14 healthy subjects, to assess cerebral vasomotor reactivity (VMR) to hypocapnia induced by voluntary hyperventilation. VMR was expressed as the relative change in blood flow velocity (V) (%) as a function of the reduction in end-tidal PCO2 (PETCO2) (kPa), i.e. V/P ETCO2. TCD with simultaneous PETCO2 monitoring, was also performed in 5 patients during spontaneous attacks. Prior to hyperventilation, there was bilaterally lower anterior cerebral artery velocity (VACA) during the bout than during remission (P < 0.05 on the symptomatic side), and also lower than in the controls. During remission, VACA was higher on the symptomatic side than on the other side (P < 0.05). ACA also showed a lower VMR during the bout than during remission, and it was also lower than in controls (bout vs. remission on the non-symptomatic side, P < 0.01; on the symptomatic side, P > 0.1). Approximately 30 minutes after the onset of attack, PETCO2 started to decrease gradually from 4.65 to 4.10 kPa in one patient with severe attack. The VACA decreased markedly and bilaterally already at an early stage of the attack, i.e. prior to the hyperventilation. Middle cerebral artery velocity tended to decrease 30 minutes after the onset of attack on the symptomatic side, and 50 minutes after onset on the non-symptomatic side. It is concluded that the vascular changes observed most likely are secondary phenomena during the cluster headache attack.

[Microsurgery in lumbar nucleus prolapse]. / Mikrokirurgi ved lumbale nukleusprolaps.

The article describes the cases of 83 patients with lumbar herniated discs operated by means of microsurgical technique since August 1987. In 69 patients the result was good and they had no symptoms. Ten patients had improved, but were not free of symptoms. Four patients had not improved. The time spent in hospital postoperatively varied from one to ten days, with a mean of five days. The mean period off work after operation was two months and three days. The method is an alternative to standard discectomy in patients with lateral herniated discs.

[Head injuries in sports--evaluation during admission, follow-up and routine check-ups]. / Hodeskader innen idrett--evaluering på skadestedet, oppfølging og kontrollrutiner.

The authors review head injuries during sport. Among 3,206 such injuries treated at the Regional Hospital, Trondheim, in the course of one year, 12% were injuries to head and face. Minor injuries are classified as. Mild (no amnesia or loss of consciousness), no symptoms, the activity can continue, but one week of rest is recommended. Moderate (amnesia or loss of consciousness < 1 min), medical examination, and two weeks of rest are recommended. Major (loss of consciousness < 5 min), CT scan and one month of rest are recommended. With repeated moderate or triple mild traumas, CT and the possible termination of the sporting season should be considered. Serious head injuries with intracranial pathology will generally disqualify the person from further elite competition. The possible consequences of repeated head injuries during football and other contact sports are stressed, and more regular use of neurophysiologic methods (EEG) and magnetic resonance (MR) in selected cases is recommended. The authors also point out the advantages of using helmets and protective gear, and the doctors' role in advocating such equipment.

Atrial natriuretic peptide-LI following subarachnoid haemorrhage in man.

Atrial natriuretic peptide-like immunoreactivity (ANP-LI) was measured in plasma from the external jugular vein (EJV) in the postoperative course of 11 patients with aneurysmal subarachnoid haemorrhage. Samples were taken on day, 1, 2, 3, 5, 7 and 9 after operation and ANP-LI levels were determined using radioimmunoassay. Ten healthy volunteers were investigated with one EJV plasma sample. Comparing the whole group of SAH patients with the control group, no significant differences in ANP-LI levels were found. In one patient very high ANP-LI levels were found together with high mean plasma sodium levels and high urine sodium excretion. This suggests that there is no general correlation between plasma ANP-LI and SAH; in occasional patients such a correlation may be secondary to changes in plasma sodium levels.

Cerebral haemodynamics during thoracic- and thoracoabdominal aortic aneurysm repair.

OBJECTIVE: To investigate cerebral haemodynamics during operations for thoracic and thoracoabdominal aortic aneurysms. DESIGN: Prospective clinical study. MATERIAL: 10 patients operated on consecutively with resection for thoracic (5) or thoracoabdominal aortic (5) aneurysms. METHODS: Blood flow velocity of the middle cerebral artery was measured through a temporal approach using a TC Doppler with a 2 MHz probe. Recordings were made during induction of anaesthesia and performed continuously before, during and after cross-clamping of the aorta. RESULTS: Following 10 min. of aortic cross-clamping blood flow velocity of the middle cerebral artery increased from 44 to 55 cm/s (p < 0.01). A further increase to 69 cm/s (p < 0.01) was observed 5 min after declamping. The pulsatility index averaged 0.74 increasing to 1.21 (p < 0.05) at clamping and 0.87 (p < 0.05) after declamping. CONCLUSION: There was an increased blood flow velocity of the middle cerebral artery during cross-clamping of the descending thoracic aorta in patients operated on for thoracic and thoracoabdominal aortic aneurysms. This increase in cerebral blood flow and blood volume could explain the acute increase in cerebrospinal fluid pressure observed during cross-clamping of the thoracic aorta.

Cerebral haemodynamics during proximal aortic cross-clamping.

This study was carried out to examine cerebral blood flow, including the microcirculation and intracranial pressure during cross-clamping (XC) of the thoracic aorta in pigs. Blood flow in the internal carotid artery was measured by electromagnetic flowmetry. Cerebral microcirculation was studied by the laser Doppler technique, and intracranial pressure measured by applying a fibre optic pressure monitoring catheter in the same craniotomy. Maximal and mean blood flow velocity of the middle cerebral artery was recorded using a transcranial Doppler and cardiac output measured by thermodilution. The thoracic aorta was cross-clamped distal to the left subclavian artery for 30 min. During aortic XC the internal carotid artery blood flow increased 191% (p less than 0.05). Simultaneously mean and maximal blood flow velocity of the middle cerebral artery both increased 125% (p less than 0.01). Intracranial pressure increased 163% (p less than 0.05), and there was an increase in cerebral flux of 23% (p less than 0.05). Within the first minutes following the release of XC, all values decreased to preocclusive values. In conclusion, we observed a significant increase in cerebral blood flow during XC of the thoracic aorta. This is in accordance with the finding of a simultaneous increase in cardiac output. These haemodynamic changes support the theory that an increased blood flow via the proximal feeding system to the anterior spinal artery might be important in avoiding neurological sequelae following proximal aortic XC.

Exfoliative glaucoma and primary open-angle glaucoma: associations with death causes and comorbidity.

PURPOSE: To investigate whether type of glaucoma or use of acetazolamide are associated with main cause of death and comorbidity. MATERIAL AND METHODS: The survival data, including date and cause of death, for 1147 patients with capsular or simple glaucoma who were ultimately hospitalized at the Eye Department, National Hospital, Oslo, between 1961 and 1970, were analysed. Binary logistic regression was carried out to investigate the patterns of death causes and comorbidity in subgroup analyses. RESULTS: Patients with exfoliative glaucoma (XFG) and those with primary open-angle glaucoma (POAG) showed no significant differences in rates of death caused by acute cerebrovascular diseases, cardiac diseases and cancer. Interestingly, we found that chronic cerebral diseases such as senile dementia, cerebral atrophy and chronic cerebral ischaemia (n = 81) were more common in patients with XFG than in those with POAG (p = 0.01) and in the group of acetazolamide users (p = 0.03). Patients with XFG had a higher probability of developing an acute cerebrovascular disease than patients with POAG (n = 228, p = 0.03). CONCLUSION: In this retrospective study, we found that comorbidity with acute cerebrovascular disease and chronic cerebral diseases (senile dementia, cerebral atrophy and chronic cerebral ischaemia) were more common in patients with XFG than in patients with POAG. Prospective data are needed in order to conclude upon the associations found in this study.