Suppressing effect of the serotonin 5HT1B/D receptor agonist rizatriptan on calcitonin gene-related peptide (CGRP) concentration in migraine attacks

Calcitonin gene-related peptide (CGRP) is one of the neuropeptides most abundant in the nervous tissue. Recent studies indicate that local cranial release of CGRP from the trigeminal nerve perivascular endings within arachnoidea plays an important role in the pathophysiology of migraine attacks and cluster headaches. Elevated CGRP levels in cranial venous blood (in the jugular vein) during an acute spontaneous migraine attack have been reported in rather few studies so far. Sumatriptan--a selective serotonin 5HT1B/D receptor agonist, highly effective in terminating migraine attacks, decreases the elevated CGRP level back to normal. The aim of our study was to determine the effect of rizatriptan (a drug from a new generation of triptans) on CGRP release in migraine attacks. In 45 patients suffering from migraine attacks with and without aura, plasma CGRP levels were assessed during an attack twice: before treatment and two hours after rizatriptan administration. In the group under study the plasma CGRP level before treatment was significantly higher than that measured two hours after rizatriptan administration. The decrease in CGRP levels was associated with subsidence of the migraine attack. There was no difference between migraine patients with and without aura. These results suggest that triptans as serotonin 5HT1B/D receptor agonists decrease CGRP plasma concentration in migraine attacks.     

Experimental pneumococcal meningitis: Cerebrovascular alterations,brain edema,and meningeal inflammation are linked to the production of nitric oxide

We investigated whether treatment with the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NA) and the free radical scavenger superoxide dismutase influences cerebral blood flow changes, brain edema, and cerebrospinal fluid pleocytosis in early experimental pneumococcal meningitis. Compared to untreated infected rats, superoxide dismutase given 3 hours after infection significantly attenuated the increase of brain water content, intracranial pressure, and cerebrospinal fluid white blood cell count, but did not modulate the increase in regional cerebral blood flow. N-Nitro-L-arginine treatment (5 mg/kg intravenously, followed by 5 mg/kg/hour) reversed the increase in regional cerebral blood flow; prevented an increase in brain water content, intracranial pressure, and cerebrospinal fluid nitrite concentrations; and reduced cerebrospinal fluid white blood cell count. With a closed cranial window preparation, N-nitro-L-arginine prevented pneumococci-induced dilatation of pial arterioles. When the effective dose was increased twofold, the effects of N-nitro-Lvarginine became more pronounced but resulted in the death of 4 of 5 rats, probably due to hemodynamic side effects. In primary cultures of rat cerebral endothelial cells, nitrite concentrations increased after pneumococcal stimulation, which could be prevented by NvnitrovLvarginine and cycloheximide. These data suggest that (a) nitric oxide accounts for regional cerebral blood flow changes and pial arteriolar dilatation in the early phase of experimental pneumococcal meningitis; (b) both superoxide radical and nitric oxide are involved as mediators of brain edema and meningeal inflammation; and (c) cerebral endothelial cells can be stimulated by pneumococci to release nitric oxide presumably via the inducible nitric oxide synthase.     

Rational migraine management: optimising treatment with the triptans

In the last two years, a number of 5-HT1B/1D agonist triptans with enhanced lipophilicity (TELs) relative to the first drug of this class, sumatriptan, have been approved for marketing in most countries of the world (naratriptan, rizatriptan and zolmitriptan). In addition, at least three others are in advanced stage of clinical development (almotriptan, eletriptan, and frovatriptan). This paper sets out to review the recent data with the aim of identifying: 1) What are the critical differences between the TELs and sumatriptan? 2) How do the currently licensed TELs compare? 3) Is it possible to provide a rational approach to migraine therapy based on objective differences in the clinical profile of these new drugs? Recent randomised controlled and comparator data were reviewed, including the independent FDA assessment of rizatriptan. Critical differences for the new TELs (naratriptan, rizatriptan and zolmitriptan) which may lead to more rational migraine management: Both rizatriptan (10 mg) and zolmitriptan (2.5 mg and 5.0 mg) have demonstrated superior efficacy to sumatriptan 100 mg, and 25 and 50 mg respectively. Therefore, for first line use either rizatriptan or zolmitriptan would be appropriate for moderate and severe headache. Rizatriptan has a more rapid onset of action than sumatriptan 100 mg. Both rizatriptan and zolmitriptan have a more rapid onset of action than naratriptan. Therefore, for a rapid onset of action either rizatriptan or zolmitriptan would be appropriate. Naratriptan would appear to have a lower recurrent headache rate than sumatriptan, rizatriptan or zolmitriptan. However, 24-hour efficacy rates for zolmitriptan 2.5 mg were significantly greater than for sumatriptan 25 mg and 50 mg and were not significantly different from naratriptan. Therefore, for headaches of long duration and with a tendency to recur (e.g. menstrual headaches) either naratriptan or zolmitriptan would be appropriate. Naratriptan has lower reported adverse event rates comparable with placebo. This would support the use of naratriptan 2.5 mg in patients who have demonstrated poor tolerance to the "triptan type" adverse events.     

A case of Mondini dysplasia with bacterial meningitis

A boy with bilateral hearing impairment developed pneumococcal meningitis at 14-month-old. Further examination revealed cerebrospinal fluid leakage due to bilateral Mondini dysplasia. He was cured by treatment with panipenem/betamiprone and dexamethasone, and then, he was performed an operation to fill the inner ear on day 30. He did not have bacterial meningitis 19 months after the operation. Children with congenital hearing impairment should be examined for malformation of the inner ear because the inner ear malformation has cerebrospinal fluid leakage and bacterial meningitis frequently.     

Myelomatous meningitis: a case report

Multiple myeloma is characterized by the production of a monoclonal immunoglobulin. Myelomatous meningitis is a rare occurrence in multiple myeloma. The signs of meningeal myelomatosis include impairment of consciousness, cranial nerve palsies, convulsions and plasmatic cells in the cerebrospinal fluid. Atypical, plasmatic cells in the cerebrospinal fluid are an important finding for the diagnosis of meningeal myeloma. A combination of radiation therapy and chemotherapy is the usual treatment. Patients with meningeal myelomatosis can have a good response to treatment initially, but their prognosis is poor and death occurs within a few months. We present the case of a woman with myelomatous meningitis. Multiple myeloma was diagnosed by serum protein electrophoresis and bone marrow aspiration. This case and a review of the literature show that clinical manifestations of meningeal myeloma are non-specific.     

Induced hypothermia in experimental pneumococcal meningitis.

Pneumococcal meningitis resulting from Streptococcus pneumoniae has a death rate of 28% in adults. In severe head injury and stroke, inflammatory changes and intracranial hypertension are improved by induced hypothermia, which also is neuroprotective. We hypothesized that moderate hypothermia ameliorates inflammatory changes in experimental pneumococcal meningitis. Wistar rats were cooled systemically, and meningitis was induced by pneumococcal cell wall components. The increase of regional cerebral blood flow in the meningitis animals was blocked by hypothermia at 6 hours. The reduction of intracranial pressure correlated with temperature. The influx of leukocytes into the cerebrospinal fluid and levels of tumor necrosis factor alpha in the cerebrospinal fluid were decreased. Cooling the animals 2 hours after meningitis induction to 30.5 degrees C was also protective. We conclude that hypothermia is a new adjuvant approach to reduce meningitis-induced changes, in particular intracranial pressure, in the early phase of the disease.     

Primary diffuse leptomeningeal gliomatosis

A review of the literature on primary diffuse meningeal gliomatosis (DMG) yielded three cases and we report a fourth. DMG is a syndrome characterized by extensive basal and spinal chronic meningitis with mental confusion, headaches, diplopia, papilledema and cranial nerve palsies. The cerebrospinal fluid (CSF) has a markedly elevated protein content, moderate mononuclear pleocytosis and a normal or low glucose. This picture invariably leads to the diagnosis and treatment of tuberculous or fungal meningitis despite persistently negative cerebrospinal fluid (CSF) cultures. Reaction of exfoliated CSF cells with glial fibrillary acidic protein (GFAP) immunoperoxidase labelled antibody is suggested as a diagnostic tool. A basal meningeal biopsy appears to be the only alternative diagnostic approach.     

A systematic review of the use of triptans in acute migraine

OBJECTIVE: A systematic review of the literature was undertaken, to consolidate evidence concerning the efficacy and safety of triptans currently available in Canada (sumatriptan, rizatriptan, naratriptan, zolmitriptan), and to provide guidelines for selection of a triptan. METHODS: Data from published, randomized, placebo-controlled trials were pooled and a combined number needed to treat (NNT) and number needed to harm (NNH) was generated for each triptan. Direct comparative trials of triptans were also examined. RESULTS: The lowest NNT for headache response/pain-free at one/two hours is observed with subcutaneous sumatriptan. Among the oral formulations, the lowest NNT is observed with rizatriptan and the highest NNT with naratriptan. The lowest NNH is observed with subcutaneous sumatriptan. CONCLUSIONS: Triptans are relatively safe and effective medications for acute migraine attacks. However, differences among them are relatively small. Considerations in selecting a triptan include individual patient response/tolerance, characteristics of the attacks, relief of associated symptoms, consistency of response, headache recurrence, delivery systems and patient preference.     

Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target?

Triptans, serotonin 5-HT(1B/1D), receptor agonists, which are so effective in acute migraine, are considered to act directly on the trigeminovascular system. Using an in vivo model of trigeminovascular nociception, we report a potentially novel action for the triptans within the somatosensory thalamus. Both microiontophoretically applied and intravenous naratriptans potently and reversibly modulate nociceptive neurotransmission by trigeminovascular thalamic neurons in the ventroposteromedial nucleus (VPM) driven by stimulation of the superior sagittal sinus. Naratriptan also suppresses l-glutamate activated trigeminovascular VPM neurons. Co-ejection of naratriptan with the 5-HT(1B/1D) receptor antagonist GR127935 antagonized this effect. (S)-WAY 100135 the 5-HT(1A) receptor antagonist also partially inhibited the effect of naratriptan in the VPM when co-ejected with it. Taken together, the new data suggest a potential effect of triptans in the VPM nucleus of the thalamus acting through 5-HT(1A/1B/1D) mechanisms, and offer an entirely new direction for the development of and understanding of the effects of anti-migraine medicines.     

An 11-year-old girl with recurrent bacterial meningitis due to liquorrhea caused by bone malformation of the skull base

The patient is a healthy 11-year-old girl with no history of trauma or hearing impairment. She developed pneumococcal meningitis three times, at ages 7, 10, and 11. Intracranial examination revealed, pore expansion and cerebrospinal fluid leakage in the right internal acoustic foramen, which were attributed to a bone malformation of the base of the skull. A procedure was performed to close the cerebrospinal fluid leakage; no relapse has been observed thus far. Previous case reports indicate that repetitive bacterial meningitis is often caused by internal ear malformation, trauma, tumors, or surgical operation. This case suggests the possibility that underlying disorders may not be apparent in cases of repetitive bacterial meningitis and, more proactive investigations are required to prevent further recurrence of meningitis.     

Total antioxidant/oxidant status in meningism and meningitis

The objective of this study was to investigate the antioxidant/oxidant status of serum and cerebrospinal fluid in children with meningismus and acute bacterial meningitis. Twenty-three children (age range, 0.75 to 9 years) with fever and meningeal signs that required analysis of the cerebrospinal fluid, but no cytologic or biochemical evidence of meningitis in their serum and cerebrospinal fluid, constituted the meningismus group. Thirty-one children (age range, 0.5 to 10 years) with acute bacterial meningitis constituted the meningitis group. Twenty-nine healthy children (age range, 0.5 to 11 years) were recruited as control subjects. Antioxidant status (ascorbic acid, albumin, thiol, uric acid, total bilirubin, total antioxidant capacity, catalase and ceruloplasmin concentrations) and oxidant status (lipid hydroperoxide and total oxidant status) were measured. The serum antioxidant status was lower, and oxidant status levels higher in both meningitis and meningismus subjects than in the control children (P < 0.001). Cerebrospinal fluid oxidant status was lower in the meningitis group than in the meningismus group (P < 0.05). These results indicate that serum antioxidant status was lower, and serum oxidant status was higher in children in the meningismus and meningitis groups, whereas cerebrospinal fluid oxidant status was higher in the meningismus group than in the meningitis group.     

Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception

It is considered that the site of action of the abortive antimigraine compounds acting at serotonin, 5-HT(1B/1D,) receptors (triptans) is the trigeminovascular system. We tested whether there is a non-trigeminal site of action. The 5-HT(1B/1D) agonist, naratriptan, was microinjected into the ventrolateral periaqueductal gray (vlPAG), and activity in the trigeminal nucleus caudalis (TNC) was monitored. Recordings were made from 20 nociceptive neurons in the dorsal horn of the TNC that received convergent input from the dura mater and face. Responses of neurons to dural, facial cutaneous and corneal stimulation were studied before and after injection of naratriptan. Naratriptan decreased the excitability to electrical stimulation of the dura mater as the A-fiber response decreased by 24 +/- 4.1% (p < 0.001) and the C-fiber response decreased by 42 +/- 8.2% (p < 0.001). Spontaneous activity was decreased by 38 +/- 7.5% (p < 0.001). After injection, the mechanical thresholds of the dura mater increased from (n = 14, p < 0.01). Responses to stimulation of the face and cornea were not altered by injection of naratriptan. These results suggest that 5-HT(1B/1D) receptor activation in the vlPAG activates descending pain-modulating pathways that inhibit dural, but not facial and corneal nociceptive input. These findings have implications for the understanding of the action of triptans in migraine and cluster headache, suggesting that brain loci other than the trigeminal nucleus may play a role in the clinical action of triptans.     

Absolute neutrophil count in aseptic and bacterial meningitis related to time of lumbar puncture

Previous studies have demonstrated that during the first 24 hours of illness caused by aseptic meningitis, polymorphonuclear cells predominate in cerebrospinal fluid and decline afterward. To test the hypothesis that the absolute neutrophil count and percentage of polymorphonuclear cells in cerebrospinal fluid of bacterial meningitis patients are elevated and sustained after 24 hours compared with that of patients with aseptic meningitis. Seventy-two patients with aseptic meningitis and 13 with bacterial meningitis participated. All patients with aseptic meningitis and four patients with bacterial meningitis were followed-up prospectively. The patients were enrolled in four groups according to the interval between onset of symptoms and performance of the lumbar puncture (<12 hours, 12-24 hours, 24-36 hours, and >36 hours). In aseptic meningitis the mean absolute neutrophil count was 182, 164, 79, and 68 cells/mm³, respectively (P = 0.025). In bacterial meningitis the absolute neutrophil count was 28, 1,466, 5,853, and 235 cells/mm³, respectively. The mean percentage of polymorphonuclear cells in aseptic meningitis was 49%, 46%, 40%, and 26%, respectively (P = 0.038); in bacterial meningitis, 70%, 83%, 81%, and 58%, respectively. The findings suggest that the absolute neutrophil count and the polymorphonuclear cell percentage in cerebrospinal fluid have different kinetics in aseptic vs. bacterial meningitis.     

Pathophysiology of migraine--new insights

Current theories propose that the primary dysfunction in migraine occurs within the CNS and that this evokes changes in blood vessels within pain-producing intracranial meningeal structures that give rise to headache pain. Migraine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreading depression-like phenomena and activation of brain stem monoaminergic nuclei that are part of the central autonomic, vascular and pain control centers. It is generally thought that local vasodilatation of intracranial extracerebral blood vessels and a consequent stimulation of surrounding trigeminal sensory nervous pain pathways is a key mechanism underlying the generation of headache pain associated with migraine. This activation of the 'trigeminovascular system' is thought to cause the release of vasoactive sensory neuropeptides, especially CGRP, that increase the pain response. The activated trigeminal nerves convey nociceptive information to central neurons in the brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesized that these central neurons may become sensitized as a migraine attack progresses. The 'triptan' anti-migraine agents (e.g. sumatriptan, rizatriptan, zolmitriptan naratriptan) are serotonergic agonists that have been shown to act selectively by causing vasoconstriction through 5-HT1B receptors that are expressed in human intracranial arteries and by inhibiting nociceptive transmission through an action at 5-HT1D receptors on peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem sensory nuclei. These three complementary sites of action underlie the clinical effectiveness of the 5-HT1B/1D agonists against migraine headache pain and its associated symptoms.     

Role of Caspase-1 in experimental pneumococcal meningitis: Evidence from pharmacologic Caspase inhibition and Caspase-1-deficient mice

Caspase 1 plays a pivotal role in generating mature cytokine interleukin-1beta. Interleukin-1beta is implicated as a mediator of pneumococcal meningitis, both in experimental models and in humans. We demonstrated here that (1) Caspase 1 mRNA and protein expression is upregulated in the brain during experimental pneumococcal meningitis, and (2) Caspase 1 levels are elevated in the cerebrospinal fluid of patients with acute bacterial meningitis. The upregulation/activation of Caspase 1 was associated with increased levels of interleukin-1beta. Depletion of the Caspase 1 gene and pharmacologic blockade of Caspase 1 significantly attenuated the meningitis-induced increase in interleukin-1beta. This was paralleled by a significantly diminished inflammatory host response to pneumococci. The antiinflammatory effect of Caspase 1 depletion or blockade was associated with a marked reduction of meningitis-induced intracranial complications, thus leading to an improved clinical status. In humans, cerebrospinal fluid Caspase 1 levels correlated with the clinical outcome. Thus, pharmacologic inhibition may provide an efficient adjuvant therapeutic strategy in this disease.     

Comparison of rizatriptan and other triptans on stringent measures of efficacy.

OBJECTIVE: To compare the efficacy of oral rizatriptan 10 mg with oral doses of sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures. METHODS: Retrospective analysis of data from five randomized, placebo-controlled, double-masked clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (n = 772), 50 mg (n = 1116), 25 mg (n = 1183), naratriptan 2.5 mg (n = 413), and zolmitriptan 2.5 mg (n = 580) for the acute treatment of a moderate or severe migraine attack. OUTCOME MEASURES: Percentage of patients pain-free at 2 hours, symptom-free at 2 hours (no pain, nausea, photophobia, phonophobia, vomiting, or functional disability), 24-hour sustained pain-free (no headache at 2 hours, no recurrence, and no additional antimigraine medications for 24 hours). RESULTS: More patients taking rizatriptan 10 mg were pain-free at 2 hours than were patients taking sumatriptan 100 mg (40% vs 33%, p = 0.019), sumatriptan 50 mg (40% vs 35%, p = 0.009), sumatriptan 25 mg (38% vs 27%, p < 0.001), naratriptan 2.5 mg (45% vs 21%, p < 0.001), and zolmitriptan 2.5 mg (43% vs 36%, p = 0.041). More patients taking rizatriptan 10 mg were symptom-free at 2 hours than were patients taking sumatriptan 100 mg (31% vs 22%, p = 0.002), sumatriptan 50 mg (33% vs 28%, p = 0.003), sumatriptan 25 mg (33% vs 24%, p < 0.001), naratriptan 2.5 mg (30% vs 11%, p < 0.001), and zolmitriptan 2.5 mg (31% vs 24%, p = 0.042). More patients taking rizatriptan 10 mg had a 24-hour sustained pain-free response than did patients taking sumatriptan 100 mg (27% vs 23%, p = 0.112), sumatriptan 50 mg (30% vs 26%, p = 0.015), sumatriptan 25 mg (27% vs 20%, p = 0.005), naratriptan 2.5 mg (29% vs 17%, p = 0.004), and zolmitriptan 2.5 mg (32% vs 24%, p = 0.013). CONCLUSION: Oral rizatriptan 10 mg was more effective than oral sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures of pain-free response at 2 hours, symptom-free response at 2 hours, and 24-hour sustained pain-free response.     

Two cases of recurrent bacterial meningitis following traumatic cerebrospinal fluid rinorrhea

We report here two cases of recurrent bacterial meningitis following traumatic cerebrospinal fluid rhinorrhea. Case-1: an 1-year-old girl had a penetrating injury to the nasal cavity with a chopstick. From 1 day after this accident, she had suffered from recurrent bacterial meningitis. She was diagnosed as having cerebrospinal fluid rhinorrhea, and underwent surgical repair of the bone defect. Case-2: a 5-year-old girl had suffered from bacterial meningitis 4 times after head trauma. A bone defect was demonstrated by 3-D CT and repaired surgically. We consider that 3-D CT is a useful tools to detect cerebrospinal fluid fistula.     

Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis.

Nitric oxide (NO) plays a central role in the pathogenesis of bacterial meningitis. However, the role of NO produced by endothelial NO synthase (eNOS) in meningitis is still unclear. We investigated the influence of eNOS depletion on the inflammatory host response, intracranial complications, and outcome in experimental pneumococcal meningitis. Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected eNOS-deficient mice than in infected wild type mice. This effect could be attributed to an increased expression of P-selectin, macrophage inflammatory protein-2, keratinocyte-derived cytokine, and interleukin (IL)-1beta in the brain of infected eNOS-deficient mice. However, no differences in the cerebral expression of intercellular adhesion molecule-1, tumor necrosis factor-alpha, and IL-6 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice. In addition to enhanced leukocyte infiltration into the CSF, meningitis-associated intracranial complications including blood-brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected eNOS-deficient mice. The aggravation of intracranial complications was paralleled by a worsening of the disease, as evidenced by a more pronounced hypothermia, an enhanced weight reduction, and an increased death rate. The current data indicate that eNOS deficiency is detrimental in bacterial meningitis. This effect seems to be related to an increased expression of (certain) cytokines/chemokines and adhesion molecules; thus leading to increased meningeal inflammation and, subsequently, to aggravated intracranial complications.     

The effect of S. pneumoniae bacteremia on cerebral blood flow autoregulation in rats.

In the present study, we studied the effect of bacteremia on cerebral blood flow (CBF) autoregulation in a rat model of pneumococcal bacteremia and meningitis. Anesthetized rats were divided into five groups (A to E) and inoculated with pneumococci intravenously and normal saline intracisternally (group A, N=10); saline intravenously and pneumococci intracisternally (group B, N=10); pneumococci intravenously and pneumococci intracisternally (group C, N=5); saline intravenously, antipneumococcal antibody intravenously (to prevent bacteremia), and pneumococci intracisternally (group D, N=10); or saline intravenously and saline intracisternally (group E, N=10), respectively. Positive cultures occurred in the blood for all rats in groups A, B, and C, and in the cerebrospinal fluid for all rats in groups D and E. Twenty-four hours after inoculation, CBF was measured with laser-Doppler ultrasound during incremental reductions in cerebral perfusion pressure (CPP) by controlled hemorrhage. Autoregulation was preserved in all rats without meningitis (groups A and E) and was lost in 24 of 25 meningitis rats (groups B, C, and D) (P<0.01). In group A, the lower limit was higher than that of group E (P<0.05). The slope of the CBF/CPP regression line differed between the meningitis groups (P<0.001), being steeper for group B than groups C and D, with no difference between these two groups. The results suggest that pneumococcal bacteremia in rats triggers cerebral vasodilation, which right shifts the lower limit of, but does not entirely abolish, CBF autoregulation in the absence of meningitis, and which may further aggravate the vasoparalysis induced by concomitant pneumococcal meningitis.     

Fibrin degradation products in the cerebrospinal fluid of patients with pneumococcal meningitis.

Raised levels of fibrin degradation products were found in the cerebrospinal fluid of nearly all of 35 patients with pneumococcal meningitis. The mean level was higher in patients who died subsequently than in those who survived. Cerebrospinal fluid from patients with pneumococcal meningitis showed increased fibrinolytic activity as assessed by clot lysis, suggesting local production of fibrin degradation products within the subarachnoid space.