Naoyuki Tsukada

A Study to Compare Oral Sumatriptan with Oral Aspirin plus Oral Metoclopramide in the Acute Treatment of Migraine

In a double-blind, placebo-controlled study, the efficacy, safety and tolerability of 100 mg oral sumatriptan, given as a dispersible tablet, was compared with that of 900 mg oral aspirin plus 10 mg oral metoclopramide in the acute treatment of migraine. A total of 358 patients treated up to three migraine attacks within 3 months, recording clinical information on a diary card. In attack 1, headache relief after 2 h, defined as a reduction in severity from severe or moderate pain to mild or no pain, was recorded in 56% (74/133) of patients who took sumatriptan and 45% (62/138) of patients who took aspirin plus metoclopramide (p = 0.078). This analysis of the primary efficacy end point was not statistically significant. However, for attacks 2 and 3 (secondary end points), headache relief was achieved in 58 versus 36% of patients (p = 0.001) and 65 versus 34% of patients (p less than 0.001), respectively. Relief from nausea, vomiting, photophobia and phonophobia was similar in both treatment groups. Rescue medication was required by fewer patients treated with sumatriptan than by those who received aspirin plus metoclopramide (attack 1, 34 versus 56%, p less than 0.001; attack 2, 32 versus 51%, p = 0.001, and attack 3, 35 versus 54%, p = 0.001). Sumatriptan also produced a faster improvement and resolution of migraine attacks. Comparing the sumatriptan and aspirin plus metoclopramide treatment groups, complete resolution of the attack occurred within 6 h in 32 versus 19% (attack 1), 35 versus 23% (attack 2) and 32 versus 20% of patients (attack 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor and interleukin-1 in the CSF and sera of patients with multiple sclerosis

Serum and cerebrospinal fluid (CSF) from 31 patients with multiple sclerosis (MS) were examined to determine the levels of tumor necrosis factor (TNF) and interleukin (IL)-1 alpha (or IL-1 beta) by an enzyme-linked immunosorbent assay. TNF was detected in 29 (93.5%) of CSF from 31 cases of MS. TNF was also detectable in 100% of CSF from patients with acute relapsing MS in exacerbation. Patients with acute relapsing MS in exacerbation showed significantly higher CSF levels of TNF as compared with either those in remission or the controls (P less than 0.001 and P less than 0.0001, respectively). Increased levels of TNF were also detected in 35.5% of the MS sera, and especially in those with acute relapsing MS in exacerbation. Increased TNF levels were also frequent in the CSF and sera of patients with Guillain-Barré syndrome (GBS), which is also a demyelinating disease. No IL-1 alpha (or IL-1 beta) was detected in either CSF or sera of 31 MS patients. It is considered likely that TNF CSF levels may reflect disease activity in MS.

Increased levels of intercellular adhesion molecule‐1 (ICAM‐1) and tumor necrosis factor receptor in the cerebrospinal fluid of patients with multiple sclerosis

We investigated the presence of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble tumor necrosis factor receptor (sTNF-R) antigens in the CSF of patients with multiple sclerosis (MS) using a double-determinant ELISA. Patients with acute relapsing MS during an exacerbation (p < 0.001) and those with chronic progressive MS (p < 0.001) had significantly increased CSF levels of SICAM-1 compared with subjects with other neurologic diseases. CSF levels of sTNF-R were also significantly increased in patients with acute relapsing MS during an exacerbation (p < 0.001) and chronic progressive MS (p < 0.001) compared with subjects with other neurologic diseases. CSF levels of sICAM-1 and sTNF-R were positively correlated in patients with acute relapsing MS during an exacerbation (r = 0.81, p < 0.01) and chronic progressive MS (r = 0.86, p < 0.001). These results suggest that active immune reactions involving ICAM-1 and TNF-R production are present within the CNS and that both sICAM-1 and sTNF-R are important immunologic markers of the clinical activity of MS.

Anti-endothelial cell antibodies and circulating immune complexes in the sera of patients with multiple sclerosis

Sera from patients with multiple sclerosis (MS) were examined for anti-endothelial cell antibodies and immune complexes by enzyme-linked immunosorbent assays (ELISAs) using cultured brain endothelial cells and Raji cells respectively. The concentrations of immunoglobulin (Ig) G which bound to cerebral endothelial cells and of immune complexes were significantly increased in the sera of patients with MS, especially those with an exacerbation. The levels of IgG binding to endothelial cells were still increased in the sera of exacerbated MS patients after blocking Fc receptors compared to those of controls. These findings indicate that IgG binding to endothelial cells may be mediated via an immunologically specific antigen-antibody interaction. The results show that anti-endothelial cell antibodies and immune complexes are present in cases of MS and they may play a pathogenetic role in the blood-brain barrier (BBB) damage.

Demyelinating neuropathy associated with hepatitis B virus infection: Detection of immune complexes composed of hepatitis B virus surface antigen

We observed 4 patients with the Guillain-Barré syndrome (GBS) type of polyneuropathy and one patient with chronic relapsing polyneuropathy associated with hepatitis B virus infection, and examined the sera, cerebrospinal fluid (CSF) and sural nerve specimens from the patients in search of the pathogenetic factors involved. It was demonstrated that hepatitis B surface antigen(HBsAg)-immune complexes were significantly increased in both the sera and the CSF of the 4 patients with GBS. The serum levels of immune complexes were also closely related to the clinical status of these patients. In all patients, HBsAg-positive labelling of immunofluorescence was found around the endoneural small blood vessels and in the endoneurium. Electron-dense deposits, suggestive of immune complexes composed of hepatitis B virus, were demonstrated in the endoneurium of the patient with chronic relapsing polyneuropathy. These results suggest that HBsAg immune complexes may be of importance in the etiology of GBS or chronic relapsing polyneuropathy associated with hepatitis B virus infection.

Increased levels of soluble vascular cell adhesion molecule-1 ( VCAM-1) in the cerebrospinal fluid and sera of patients with multiple sclerosis and human T lymphotropic virus type-1-associated myelopathy

We evaluated the relationship between the soluble form of vascular cell adhesion molecule-1 (sVCAM-1) and disease activity in patients with multiple sclerosis (MS) or with human T lymphotropic virus type 1-associated myelopathy (HAM), and measured levels of sVCAM-1 in their cerebrospinal fluid (CSF) and sera. Serum and CSF levels of sVCAM-1 were significantly increased in patients with acute relapsing MS during an exacerbation (P < 0.01 and P < 0.001), as well as in chronic progressive MS (P < 0.05 and P < 0.001), compared with healthy individuals and patients with other neurological diseases, respectively. Patients with acute relapsing MS during an exacerbation also exhibited significantly higher serum and CSF levels of sVCAM-1 vs. patients with acute relapsing MS in remission (P < 0.001). Significantly higher serum levels of sVCAM-1 were observed in patients with HAM vs. either healthy individuals (P < 0.01) or non-HAM carriers (P < 0.01). These results suggest that the determination of sVCAM-1 in the sera and CSF may be useful in monitoring the activity of MS and HAM.

A new model for multiple sclerosis: Chronic experimental allergic encephalomyelitis induced by immunization with cerebral endothelial cell membrane

SummaryMultiple sclerosis is considered to be an autoimmune demyelinating disease of the central nervous system. Damage to the blood-brain barrier, of which endothelial cells are the main constitutent, occurs in multiple sclerosis, probably due to immunological mechanisms. We report here the results of immune-mediated damage to these cells, produced by immunizing guinea pigs with an endothelial cell membrane fraction. The fraction was obtained from cerebral endothelial cells grown in vitro and was free from myelin basic protein. The immunized animals developed a chronic neurological illness with evidence of delayed hypersensitivity to the cell membrane fraction but not to myelin antigens. Histological examination of the brain in the acute stage showed mononuclear cell infiltrates aroud blood vessels, while in the chronic phase large areas of demyelination, especially in the periventricular region, were present. This bore a striking similarity to the brain in multiple sclerosis. This may prove to be a useful new animal model for the investigation of the human demyelinating disease.

Cytotoxicity of T cells for cerebral endothelium in multiple sclerosis

We investigated the cytotoxic effect of peripheral blood T cells on cerebral endothelium in patients with MS. We examined in vitro the damage to 51Cr-labelled dissociated human brain endothelial cells produced by mitogen-stimulated T cell lines from patients with MS and controls. Endothelial targets were lysed by T-lymphocytes from patients with acute relapsing MS during an exacerbation at every target-effector cell ratio tested compared with controls (P < 0.001). The percentage of endothelial targets lysed was not significantly increased by incubation with T cells from patients with acute relapsing MS in remission and chronic progressive MS, compared with that of normal subjects. Relapsing MS patients during an exacerbation had significantly higher interleukin-1 (IL-1)-alpha concentrations in cultures of targets with effector cells than normal subjects (P < 0.02). Experiments of major histocompatibility complex (MHC)-restricted cytotoxicity in MS demonstrated incomplete blocking of specific lysis by either anti-MHC class I or class II monoclonal antibody (mAb). These results indicate that cytotoxicity of T cells for cerebral endothelial cells may play a role in the initiation of immune response in acute relapsing MS during an exacerbation which appears to cause an increase in blood-brain barrier (BBB) permeability.

Chronic relapsing demyelinating polyneuropathy associated with hepatitis B infection.

We studied a patient with chronic relapsing polyneuropathy associated with immune complexes of hepatitis B virus. There were cycles of remission and exacerbation in parallel with liver dysfunction. Immunofluorescent deposits of hepatitis B antigen, immunoglobulin, and C3 component were detected in the vasa nervorum. Ultrastructural study revealed electron-dense deposits that might have been immune complexes composed of hepatitis B virus, both around the endoneural capillary and in the endoneurium. Immune complexes composed of hepatitis B virus may play a role in the pathogenesis of chronic relapsing polyneuropathy.

Chronic neuropathy associated with immune complexes of hepatitis B virus

In 7 patients, including one autopsied case, with neuropathy associated with hepatitis B virus infection, histologic examination of sural nerve biopsies revealed small vessel vasculitis in the vasa nervorum. In all cases, immunofluorescent deposits of hepatitis B surface antigen, immunoglobulin and C3 complement were detected in the vasa nervorum. That these deposits could represent immune complexes composed of hepatitis B virus was supported by the serologic demonstration of high serum-level of immune complexes and by the ultrastructural demonstration of electron-dense deposits around the endoneural capillary and in the endoneurium. The densities of large myelinated fibers were significantly lower than controls (P less than 0.01) in 6 of 7 cases. These results suggest that immune complexes composed of hepatitis B virus might play a significant role in the pathogenesis of endoneural and epineural vascular lesions, through which neuropathy may be induced in patients with hepatitis B virus infection.