A dosage study of the effect of the 21-aminosteroid U74006F on chronic cerebral vasospasm in a primate model

The efficacy of the 21-aminosteroid U74006F was investigated using different dosages in a restricted, randomized, placebo-controlled trial. Forty cynomolgous monkeys were divided into five groups of eight. There were two groups given treatment with placebos, one being saline and the other the vehicle in which U74006F was delivered. There were three U74006F treatment dosage groups: 0.3, 1.0, and 3.0 mg/kg. Each monkey underwent baseline cerebral angiography followed by right-sided craniectomy and subarachnoid placement of a clot around the middle cerebral artery (MCA). Treatment was administered intravenously every 8 hours for 6 days. Seven days after experimental subarachnoid hemorrhage, angiography was repeated, and the animals were killed. In both saline or vehicle placebo treatment groups, significant vasospasm (VSP) occurred on the clot side in the extradural internal carotid artery (C3), the intradural internal carotid artery, the precommunicating segment of the anterior cerebral artery (A1,) and the MCA (P less than 0.01). After U74006F treatment, significantly less VSP developed in the A1 on the clot side (0.3 mg/kg U74006F treatment group) and the MCA (all U74006F treatment groups, P less than 0.05). When the percentages of change from the baseline for the vessel diameters on the clot side were compared, VSP was attenuated in the A1 (P less than 0.05) and MCA (P less than 0.001) of all U74006F treatment groups as compared with the placebo treatment groups. Only 0.3 mg/kg of U74006F significantly prevented VSP in C3 (P less than 0.01). Although the 0.3 mg/kg dosage appeared to have the most favorable effect, no significant differences were observed among the three dosage groups. Electron microscopy of the MCA on the clot side in the animals treated with U74006F still showed luminal convolutions and morphological changes in the endothelial cells. These changes appeared less prominent in those MCAs with milder VSP. If these results in primates are applicable to humans, U74006F would be useful in reducing VSP after aneurysmal subarachnoid hemorrhage.     

Clinico-pharmacological evaluation of omeprazole, as a proton pump inhibitor, compared with H2-blockers]

We evaluated the safety, tolerance, pharmacokinetics and pharmacodynamics of omeprazole, a new anti-ulcer agent chiefly on the basis of our studies in healthy male volunteers. The type and incidence of side effects of omeprazole have been reported to be similar to those of H2-antagonists, and in our studies too, omeprazole was estimated to be safe and tolerable. Following single doses, the increase in AUC was not proportional to the increase in dosage. In the multiple-dose study, the AUC was greater on day 7 than on day 1. This finding may be due to a partial saturation of first pass elimination. Repeated omeprazole treatment (20 mg once daily for 4 days) inhibited the basal and stimulated acid secretion. Though H2-blockers inhibit the basal and stimulated pepsin secretion, omeprazole inhibited the stimulated pepsin secretion only.     

Ketamine infusion for control of pain in patients with advanced cancer

The effect of ketamine infusion to control the intractable pain which had not responded to ordinary procedures in 12 patients with advanced cancer were evaluated. Ketamine 250 mg or 500 mg in 500 ml of transfusion fluid with or without 10 to 20 mg of droperidol was administered intravenously at the rate of 3 to 20mg of ketamine per hour. The pain scores by VAS in most of the patients decreased significantly with an averaged value of 8.3 before the treatment to 1 during the procedure. The durations of this therapy lasted from over 6 hours to 48 days. Slight disorientation in one patient and drowsiness in 5 were seen during the infusion. No cardiovascular or respiratory complications were noted. These results indicate that ketamine infusion is a useful therapeutic procedure to treat cancer pain which resist ordinary pain therapies.     

Phase II study of etoposide (VP-16) in the form of intravenous injection for malignant lymphomas and acute leukemias: Hanshin Cooperative Study Group for Hematological Disorders

Twenty patients with malignant lymphomas and 12 with acute leukemias were treated with intravenous administration of etoposide, 60-100 mg/m2/day for five days, repeated for three to four weeks. Eighteen cases of malignant lymphoma and nine of acute leukemia were evaluable. CR was achieved in three cases (16.7%) and PR in four cases (22.2%) of malignant lymphoma. Although CR was not achieved in any patients with acute leukemia, and PR was in three (33.3%), it was found that etoposide was most effective for the patients with the M4 or M5 subtype in the FAB classification. The most serious adverse effect of the drug was leukopenia in patients with lymphoma. In three patients (30.0%), the leukocyte count was lower than 1,000/mm3. Gastrointestinal complications, such as anorexia, nausea, vomiting and diarrhea occurred in 60.7% of all patients, but were not serious. Alopecia was observed in 73.1%. Intravenous administration of etoposide was apparently effective for the patients with malignant lymphoma of the diffuse mixed type, and this efficacy found in our study was the same as that for oral administration of etoposide reported by us previously.     

Long-term potentiation in the optic tectum of rainbow trout

We examined synaptic plasticity in the optic tectum of rainbow trout by extracellular recordings. We found that the field-excitatory postsynaptic potential in the retinotectal synapses was potentiated by repetitive stimuli of 1.0 Hz for 20 s to the retinotectal afferents. The long-term potentiation (LTP) developed slowly, and was maintained for at least 2 h. Applications of an antagonist for N-methyl-D-aspartic acid (NMDA) receptors or Mg²⁺-free saline showed that activation of NMDA receptors was required to form the LTP beyond the induction period. The present findings indicate that presynaptic stimulation in the retinotectal synapses causes LTP mediated by NMDA receptors in the optic tectum of rainbow trout.     

Investigation of optimal drug in moderate bronchial asthma]

BACKGROUND: Many drugs and the combinations of drugs are recommended for each treatment step in bronchial asthma. However, there are few issues examined about the optimal drug and combination of drugs in a long term prognosis. In this study, we investigated the optimal drugs and combinations of drugs from a point of view of prognosis. METHODS: One hundred and ninety four patients who visited our hospital for treatment from November, 2003 to October, 2004 and were managed according to GINA guideline were surveyed retrospectively. We compared the rate of step up and the frequency of urgent visit and urgent hospitalization in one year between drug groups in each treatment step. RESULTS: The rate of step up was significantly higher in leukotriene receptor antagonist (LTRA) group than in inhalation corticosteroid (ICS) group and theophylline group in Step 2. The frequency of urgent visit and urgent hospitalization was significantly higher in ICS+LTRA group than in ICS+theophylline group and ICS+long-acting beta 2-agonist (LABA) group in Step 3. CONCLUSION: There is a possibility that the prognosis becomes bad when we use LTRA in the practical treatment according to GINA guideline.     

Prevention of endotoxin shock by an antibody against leukocyte integrin {beta}2 through inhibiting production and action of TNF

Septic shock remains a serious disorder associated with highmortality. Accumulating evidence indicates that TNF is a majorand essential mediator of endotoxin shock. We report here thatadministration of an antibody against CD18 dramatically reducedendotoxin-induced shock inrabbits as revealed by preventionof severe hypotension, metabolic acidosis and a pathologicalchange suggestive of disseminated intravascular coagulationwith concomitant inhibition of elevation of plasma TNF activity.The anti-CD18 antibody also inhibited the hypotension inducedby administering recombinant TNF. Furthermore, an antibody againsta ligand for CD18 complexes, intercellular adhesion molecule-1,also prevented TNF-induced shock as well as endotoxin shockinrabbits. These observations suggest that adhesion of leukocytesto endothelium may be of primary importance in the action ofTNF as well as in the production of TNF in vivo and that theantibody against adhesion molecules could be of therapeuticbenefit in life-threatening septic shock in humans.     

Detection of the putative E2 protein of hepatitis C virus in human liver

The question was asked whether a predicted envelope protein, considered to be processed from the polyprotein precursor encoded by the putative E2/NS1 region of the hepatitis C virus (HCV) genome, may be observed in HCV-infected humans. Two polyclonal antibodies against recombinant E2/NS1 proteins were prepared and their reactivity tested against liver extracts from HCV-infected patients by immunoblotting analysis. A band corresponding to a size of 44 kDa was detected in liver extracts from patients who were positive for the HCV-specific antibody anti-C100-3 but not in liver extracts from patients who did not have anti-C100-3 antibody. Additionally, no band was detected using preimmune sera or antisera which had been preabsorbed with recombinant E2/NS1 proteins. Deglycosylation studies demonstrated that the 44 kDa protein was a glycosylated form of a 38 kDa protein which corresponds to the predicted molecular weight of the putative E2/NS1 protein. These results suggest that the 44 kDa protein is a product of the E2/NS1 region. Frequent observation of the 44 kDa band in cases of chronic active hepatitis C suggests a correlation between the expression of this protein and the progression of hepatitis. © 1994 Wiley-Liss, Inc.