Phase I study of E1040, a new parenteral cephem antibiotic

The safety and pharmacokinetics of E1040, a new injectable cephem antibiotic, were evaluated in healthy volunteers. In single-dose studies, 125, 250, 500, 1000 and 2000 mg of E1040 were administered by I.V. infusion over 1 hour. Results of 5 minutes I.V. infusions of 500, 1000 and 2000 mg of the drug were also studied. Plasma concentration-time profiles were well suited to a two-compartment open model. The half-life of elimination from plasma was 1.85 +/- 0.16 hours, and the Cmax and AUC paralleled the doses given. The mean urinary recovery within the first 24 hours was 85.7 +/- 6.43% of the dose. In a multiple-dose study, 2000 mg of E1040 (I.V. over 1 hour) was administered every 12 hours (total 9 times) and no abnormal accumulation of the drug in plasma was observed. There were no significant differences in plasma levels or in urinary recoveries between single- and multiple-dose regimens. There were no subjective or objective abnormal findings definitely attributable to the drug except that one subject given 250 mg over 1 hour reported diarrhea, and another complained of nausea during the infusion of 2000 mg over 5 minutes. From these results E1040 was concluded to be safe and well tolerated.     

Clinical features of patients with obsessive-compulsive disorder showing different pharmacological responses]

BACKGROUND: Although selective serotonin reuptake inhibitors (SSRIs) are the mainstay of pharmacological treatment for obsessive-compulsive disorder (OCD), some OCD patients do not show improvement. Sometimes, the addition of a low-dose atypical antipsychotic, such as risperidone, or olanzapine, to ongoing SSRI treatment has been shown to be effective. However, there are patients who still show no response after trials with this augmentation therapy. In the present study, we examined the clinical features of OCD patients who showed different responses to pharmacological treatment. SUBJECTS AND METHOD: Fifty OCD patients were divided into three groups according to their pharmacological responses: responders to SSRI (group A: n= 25), responders to SSRI with an atypical antipsychotic (group B: n= 15), and non-responders to both SSRI and SSRI with an atypical antipsychotic (group C: n= 10). We examined the clinical features such as age, sex, age of onset, duration of illness, types of obsessive-compulsive symptoms, severity, improvement after treatment, insight into disease, depression, comorbidity, involving family members in compulsive or ritualistic behavior, and the level of social adaptation of each OCD group. RESULTS: Twenty five patients showed a good response to SSRI monotherapy, 15 showed a response to antipsychotic augmentation, and 10 were non-responders to both SSRI and SSRI with an atypical antipsychotic. Significantly lower insight levels were observed only in group B and higher depressive levels in group C. OCD patients who were refractory to SSRI monotherapy showed comorbidity at a significantly higher frequency. OCD patients in group A showed significantly greater improvement, and group B showed inferior social adaptation after treatment. There were no significant differences in age, sex, age of onset, duration of illness, severity, involving family members in compulsive or ritualistic behavior, and social adaptation before treatment in the three OCD groups. CONCLUSION: There were differences in the clinical features of OCD patients who showed different responses to pharmacological treatment. Our results suggest that OCD is clinically and biologically heterogeneous. It may be important to divide OCD patients into subgroups for future studies.     

Fumonisins as a possible contributory risk factor for primary liver cancer: A 3-year study of corn harvested in Haimen, China, by HPLC and ELISA

Employing HPLC fluorometry, gas-liquid chromatography (GLC) and a novel enzymelinked immunosorbent assay (ELISA) based on a monoclonal antibody, 40 corn samples, each collected in 1993 from agricultural stocks for human consumption in Haimen (Jiangsu County) and Penlai (Shandong Province), high- and low-risk areas for primary liver cancer (PLC) in China, respectively, were analysed for fumonisins (FBs), aflatoxins (AFs) and trichothecenes. Levels and positive rates of FBs and deoxynivalenol (DON) were significantly higher in Haimen than in Penlai. ELISA of the 40 corn samples harvested in the two areas in 1994 revealed that FB contamination levels and rates in these areas were comparable to those observed in 1993 in Haimen. ELISA analysis of 1993 and 1994 products revealed a wide occurrence of AFB₁ but the positive rates as well as levels were not significantly different between these areas. ELISA of the same sample number of corn harvested in 1995 revealed that FB contamination in Haimen was significantly higher than in Penlai. These 3-yearly surveys of corn samples (240 in total) demonstrated that corn harvested in Haimen was highly contaminated with FBs and that the contamination level, as well as positive rate in 1993 and 1995, were 10–50-fold higher than those in Penlai, suggesting FBs as a risk factor for promotion of PLC in endemic areas, along with the trichothecene DON. Co-contamination with AFs, potent hepatocarcinogens, was assumed to play an important role in the initiation of hepatocarcinogenesis.     

Antimicrobial activity of AO-128, a novel inhibitor of alpha-D-glucosidase, against anaerobic bacteria]

The in vitro antimicrobial activity of AO-128, an inhibitor of alpha-D-glucosidase, was evaluated against anaerobic bacteria of 45 reference strains (12 genera, 44 species). AO-128 inhibited no strains tested at a concentration of 1,600 micrograms/ml. The results strongly suggested that this compound would not have any influence on the human intestinal microflora, a majority of which is composed of anaerobic bacteria.     

Reduced levels of MMP-2 and TIMP-1 in dyssegmental dysplasia.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were measured in a mild case of dyssegmental dysplasia. X-ray pictures of a female baby born vaginally at 39 weeks of gestation showed short, bent, dumbbell-shaped long bones of the limbs and profound dyssegmental ossification in the spine, findings characteristic of dyssegmental dysplasia. When the levels of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured, the levels of MMP-2 and TIMP-1 were significantly reduced. This case might provide a clue to disclose the etiology of dyssegmental dysplasia.     

Overestimation of myocardial viability due to an increase in thallium uptake by the lung

Thallium lung uptake (TL-uptake) was usually treated as background for myocardial image and increase of TL-uptake in exercise test was considered as marker of depressed cardiac function. It was reported that marked increase of TL-uptake in patients with acute myocardial infarction (AMI) corresponded to acute severe congestive heart failure. Here effect of TL-uptake on myocardial planar images was studied in 61 patients with AMI. In acute phase anterior, LAO 30 degrees and LAO 60 degrees myocardial images were collected. In 29 cases of 61 cases 3 to 6 hours delayed images could be collected. Each myocardial images was divided to 3 division and both images were compared. In 5 of 6 patients with marked increase of TL-uptake new defects were noted in anterior division of delayed images and in one case also in lateral division. In 7 patients of 12 patients with moderate increase of TL-uptake new defects were also noted in delayed images, i.e. 3 in anterior, 3 in inferior and one in apical division. It was concluded that over estimation of myocardial viability due to marked increase of TL-uptake was often noted in patients with AMI accompanying severe congestion. It became clear that delayed images were necessary to correctly estimate myocardial viability in such case.     

Ethylnitrosourea-induced apoptosis in primordial germ cells of the rat fetus.

Ethylnitrosourea (ENU) is a simple alkylating agent. It induces gene mutations in fetal primordial germ cells (PGCs), and a high incidence of congenital malformations is also found in the offspring of male mice treated with ENU at the embryonic stage. It is also reported that decreases in the fertility rate and weights of the testis and ovary were found in the offspring from dams treated with ENU. In this study, we analyzed the occurrence of apoptotic cell death and the expression of p53 protein which is thought to play an important role in the DNA damage-induced apoptosis after administration of ENU to pregnant rats on day 13 of gestation to obtain a clue for clarifying the toxic effect of ENU on PGCs. Apoptotic cells increased in PGCs in fetal gonads from 3 h after treatment. The number of apoptotic PGCs peaked at 6 h and gradually decreased towards 24 h after treatment. On the other hand, p53-positive PGCs increased from I h after treatment, prior to the induction of apoptosis. The number of p53-positive PGCs peaked at 3 h and returned to the control level at 24 h after treatment. These results suggest that ENU induces apoptosis in rat fetal PGCs immediately after its administration to dams and excess cell death by apoptosis may have a close relation to the later occurrence of decreases in the fertility rate and gonadal weight. Moreover, a possible involvement of p53 is suggested in the ENU-induced apoptosis in PGCs.     

Intracranial MR imaging of achondroplasia]

Intracranial MR imaging was performed in five patients with achondroplasia. All patients had narrowing of the subarachnoid space at the level of the foramen magnum that was mainly due to protrusion of the posterior aspect. Three patients had compressive deformities of the brainstem and/or upper cervical spine. Among them, two patients had deformities of the pons. Relative upward displacement of the brainstem was seen in all patients. Hydrocephalus was seen in three patients.