Inhibition of urease activity by hydroxamic acid derivatives of amino acids.

Hydroxamic acids have been reported to be potent and specific inhibitors of urease (EC 3.5.1.5) activity of plant and bacterial origin. The present investigation was performed on the inhibitory effect of hydroxamic acid derivatives of naturally occurring amino acids on the urease activity of the Jack Bean and the alimentary tracts of rats. Methionine-hydroxamic acid was the most powerful inhibitor (I50=3.9 X 10(-6) M) among nineteen alpha-aminoacyl hydroxamic acids. Phenylalanine-, serine-, alanine-, glycine-, histidine-, threonine-, leucine-, and arginine-hydroxamic acids followed, in order of decreasing inhibitory power. The inhibition proceeded with time at a comparable rate to fatty acyl hydroxamic acid inhibition. The I50 values of alpha-aminoacyl hydroxamic acids were found to be almost equal to those of the corresponding fatty acyl hydroxamic acids. This fact shows that the alpha-amino group did not affect inhibitory power. However, aspartic-beta-, lysine-, and glutamic-gamma-hydroxamic acids, in descending order, were much less inhibitory, probably due to the presence of a carboxyl or omega-amino group. Furthermore, the pH optimum of the inhibition shifted to lower pH in the presence of a carboxyl group, and to a higher pH in e presence of an amino group. The results suggest that the dissociation of an acidic or a basic group reduces the inhibitory power of hydroxamic acid. Hydroxamic acid inhibits urease activity with strict specificity, excpet for aspartic-beta-hydroxamic acid, which inhibited asparaginase competitively. Hydroxamic acid derivatives of amino acids inhibited not only the urease activity of the Jack Bean, but also that of the caecum and ileum parts of the rat intestine.

Comparison of 99Tcm-pyrophosphate, 201T1 perfusion, 123I-labelled methyl-branched fatty acid and sympathetic imaging in acute coronary syndrome.

Among a group of patients (n = 15) with acute coronary syndrome, the results of using two new myocardial radiopharmaceuticals--123I-labelled 15-(p-iodo-phenyl)-3,R,S-methylpentadecanoic acid (BMIPP) and 123I-meta-iodobenzyl guanidine (MIBG)--were compared with dual 201Tl/99Tcm-pyrophosphate (Tl-PYP) imaging using single photon emission tomography (SPET). Defect scores were evaluated on a segment-by-segment basis for a total of 270 segments. For the 201Tl, BMIPP, and early and delayed MIBG studies, the mean (+/- S.D.) sums of defect scores were 9 +/- 8, 18 +/- 9, 22 +/- 12 and 29 +/- 9, respectively, revealing significantly higher scores for BMIPP and MIBG than 201Tl (P < 0.005). This was the case irrespective of various functional conditions, such as successful recanalization, failure of coronary angioplasty or restenosis. The culprit coronary artery was best identified using BMIPP, while MIBG SPET showed the most extensive defects. Normal perfusion with decreased BMIPP and MIBG uptake was frequently observed and associated with hypokinesis. 123I-BMIPP and MIBG are more sensitive for the detection of damaged myocardium, and the difference between perfusion and metabolism seems to reflect myocardial stunning.

[General pharmacology of T-3761, a new oral quinolone antibacterial agent (2). Effect on the respiratory and cardiovascular systems, autonomic nervous system and other functions].

General pharmacological effects of T-3761, a new oral quinolone antibacterial agent, on the respiratory and cardiovascular systems, autonomic nervous system and other functions were investigated in laboratory animals. The results obtained are summarized as follows. 1. Respiratory and cardiovascular systems: Oral administration of T-3761 at doses of 100-1,000 mg/kg did not affect in conscious rats. But intravenous administration of T-3761 at doses of 10-100 mg/kg caused an increase in respiratory rate, induced hypotension, caused increase or decrease in heart rate and altered ECG patterns (elevation of T waves and reduction of voltage of QRS complexes, etc.) in anesthetized dogs. Intravenous administration of T-3761 at doses of 10-100 mg/kg showed respiratory rate increase or decrease, hypertension, heart rate decrease and ECG patterns changes (T waves elevation and extrasystole) in anesthetized rabbits. 2. Autonomic nervous system and smooth muscle organs: T-3761 increased the epinephrine-induced contraction of the isolated guinea pig vas deferens at concentration of 10(-5)-10(-4) g/ml. T-3761 decreased the acetylcholine-induced contraction of the isolated guinea pig ileum and epinephrine-induced relaxation of the isolated guinea pig trachea-chain at concentration of 10(-4) g/ml. T-3761 increased the norepinephrine-induced contraction of the isolated rabbit thoracic aorta at concentration of 10(-4) g/ml. Oral administration of T-3761 at a dose of 1,000 mg/kg exerted slight mydriasis in mice. 3. Digestive system: T-3761 decreased the spontaneous motilities of isolated ileum and colon at concentration of 10(-4) g/ml. Oral administration of T-3761 at a dose of 1,000 mg/kg inhibited gastric output and intestinal transit time in rats or mice. 4. Renal functions: Oral administration of T-3761 at a dose of 300 mg/kg increased Na+ excretion but did not affect PSP excretion in rats. 5. Hematological examinations: T-3761 showed no effects on resistance to hemolysis, blood coagulation and platelet aggregation in rabbits at concentration of 10(-6)-10(-4) g/ml. Oral administration of T-3761 at dose of 100-1,000 mg/kg did not affect bleeding time or blood glucose level in rats. 6. Miscellaneous effects: Intravenous administration of T-3761 at a dose of 100 mg/kg slightly inhibited the twitch tension of gastrocnemius in anesthetized rats. Oral administration of T-3761 at doses of 300-1,000 mg/kg exerted slight augmentation of carrageenin-induced hind paw edema in rats. From these results, it can be assumed that T-3761 had a wide safety margin as an oral antibacterial agent.

Effect of iguratimod and other anti-rheumatic drugs on adenocarcinoma colon 26-induced cachexia in mice.

OBJECTIVE: To examine the effect of iguratimod (T-614) and other anti-rheumatic drugs on a mouse model of adenocarcinoma-induced cachexia. METHODS: Cachexia was induced in BALB/c mice by s.c. inoculation of colon 26/clone 20 cells (day 0). The drugs were administered p.o. daily from day 0 for 15 days for prophylactic experiments and from day 7 for 8 days for therapeutic experiments. Serum biochemical parameters and wasting of adipose tissue and muscle were evaluated as the nutritional condition in tumor-bearing mice at day 14. Interleukin-6 (IL-6) levels in serum and tumor tissue of those mice were also quantified. RESULTS: Administration of T-614 did not inhibit the tumor growth, but it resulted in attenuation of cachexia symptoms, such as the reduction in epididymal fat and gastrocnemius muscle, and the decrease of serum albumin. Furthermore, T-614 decreased the serum levels of IL-6, and reduced its gene expression in the tumor tissues. Exogenously administered IL-6 nullified the suppressive effect of T-614. Prednisolone prevented the weight loss and the wasting without inhibiting tumor growth. Methotrexate and indomethacin did not exert any preferable effects in a therapeutic dosing schedule. CONCLUSIONS: Our results demonstrate that T-614 exerts an anticachectic effect in tumor-bearing mice through the inhibition of IL-6 gene expression.

Right ventricular metastasis from a primary cervical carcinoma.

A 49-year-old female presented with a 1-month history of cough and low-grade fever. Echocardiography showed a large mass in the right ventricle and percutaneous right ventricular endomyocardial biopsy provided the histologic diagnosis. Despite radiotherapy and chemotherapy, the patient died. At autopsy, the metastatic deposit in the heart was larger than the primary cervical carcinoma.

Statistical analysis of symptoms and signs in pediatric patients with peptic ulcer.

It is not well known which symptoms or signs related to peptic ulcer are crucial for its diagnosis in children. In order to clarify this problem, we evaluated the sensitivity, specificity, and positive and negative predictability of 13 ulcer-related symptoms and signs. The data of 160 patients, who were suspected of having peptic ulcer and had undergone endoscopic examinations, were studied. It was significant that five symptoms, i.e., presence of pain in the epigastrium, relationship between the time of pain and that of eating, family history, vomiting, and bleeding, were frequently found in ulcer patients. There was, however, no symptom or sign that predicted by itself precisely the existence of a peptic ulcer. Thus, we computed a discriminant function by combining the data by multivariate analysis. With this score, we could predict the existence of ulcer more precisely. Finally, it was concluded that epigastric pain, food-related pain, vomiting, bleeding, and family history were crucial factors for the diagnosis of peptic ulcer in childhood and that an overall consideration of symptoms and signs was needed for the evaluation of these factors.