Pharmacological studies of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate. Effects on experimental pancreatitis

The effects of FUT-187 (6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, CAS 103926-82-5), a novel synthetic protease inhibitor, were examined in experimental rat and canine models of pancreatitis. 1. FUT-187 significantly increased the survival of rats with trypsin- and phospholipase A2-induced pancreatitis in a dose-dependent manner (10-100 mg/kg, p.o.). 2. FUT-187 decreased plasma enzymatic activity reflecting the degree of pancreatitis in rats with ethionine-induced pancreatitis, and showed a tendency to ameliorate histopathological changes in the pancreas (10-100 mg/kg p.o.). 3. FUT-187 (10 mg/kg) produced an obvious improvement of various biochemical parameters of pancreatitis and also reduced histopathological changes in the pancreas in animals with experimental pancreatitis produced by the closed duodenal loop method. In addition, FUT-187 significantly increased the survival of dogs when given by direct administration into the lumen of the closed duodenal loop. The therapeutic effects of FUT-187 in experimental pancreatitis were nearly equal in most instances to those of camostat mesilate. Thus, FUT-187 would appear to be an effective new agent for the treatment of pancreatitis.     

Kappa-opioid-receptor agonists modulate the renal excretion of water and electrolytes in anaesthetized rats.

1. Subcutaneous injection of the kappa-opioid agonists U50,488 (10 mg kg-1) and tifluadom (3.5 mg kg-1) into Inactin-anaesthetized, saline-infused rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 2 h. A high (5 mg kg-1), but not low (0.1 mg kg-1), dose of naloxone blocked the renal effects of U50,488. 2. U50,488 administration in anaesthetized, vasopressin-deficient Brattleboro DI rats was associated with an attenuated diuresis, though the antinatriuretic response remained intact. 3. The diuretic action of U50,488 was associated with an increase in glomerular filtration rate while fractional fluid reabsorption remained steady. In contrast, fractional sodium and potassium reabsorption were increased. 4. These data suggest that kappa-opioid agonists alter renal handling of both water and electrolytes. This appears to be mediated by two separate mechanisms: increased fluid loss largely reflects altered glomerular events while the fall in electrolyte excretion results from altered tubular handling.     

Mycenon, a new metabolite from a Mycena species TA 87202 (basidiomycetes) as an inhibitor of isocitrate lyase

Mycenon (C11H5Cl3O3), a new inhibitor of isocitrate lyase (EC 4.1.3.1) was isolated from the culture broth of a basidiomycete, Mycena sp. Mycenon is a novel chlorinated benzoquinone derivative which is also active against bacteria and fungi. Malate synthase (EC 4.1.3.2) the second key enzyme of the glyoxylate cycle was not affected by mycenon. Isocitrate lyase preparations from plants, bacteria and fungi were sensitive. The following Ki-values for mycenon have been determined: Ricinus communis, 5.2 microM; Acinetobacter calcoaceticus, 11 microM; Neurospora crassa, 7.4 microM. The structure of mycenon has been determined by a single crystal X-ray analysis.     

Levodopa up-regulates platelet alpha 2-adrenoceptors

Treatment of dogs for 21 days with oral levodopa (100 mg b.i.d.) plus benserazide (25 mg b.i.d.) induced a significant increase in the number of platelet alpha 2-adrenoceptors labelled by [3H] yohimbine with no change in Kd. The rise was maximal at the end of the treatment and remained significant during the month following the cessation of treatment. Plasma catecholamine levels did not vary. Competition experiments showed a low affinity of both dopamine and levodopa for platelet alpha 2-adrenoceptors. These results suggest that levodopa treatment regulates alpha 2-adrenoceptor number in dog platelets.     

Effects of a new analog of thyrotropin-releasing hormone, N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate (YM-14673) on spinal reflex potentials and flexor reflexes in spinalized rats

Experiments were performed on spinalized rats, transected at the Cl level. The intravenous administration of TRH and its analog YM-14673 (N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate) produced marked increases in the amplitude of mono- and polysynaptic reflex potentials and those of the withdrawal flexor reflexes. The effects of YM-14673 were stronger and longer-lasting than those of TRH. The stimulant action of TRH and YM-14673 on the flexor reflexes was not antagonized by prazosin, chlorpromazine, haloperidol or cyproheptadine, suggesting no involvement of the release of catecholamines or serotonin in the stimulant effects of TRH and its analog. Therefore, YM-14673 may be beneficial for the treatment of several spinal motor neuron diseases.     

Reduction using an immunomodulator of the level of respiratory infections in chronic bronchitis

Fifty-six patients with recurrent bronchopulmonary infections associated with chronic bronchitis were randomly allocated to 2 groups, to assess whether treatment with an immunomodulator, Diribiotin CK, could enhance resistance to infection. The double-blind, placebo-controlled prospective trial over a 9 month period showed that this immunomodulator was well tolerated and significantly reduced the rate of respiratory tract infection. The drug also significantly reduced the prescribing of antibiotic medication and the rate of absenteism from work. These effects have been demonstrated in a rigorously designed clinical study. This is the first time that a clear clinical activity has been attributed to an inducer of soluble mediators of immunity.     

Alcoholism in patients with sexual disorders

The authors screened for alcoholism 145 consecutive patients who presented with sexual dysfunction or disorders. Using the Michigan Alcoholic Screening Test (MAST), 29% of the patients scored in the probable alcoholic range. Probable alcoholics were more likely to present without a partner and claimed higher sex drive than nonalcoholic patients. Probable alcoholic males reported less joy and vigor than probable alcoholic females, while the reverse held for the nonalcoholic groups. Blind to the MAST results, the staff made six alcohol-related diagnoses and referred one patient for alcohol treatment. The authors discussed the importance of training faculty and resident staff in the relationship of alcohol abuse associated with psychosexual dysfunctions.     

A case of a small hepatoma with multicentric development in precirrhotic fibrosis

Multicentricity of hepatocellular carcinoma (HCC) is considered, especially in patients with liver cirrhosis. This paper describes an operative case of a male patient with probable multicentric development of HCC in precirrhotic fibrosis. The main tumors inside the capsule were completely necrotic due to transarterial embolization (TAE). Histologic examination disclosed discrete tiny nodules of HCC that were not detected grossly. They showed highly differentiated trabecular arrangements: Edmondson I. A scirrhous type was noted in the center of the tumors. At the borders of the tumors the carcinoma cells exhibited replacing growth patterns and it was thought that they developed multicentrically. Partial resection must be performed as extensively as possible in a case such as the present one.     

Respiratory function and bronchial reactivity in mill workers

Professional exposure to vegetable dusts affect the respiratory function of the exposed subjects. A previous survey conducted in an industrial flour-mill demonstrated a higher frequency of respiratory symptoms in workers compared to a control group. Ten subjects employed in a work site particularly exposed to dust were studied. Each subject answered a questionnaire and performed on Mondays and Fridays, at the begenning and end of his work shift, a flow volume curve and an isocapnic hyperventilation test. The aerobiology of the professional environment was also measured. We noted: 1) in the flow volume curves: a drop in the FEV₁ during the Monday morning shift, a significant difference between the FEV₁ (p<0.05) and the MMEFR 25–75 (p<0.05) measured at 6 am on Monday and Friday, and between the MMEFR 25–75 values obtained at 12 noon on Monday and Friday (p<0.05). 2) after isocapnic hyperventilation, a significant drop in the MMEFR 25–75 at 6 am on Monday (p<0.01) and in the FEV₁ and MMEFR 25–75 at 12 noon on Mondays (p<0.05), a significant drop in the FEV₁ at 1 pm on Monday (p<0.01).     

Risk of non-Hodgkin's lymphoma among men occupationally exposed to organic solvents

An occupational history of exposure to organic solvents, defined as daily occupational exposure for at least one year, was more common among 167 men with newly diagnosed non-Hodgkin's lymphoma than among 130 healthy referents from the general population (38 versus 14%). Categorization in five-year age groups gave 3.3 as a Mantel-Haenszel estimate of the odds ratio (95% CI 1.9-5.8). The odds ratio was 6.5 (95% CI 3.2-13.3) for localized supradiaphragmatic tumors and 2.3 (95% CI 1.3-4.3) for other lymphoma presentations. In a logistic model including age and organic solvent, phenoxy acid, and chlorophenol exposure, it could be shown that solvent exposure was an independent risk factor and that no important interaction occurred between the risk factors. With increasing duration of exposure there was a significantly increased risk of lymphoma, a finding implying a dose-response relationship. There was no significant difference in tumor histology between the exposed and unexposed patients. These findings support the concept that occupational exposure to organic solvents is a risk factor for non-Hodgkin's lymphoma. The results also confirm a strong association between such exposure and an initial supradiaphragmatic location of the lymphomas.