[A case of multiple liver metastases from sigmoid colon cancer effectively treated by hepatic intra-arterial administration of levoforinate and 5-fluorouracil].

A 62-year-old female patient, who was diagnosed with sigmoid colon cancer with multiple liver metastases, was admitted to our hospital. She underwent sigmoidectomy with D3 lymph node dissection on January 31, 2000. In addition to that, she received hepatic intra-arterial infusion of levoforinate (l-LV) 250 mg and 5-fluorouracil (5-FU) 500 mg for combined multiple hepatic metastases starting on postoperative day 14, and these medications were administered over 48 hours once weekly by infuser pump. The tumor diminished by 59% 2 months after the start of administration and further diminished at 4 months. PR was achieved. Cancer metastasis to the cerebellum and metastasis to the lung were detected at month 9 and month 11, respectively, but the liver metastatic tumor continued to diminish in size, ultimately becoming undetectable by CT scan at month 10. Surgery and radiotherapy were performed for the cerebellar metastasis, and intravenous administration of a combination of l-LV and 5-FU was performed systemically for the pulmonary metastatic tumor. At present, the patient receives regular outpatient treatment continuously. To our knowledge, there has been no report on the combination therapy with l-LV and 5-FU through the hepatic artery. Since good antitumor efficacy was demonstrated in the present patient, this case is described in this report together with four other cases of hepatic metastasis from colorectal cancer.

[A case of miliary tuberculosis and chest wall cold tuberculous abscess with contents draining into the epidural space].

A 37-year-old man was admitted because of miliary tuberculosis. However, his fever and general condition did not improve with chemotherapy. Six months later, paraplegia occurred following sudden radicular back pain without any alteration of segmental sensation. There were no abnormal findings on X-ray films of the thoracic and lumbar vertebrae. Examination by magnetic resonance imaging revealed that the contents of a cold tuberculous abscess in the right chest wall had drained into the epidural space through the intervertebral foramen. Drainage of the chest wall abscess and laminectomy were performed. Further investigation showed that this case did not belong to the usual type of atypical spinal tuberculosis reported previously.

[Pulmonary nodule confirmed by rib consolidation on thoracic computed tomography].

Coin lesions in the thoracic cavity, skin, muscle and connective tissue are clearly observed by computed tomography (CT). However, it is very difficult to detect abnormal shadows in the ribs by thoracic CT at the mediastinal level. We describe 3 cases of pulmonary nodules that were not detected by CT at the mediastinal or lung field level, however, but could be detected at the bone level. When pulmonary nodules cannot be detected by thoracic CT at the mediastinal or lung field level, it is recommended to change the window to the bone level.

Similarity and dissimilarity in the stereogeometry of the active sites of thrombin, trypsin, plasmin and glandular kallikrein.

The relationship between chemical modifications of arginine derivatives and inhibitory activity to trypsin, plasmin and glandular kallikrein was investigated comparing with that of thrombin and concluded as follows: The hydrophobic binding pocket, which has been reported previously to be stereogeometrically very similar in trypsin and thrombin, corresponded to the length of ethylpiperidine. Concerning the site (termed the P site) next to the hydrophobic binding pocket, there were large differences in stereogeometry between trypsin and thrombin; the binding site of trypsin extended further to allow propyl and phenyl group attached to piperidine, while that of thrombin would be much narrower and unable to allow them. The P sites of plasmin and glandular kallikrein resembled that of trypsin in being able to allow phenyl group. To substantialize the hydrophobic binding pocket and the P site, a (2R, 4R)-MQPA-trypsin complex model was generated using the results of X-ray crystallography of (2R, 4R)-MQPA and BPTI-trypsin complex by calculation to minimize van der Waals contacts, and it was of great use for understanding the geometry of the active sites of trypsin, thrombin, plasmin and glandular kallikrein.

Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl++ +) sulfonyl]-l-arginyl)]-2-piperidinecarboxylic acid.

The potency of thrombin inhibition by 4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfony l]- L-arginyl]-2-piperidinecarboxylic acid (MQPA) depended on the stereoconformation of the 2-piperidinecarboxylic acid moiety. Ki values for bovine alpha-thrombin were 0.019 microM with (2R,4R)-MQPA, 0.24 microM with (2R,4S)-MQPA, 1.9 microM with (2S,4R)-MQPA, and 280 microM with (2S,4S)-MQPA. (2R,4R)-MQPA of the four stereoisomers of MQPA was also the most potent inhibitor for other trypsin-like serine proteases with Ki values of 5.0 microM for trypsin, 210 microM for factor Xa, 800 microM for plasmin, and 1500 microM for plasma kallikrein. Examination of the potency of thrombin inhibition by arginine derivatives related to MQPA in structure suggested the presence of a specific binding site for the carboxamide portion (C-terminal side). The relative inhibitory potency of the four stereoisomers of MQPA for trypsin was nearly identical with that for thrombin, suggesting that the specific binding site for the carboxamide portion is present in both enzymes. Modification of thrombin by phosphopyridoxylation or the presence of heparin did not significantly alter the binding of MQPA.

Synthesis and antidepressant activity of substituted (omega-aminoalkoxy)benzene derivatives.

A series of substituted (omega-aminoalkoxy)benzene derivatives has been synthesized and screened for potential antidepressant activities. The effect of structural variation of these molecules has been systematically examined. Antidepressant activity was clearly displayed by 2-benzyl-1-[4-(methylamino)butoxy]benzene (7), 2-(2-hydroxybenzyl)-1-[4-(methylamino)butoxy]benzene (19), 1-[4-(methylamino)butoxy]-2-phenoxybenzene (29), and 1-[4-(methylamino)butoxy]-2-(phenylthio)benzene (31) in further pharmacological studies. These compounds did not possess the anticholinergic, antihistaminic, and muscle-relaxant side effects common to tricyclic antidepressants.

Pharmacological evaluation of 2-(4-methylaminobutoxy)diphenylmethane hydrochloride (MCI-2016), a new psychotropic drug with antidepressant activity.

Pharmacological properties of 2-(4-methylamino-butoxy)-diphenylmethane hydrochloride (MCI-2016) were examined in comparison with those of other antidepressants. MCI-2016 significantly antagonized the hypothermia and depression-like syndrome produced by reserpine injection. Furthermore, the drug exhibited such activities as antitetrabenazine and anti-cataleptic actions, and potentiation of the behavioural excitation induced by yohimbine, methamphetamine and L-dopa. MCI-2016 showed a definite suppressive effect on muricidal activity in olfactory bulb removed rats and the long-term isolation-induced fighting in mice without causing apparent motor disturbance. Judging from the effects of the drug on in vitro response to noradrenaline (NA) and serotonin (5-HT), and on p-chloramphetamine-induced hypermotility, it is suggested that MCI-2016 is a selective potentiator of NA presumably due to an inhibition of NA uptake. Anticholinergic and sedative actions of MCI-2016 were considerably weaker than those of amitriptyline and imipramine. Acute toxicity of MCI-2016 was the weakest among the drugs tested. These pharmacological profiles may suggest a potential clinical utility of MCI-2016 as a new psychotropic agent having an antidepressant activity.

Thrombin inhibitors. 3. Carboxyl-containing amide derivatives of N alpha-substituted L-arginine.

A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives having carboxamide N-substituents with a carboxyl group was prepared and tested as inhibitors of the clotting activity of thrombin. The most inhibitory compounds were obtained when a carboxyl group was introduced into the carbon next to the amide nitrogen of N alpha-(arylsulfonyl)-L-arginine amide derivatives, e.g., N alpha-(arylsulfonyl)-L-arginyl-N-butyl-, N-(methoxyethyl)- or N-(tetrahydrofurfuryl)glycine and 4-alkyl-1-[N alpha-(arylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid, with an I50 of 1-3 X 10(-7) M.

Thrombin inhibitors. 1. Ester derivatives of N alpha-(arylsulfonyl)-L-arginine.

A series of N alpha-(arylsulfonyl)-L-arginine esters was prepared and tested as inhibitors of the clotting activity of thrombin. N alpha-Dansyl-L-arginine methyl ester was the most inhibitory of the N alpha-(arylsulfonyl)-L-arginine methyl esters. The most potent inhibitors were the n-propyl and n-butyl esters of N alpha-dansyl-L-arginine with an I50 of 2 X 10(-6) M. Esters of unsaturated straight-chain alcohols with a chain length of four carbons were also as inhibitory as the n-butyl ester. The inhibitors were hydrolyzed by thrombin and trypsin more slowly than N alpha-tosyl-L-arginine methyl ester.

Thrombin inhibitors. 2. Amide derivatives of N alpha-substituted L-arginine.

A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives with substituted or unsubstituted naphthalene and heterocyclic compounds as the N alpha-substituent was prepared and tested as inhibitors of the clotting activity of thrombin. N-n-Butyl and N-n-butyl-N-methyl derivatives of N alpha-dansyl-L-arginine amide were the most inhibitory of N-alkyl and N,N-dialkyl derivatives of N alpha-dansyl-L-arginine amide. Their inhibitory effect was as potent as that of N alpha-dansyl-L-arginine-n-butyl ester with an I50 of 2 X 10(-6) M. N alpha-Substituted naphtalenesulfonyl-L-arginine amide derivatives of 4-methyl- and 4-ethylpiperidine also showed a potent inhibition with an I50 of 10(-7) to 10(-6) M. The most potent inhibitior in this study was 1-[N alpha-(4,6-dimethoxynaphthalene-2-sulfonyl)-arginyl]-4-methylpiperidine, with an I50 of 7.5 X 10(-8) M. Arginine amide derivatives of 4-methyl- or 4-ethylpiperidine with tetralin or an oxygen-containing heterocyclic compound as a N alpha-substituent showed an inhibition with an I50 less than 10(-5) M. N-Monosubstituted derivatives of N alpha-dansyl-L-arginine amide were not hydrolyzed at all by thrombin and were hydrolyzed very slowly by trypsin, and N,N-disubstituted derivatives were not hydrolyzed at all by both enzymes.