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PubMed1982

[Clinical trial of K-247].

The clinical trial of K-247, an anticancer drug showing antitumor effect by new mechanism of action, was performed in a total of 22 patients with a variety of advanced cancers, consisting of 10 cases administered singly and 12 cases combined with other anticancer agents. All patients were treated three or four times every day with oral administration of K-247 (600-800 mg/day). Including one patient receiving a high dosage (over 200 g totally) of K-247, in all cases, no appreciable side effect causing suspension of the administration was recognized. In combination therapies with other anticancer drugs there was rather found a tendency to rescue WBC from decrease. As a clinical result, although all cases tested were insusceptible to prior chemotherapy with various anticancer drugs, one case, which has received palliative operation for rectal cancer accompanied with pelvic infiltration, was experienced after administration of K-247 only, in which the destructive lesion of left sacral on X-ray photograph was restored to almost normal condition and the patient's complaints such as severe pain in the lower legs and difficulty in walking were completely disappeared.

4-Aminobenzoic Acid↗
PubMed1982

[Antitumor effects of p-aminobenzoic acid-N-xyloside Na--effects of single administration and combination with radiotherapy].

Therapeutic effect of p-aminobenzoic acid-N-xyloside Na (K-247) were studied. Eleven patients with a variety of solid tumors were treated with K-247 alone. K-247 was given orally 800mg daily for 4 weeks. As for side effect of the drug, only mild gastritis was observed in a few patients. Partial response (over 25% reduction of tumor size) with a median duration of two months was observed in 3 patients. These cases were metastatic tumor of lung from the carcinoma of thyroid, metastatic tumors of lung from the carcinoma of kidney, and mediastinal tumor. In eight patients the response was classified as no change and in one patient there was progressive disease. Thus K-247 has some therapeutic activity in patients with solid tumor. Combination therapy of irradiation and administration of K-247 were also studied. In twelve patients received the combination therapy, partial response was observed in 7 patients with complete response in 3 patients. In some patients it seems that the effect of irradiation was enhanced by K-247 administration. To confirm this observation, randomized controlled trial is required.

4-Aminobenzoic Acid↗
PubMed1982

[Immunological study of the actions of auxiliary antitumor agents--effects on lymphocyte transformation reaction and natural cytotoxicity activity in nude mice].

P-aminobenzoic acid-N-xyloside (K-247) and dimethyl-2- (tetrahydro-2-furanyl) ethylsulfonium-p-toluene sulfonate (GT-101) were tested their in vivo effects on both mitogen-induced lymphoproliferative reactions and natural cell-mediated cytotoxicities in BALB/c nude mice (homozygous and heterozygous) spleen lymphocytes. The animals were injected i.p. either 400 mg/kg of K-247 or 5 mg/kg of GT-101 (for 7 days consecutively). GT-101 caused a positive increase in lymphoproliferations by PHA and SPA, while the administration of K-247 had no effect on PHA-and SPA-induced lymphoproliferations. Furthermore, in a 12-hour 51Cr release assay, both drugs had no effect on the natural cell-mediated cytotoxicity against YAC-1 cells.

4-Aminobenzoic Acid↗
PubMed1982

[Clinical evaluation of anticancer therapy combined with p-aminobenzoic acid-N-xyloside].

Paraaminobenzoic acid-N-xyloside (K-247) is a new antitumor drug, which has no direct effect on immunologic status. Clinical trial of K-247 was performed in 8 patients with for advanced or recurred gastrointestinal cancer, who had short life expectancy. Oral administration of K-247, 600 to 900 mg/day, was carried out in combination with antitumor treatments using MMC, FT-207, 5-FU, PSK or irradiation. No toxic symptoms were observed in all patients. Of the 8 patients studied, one showed an encouraging response, while the remaining 7 patients were too far advanced to respond to these treatments.

4-Aminobenzoic Acid↗
PubMed1982

Antiatherogenic activity of cetaben sodium, sodium p-(hexadecylamino) benzoate, in the aortae of hypercholesteremic rabbits subjected to aortic endothelial cell desquamation.

The effects of sodium p-(hexadecylamino)benzoate [cetaben sodium] on plasma sterol concentrations, aortic sterol deposition and the incidence of atherosclerotic lesions in cholesterol-fed rabbits subjected to aortic deendothelialization with a balloon catheter have been studied. At a dose of 113 mg/kg/day, cetaben sodium decreased plasma cholesterol and the accumulation of aortic sterol and appeared to decrease the incidence of gross atherosclerotic lesions. At a dose of 27 mg/kg/day, no hypocholesteremic activity was observed, but cetaben sodium decreased both aortic sterol deposition and lesion development in the abdominal segment of the aorta. The decreases in total aortic sterol content observed in the drug-treated rabbits were shown to have resulted from a reduction in esterified rather than free sterol. When tested in vitro, cetaben sodium effectively inhibited (KI = 7.4 x 10(-5) M) the esterification of cholesterol catalyzed by a crude preparation of fatty acyl CoA:cholesterol acyl transferase isolated from cholesterol-fed rabbit aortae. These observations suggest that cetaben sodium possesses antiatherosclerotic activity and that this activity may result from direct actions on the aortic wall, in addition to vascular effects secondary to hypocholesteremic activity.

4-Aminobenzoic Acid↗
PubMed1981

Clinical study of exocrine pancreatic function test by oral administration by N-benzoyl-L-tyrosyl-p-aminobenzoic acid.

The clinical usefulness of a simple exocrine pancreatic function diagnostic test (PFT) was examined by the oral administration of 500 mg of N-benzoyl-L-tyrosyl-p-aminobenzoic acid. Recovery of p-aminobenzoic acid (PABA) in the urine was significantly lower in patients with calcifying chronic pancreatitis (58.6%) and noncalcifying chronic pancreatitis (68.6%) than in healthy normal subjects (81.0%; p less than 0.001 and p less than 0.05, respectively). Abnormally low values were demonstrated in 15 out of 19 (78.9%) chronic pancreatitis cases. In comparing the PFT with the pancreozymin secretin test, a good correlation (P less than 0.001) with maximum bicarbonate concentration was detected. In cases which were abnormal with respect to the PFT, the recovery rate of PABA was increased by the administration of antacids or digestive enzyme preparations (average increase of 24.1 or 29.8%, respectively). These results suggest that this test is also useful for the evaluation of therapeutic effects in patients with pancreatic diseases.

4-Aminobenzoic Acid↗
PubMed1980

New strategies in the development of anti-atherosclerotic drugs.

The results of several recently completed trials of cardiovascular prevention, by the use of hypolipidemic or anti-platelet compounds, have suggested that new strategies be followed for the development of anti-atherosclerotic drugs. The final outcome of preventive studies with hypolipidemic compounds is markedly influenced by the significance of the achieve hypolipidemia, as well as by the side-effects, some which, i.e. lithogenicity, may be related to the drugs' mechanism of action. Significant differences may, moreover, exist between the findings in animal models and in humans, particularly by clofibrate and related compounds. The evaluation of drugs active on lipoprotein biosynthesis in the gut (metformin), potent enzyme inhibitors (compactin) and with chelating activity (cetaben), is awaited with interest. In the field of drugs affected platelets, a selective sensitivity for the major compounds in different vascular areas has been observed. Aspirin appears to be mostly effective in cerebro-vascular prevention. Agents affecting the thrombin-platelet coagulation interaction, i.e. GYKI 14,451, may offer an interesting opportunity for testing the importance of this pathway in clinical thrombosis.

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PubMedDate not supplied

[Study of the histaminergic mechanisms of the action of malaben].

In rabbits (intact and with experimental myocardial infarction) histamine metabolism (histamine content and diaminoxidase activity) following introduction of malaben was studied. In intact animals the ability of malaben to reduce the blood histamine level and to activate diaminoxidase was discovered. Administration of malaben in experimental myocardial infarction promotes a quicker normalization of the disturbed metabolism of histamine.

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PubMedDate not supplied

[Protease inhibitors as immunomodulators in experimental acute pancreatitis and staphylococcal infection].

The influence of protease-inhibiting preparations on the development of humoral immune response in diseases involving the development of secondary immunodeficiency (experimentally induced acute pancreatitis and staphylococcal infection) has been studied. Five injections of contrycal and epsilon-aminocaproic acid (epsilon-ACA), starting from day 1 after the induction of acute pancreatitis, normalized the immune response induced by sheep red blood cells 24 hours after operation. In staphylococcal infection protease-inhibiting preparations (contrycal, epsilon-ACA, Amben) produced a protective effect, increasing the survival rate and the mean survival time of the animals infected with staphylococci.

4-Aminobenzoic Acid↗
PubMedDate not supplied

[The Amben regulation of the intestinal microflora and macrophage functional activity in an experiment].

The possibility of the correction of intestinal microflora disorders and the functional activity of macrophages in dysbiosis, caused by the intragastric administration of ampiox, with the use of amben (PAMBA), an inhibitor of proteolytic enzymes, was studied. Quantitative and qualitative changes in the main representatives of automicroflora, the functional activity of macrophages in the phagocytosis of 51Cr-labeled sheep red blood cells, the intensity of protein synthesis, the content of cathepsin D, acidic phosphatase and nitro blue tetrazolium activity were determined. The combined administration of ampiox and amben normalized quantitative and qualitative ratios of the main representatives of intestinal microflora, as well as the characteristics of macrophage functional activity, studied in this investigation. The administration of amben to intact animals was found to stimulate bifido- and lactoflora.

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PubMed1995

Homologous desensitization of 5-hydroxytryptamine4 receptors in rat esophagus: functional and second messenger studies.

We have studied agonist-induced desensitization of 5-hydroxytryptamine (5-HT4) receptor-mediated relaxation and 5-HT4 receptor-mediated increases in cAMP in rat esophageal tunica muscularis mucosae. In both cases, the desensitization time course was biphasic. The first phase was very rapid because more than 50% of desensitization was obtained after a 5-min incubation period with 10 microM of 5-HT. The second phase was slower and led to a complete suppression of the response after 2 h. Desensitization progressively reduced the maximal relaxation of esophagus induced by 5-HT without significantly affecting the EC50. Desensitization was a receptor-mediated event because cross-desensitization was observed between two chemically unrelated 5-HT4 receptor agonists, 5-HT itself and (S)-zacopride. Inasmuch as the kinetics of desensitization were the same when second messenger production or final responses were measured, this suggests that the limiting step in the desensitization process is at the level of the receptor itself or in its coupling to adenylyl cyclase. The desensitization was of the homologous type because exogenously applied cAMP, 8-Bromo-cAMP, or compounds increasing cAMP in the esophageal tunica muscularis mucosae such as isoproterenol and forskolin, were unable to induce any desensitization of the 5-HT4 receptor-induced relaxation response. Homologous desensitization was not followed by a rapid down-regulation of 5-HT4 receptors because no decrease in the Bmax of [3H]-GR113808 binding was observed after 30-min incubation with 10 microM 5-HT.

4-Aminobenzoic Acid↗
PubMed1994

Long-term nutritional and metabolic consequences of pancreaticoduodenectomy in children.

BACKGROUND: The long-term nutritional and metabolic consequences of pancreaticoduodenectomy in children are unknown. METHODS: Five children were evaluated in a clinical research center 2.5 to 10 years after pancreaticoduodenectomy to assess their nutritional status based on patterns of growth and to assess their gastrointestinal function. Investigation included vitamin levels, a bentiromide study, and serum immunoreactive trypsinogen levels to evaluate pancreatic function and a d-xylose absorption and a radionuclide gastric emptying scan for intestinal absorption and motility. RESULTS: Children were able to grow after pancreaticoduodenectomy. Three remained in low percentile groups for height/weight ratio, and two were near or above normal. Low normal levels of the fat-soluble vitamins were present. Very low levels of pancreatic function were found based on the bentiromide and trypsinogen studies, whereas intestinal absorption of d-xylose was normal except for one patient with extremely rapid gastric emptying. CONCLUSIONS: After pancreaticoduodenectomy children can grow and develop normally if given adequate levels of oral pancreatic supplements to replace the severely decreased level of endogenous pancreatic enzymes after operation. Routine supplementation of the fat-soluble vitamins should be considered.

4-Aminobenzoic Acid↗
PubMed1994

Antagonists of 5-HT4 receptor-mediated responses in adult hippocampal neurons.

The study of serotonin-4 (5-HT4) receptors in the central nervous system has been hindered by the lack of effective, selective antagonists. However, recently, several novel compounds have been synthesized and shown to act as antagonists at 5-HT4 receptors in smooth muscle and embryonic neurons in culture. In the present study, intracellular electrophysiological recordings were used to test the effects of three of these compounds: endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-6-methoxy- 2-oxo-1H-benzimidazole-1-carboxylate (DAU 6285), [1-[2-(methylsulfonylamino)ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate (GR 113808) and 2-diethylaminoethyl-(2-methoxy-4-amino-5-chloro) benzoate (SDZ 205-557) on the 5-HT4 reduction of the afterhyperpolarization seen in adult CA1 hippocampal neurons in brain slices. GR 113808, SDZ 205-557 and DAU 6285 all functioned as competitive antagonists at these 5-HT4 receptors. Although all three compounds tested acted as effective antagonists, they differed considerably in potency. When the potency of these antagonists at the 5-HT4 receptor that mediates the reduction of the afterhyperpolarization was compared with that observed for 5-HT4 receptors in biochemical and binding assays, an excellent correlation was observed. Among the antagonists tested, GR 113808 was the most potent (pA2 = GR 113808 > SDZ 205-507 > DAU 6285). It exhibited an apparent affinity for the 5-HT4 receptors in the low nanomolar range but did not antagonize 5-HT1A, beta-adrenergic or muscarinic receptor-mediated responses when applied at concentrations two orders of magnitude higher.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminobenzoic Acid↗
PubMed1994

[3H]RS-23597-190, a potent 5-hydroxytryptamine4 antagonist labels sigma-1 but not sigma-2 binding sites in guinea pig brain.

Recent findings have suggested a relationship between 5-hydroxytryptamine (5-HT)4 receptors and sigma binding sites. To test this idea, the affinity of 5-HT4 receptor ligands for sigma binding sites was examined. In contrast to the 5-HT4 receptor ligands BIMU-1 [endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3- dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride] and BIMU-8 [endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H-benzamidazole-1-carbox ami de hydrochloride], DAU 6215 ]N-(endo-8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-2,3-dihydro-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride], 5-HT and 5-methoxytryptamine had low affinity for sigma binding sites (pKi < 6). Conversely, the sigma ligands haloperidol and pentazocine had low affinity for 5-HT4 receptors. Thus, no relationship was found between the affinity of ligands at 5-HT4 receptors and sigma binding sites. However, one potent 5-HT4 receptor antagonist, RS-23597-190 [3-(piperidine-1-yl)propyl-4-amino-5-chloro-2-methoxybenzoate hydrochloride], had high affinity for sigma-1 (pKi = 8.4) but not sigma-2 (pKi = 6.2) binding sites. [3H]RS-23597-190 bound to a saturable site with the pharmacology of a sigma-1 binding site: (pIC50) haloperidol (9.0) > (+)-pentazocine (8.8) > (+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine (8.2) > 1,3-di-o-tolyl-guanidine (8.0) > (-)-pentazocine (7.8) = (+)-SKF 10,047 [N-allylnormetazocine] > (-)-SKF 10,047 (6.2) > BIMU-1 (5.3) > 5-HT and 5-methoxytryptamine. The distribution of [3H]RS-23597-190 binding sites was similar to that described for other sigma radioligands, with the greatest binding densities in cranial nerve nuclei, the tegmental nucleus and in the mamillary nucleus. In contrast to (+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine, [3H]RS-23597-190 binding was not allosterically modulated by phenytoin. These studies do not support the notion of an obvious relationship between sigma and 5-HT4 receptors, but they provide additional insight into the structure/affinity relationship of ligands at specific sigma binding sites, and they uncover a novel sigma-1 receptor ligand whose binding is insensitive to the action of phenytoin.

Aminobenzoates↗
PubMed1994

[Reexamination of BT-PABA test (PFD)--on the substrate specificity for pancreatic chymotrypsin in vivo].

It is widely believed that BT-PABA is a specific substrate for pancreatic chymotrypsin, and based on this concept, BT-PABA test is used to evaluate the exocrine pancreatic function. But this test shows unusual clinical results particularly in patients after total pancreatectomy. In order to reevaluate the specificity of BT-PABA for chymotrypsin, we investigated the intestinal influence on this substrate in in vivo and in vitro studies using mongrel dogs under the conditions of complete absence of pancreatic juice in the alimentary tract. In vivo study showed that serum PABA increased after BT-PABA administration in the models of complete absence of pancreatic chymotrypsin and in vitro study demonstrated BT-PABA splitting activity fo jejunum and ileum mucosal homogenate which increased after total pancreatectomy. Hence, we concluded that BT-PABA is not a specific substrate for pancreatic chymotrypsin in vivo in human and in dog.

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