Biomedical subjects
Publications and source records attributed to Y Karube.
We have developed a technique using a Mini Loop Retractor II and successfully performed video-assisted thoracoscopic surgery (VATS) in 32 patients. It is inserted into the pleural cavity through a skin puncture and a loop at its distal end is easily, and is freely adjustable in dimensions so that it can act as a retractor or holding forceps. Mini Loop Retractor II was very useful instruments in VATS.
Patients with gastrointestinal obstruction caused by peritonitis carcinomatosa suffer from chronic nausea, abdominal distension and inability to ingest food. Patients can receive home care only in rare cases. We performed a gastrostomy for the purpose of reducing gastrointestinal pressure in three patients with gastrointestinal obstruction caused by peritonitis carcinomatosa. The three patients had decreased mental and physical suffering and were able to be discharged from the hospital. We report the efficacy of gastrostomy because of the improvements in the three patients QOL at home.
A tetradentate chelating agent constituting of an iminodiacetic acid group and a nitrogen atom of pyridine, N-(2-pyridylmethyl)iminodiacetic acid (PMIDA), was coordinated with 99mTc and evaluated as a renal functional agent. The complex of PMIDA with 99mTc was prepared by using a stannous chloride solution as a reducing agent. The chelating efficiency was analyzed by thin layer chromatography and electrophoresis. Chelation with 99mTc resulted in a single radiochemical product. Biological studies were performed in mice and rats. 99mTc-PMIDA was removed from the circulation solely by the kidneys. Clearance of 99mTc-PMIDA from the blood and the kidneys was as rapid as that of 99mTc-diethylenetriaminepentaacetic acid. The rate of blood clearance was unaffected by the administration of probenecid (a test for tubular secretion by the weak-acid mechanism), so that the glomerular filtration rate could be estimated by measuring its clearance from the blood. The results in animals with myohemoglobinuric acute renal failure suggested that 99mTc-PMIDA might be a useful renal function radiopharmaceutical.
The method for subtracting the initial image from the localization image was evaluated for radioimmunoscintigraphy of tumors with technetium-99m (Tc-99m) labeled antibodies. Monoclonal antibodies were parental mouse and mouse-human chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and ChF11-39, respectively, both of which have been found to discriminate CEA in tumor tissues from the CEA-related antigens. After reduction of the intrinsic disulfide bonds, these antibodies were labeled with Tc-99m. In vivo studies were performed on athymic nude mice bearing the human CEA-producing gastric carcinoma xenografts. Though biodistribution results showed selective and progressive accumulation of Tc-99m labeled antibodies at the tumor site, high radioactivity in blood was inappropriate for scintigraphic visualization of the tumors within a few hours. We examined the subtraction of the initial Tc-99m image from the Tc-99m localization image after a few hours. Subtracted images of the same count reflected the in vivo behavior of the Tc-99m radioactivity. The subtracted scintigrams revealed excellent tumor images with no significant extrarenal background. Visualization of the tumor site was dependent on antigen-specific binding and nonspecific exudation. These results demonstrate that a method of subtraction of the initial image may serve as a potentially useful diagnostic method for an abnormal site for agents with a low pharmacokinetic value.
With the aim of overcoming the delivery problems (water-solubility and bioreductive activation problems) of phyllohydroquinone (PKH), an active form of phylloquinone (PK, vitamin K1), the N,N-dimethylglycine esters of phyllohydroquinone (1-mono, 1; 4-mono, 2; and 1,4-bis, 3) have been synthesized and assessed in vitro as a prodrug for the systemic bioreductive activation-independent delivery of PKH. The hydrochloride salts of the esters were found to be quite soluble in water. Hydrolysis of the esters in rat liver S9 fraction, rat plasma and phosphate buffer, pH 7.4, at 37 degrees C, was kinetically studied in the presence and absence of an esterase inhibitor. The hydrolysis was catalyzed by esterases located in rat liver and rat plasma and quantitatively yielded PKH. The enzymatic cleavage and the vitamin K-dependent carboxylation activity of the esters in the rat liver microsome preparation at pH 7.2 and 25 degrees C were studied. The regeneration of PKH from the esters was catalyzed by carboxylesterases located in the rat liver microsome, and the order was as follows: 1 > 3 > 2. The carboxylation was stimulated by selected ester 1 in the absence of dithiothreitol, an activator of the vitamin K cycle. The carboxylation activity of 1 was strongly inhibited in the presence of eserine, a carboxylesterase inhibitor. Compound 1 could also stimulate carboxylase under warfarin-poisoning conditions, where the vitamin K cycle was strongly inhibited. These results indicated that these highly water-soluble and liver-esterase hydrolyzable ester derivatives of PKH are potential candidates for parenteral prodrugs which can thus achieve the systemic bioreductive activation-independent delivery of PKH.
The N,N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; 1,4-bis, 3) were established in previous reports as prodrugs that could achieve the systemic bioreductive activation-independent delivery of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4), in rat. The present study was undertaken to investigate if the prodrugs could undergo cleavage to parent drug (MKH) by a human tissues enzyme catalyzed hydrolytic pathway, the mechanism of the prodrugs for vitamin K-dependent carboxylation in human liver and their action in the warfarin poisoned human liver. The hydrolysis of the esters was shown to be catalyzed by esterases located in human liver but not in human plasma. The susceptibility of the esters to undergo human liver esterase hydrolysis was affected by the esterified position: 1>2>3. By using a human liver microsomal test system, the stimulation of vitamin K-dependent carboxylation with the prodrugs was determined. The prodrug could stimulate the carboxylation activity in the absence of dithiothreitol, an artificial activator of the reductive activation pathway of MK-4. The carboxylation activity of the prodrug was strongly inhibited in the presence of eserine, an esterase inhibitor. The prodrug could also stimulate the carboxylase under warfarin-poisoned conditions, where the vitamin K cycle was strongly inhibited. The results confirmed that the prodrug could generate MKH in human liver (active site), and that the resultant MKH could act as a cofactor for the carboxylase without reductive activation processes of MK-4 to MKH. Such bioreductive activation-independent vitamin K-dependent carboxylation characteristic of the prodrug leads to enhanced pharmacological efficacy in the treatment of hypoprothrombinaemia induced in patients with coumarin and cephalosporin therapies.
Effects of the administration of a water-soluble prodrug of vitamin E on doxorubicine (DXR)-induced lethal and oxidative toxicity in mice were studied. The prodrug used was d-alpha-tocopheryl N,N-dimethylaminoacetate hydrochloride (TDMA). It was intravenously administered to animals 2 h prior to an intraperitoneal administration of DXR (15 mg/kg). The single preadministration of the prodrug (10-50 mg/kg equivalent for d-alpha-tocopherol) delayed the DXR-induced death and the ameliorative effect was TDMA-dose dependent. The extent of total lipid peroxidation of the heart and liver was assessed by 2-thiobarbituric acid reactant substance levels. DXR significantly accelerated lipid peroxidation in the liver but not in the heart. The elevation of liver lipid peroxide was significantly suppressed to a normal range by a single preadministration of TDMA (50 mg/kg equivalent for d-alpha-tocopherol). TDMA did not significantly affect the antitumor activity of DXR in mice inoculated with L1210 leukemia cells.
Conjugates of 2-aminooxyethyliminodiacetic acid with estrone, testosterone, epiandrosterone, 17-alpha-hydroxy-progesterone and progesterone were synthesized and their complexes with Tc-99m were successfully prepared in good yields, which indicated the agent to be promising for metal-labeling of biomolecules and related substances containing one or more carbonyl groups. The biodistribution and scintigraphic studies in mice bearing Ehrlich tumor and mammary tumor showed that the radioactivity accumulated considerably in the tumor tissues, but the tumor images were somewhat obscured.
The acid salts of aminoalkanecarboxylic acid esters of d-alpha-tocopherol were in a previous in vitro study identified as prodrug candidates for a parenteral form of d-alpha-tocopherol. The disposition of d-alpha-tocopheryl N,N-dimethylaminoacetate hydrochloride (TDMA), the most potential candidate for the prodrug, after a single intravenous administration was investigated and compared with that of the d-alpha-tocopheryl acetate (TA) and dl-alpha-tocopherol, solubilized with HCO-60, in order to establish the utility as a prodrug for i.v. administration. The preventive effect of the prodrug against endotoxin (lipopolysaccharide (LPS))-induced liver lipid peroxidation was also investigated in mice. The plasma and liver levels of alpha-tocopherol (Toc) were increased rapidly after i.v. administration of the prodrug. The distribution of Toc and TDMA in the plasma and the liver at 1 h was as follows; 2.1 +/- 0.2 (plasma, Toc), 2.0 +/- 0.2 (plasma, TDMA), 32.8 +/- 2.9 (liver, Toc), and 35.3 +/- 6.5% of dose (liver, TDMA). The rapid and liver-selective uptake and liver-esterase specific regeneration characteristics of the prodrug enhance the delivery of Toc to liver. The liver availability of Toc after i.v. administration of TDMA, TA and Toc were 116, 50 and 100%, respectively. The elevation of liver lipid peroxide induced with LPS was significantly suppressed to a normal range by a single i.v. postadministration of TDMA (over 10 mg/kg equivalent for Toc). These results indicated that the water-soluble and liver-esterase hydrolyzable derivative of Toc was a potential candidate for a parenteral prodrug which can thus achieve the systemic liver-specific delivery of Toc. Such effective and selective delivery of Toc into the liver can therefore lead to enhanced pharmacological efficacy against liver oxidative injury associated with free radicals.
Fibrinogen was labeled with Tc-99m by two methods and in vitro stability and the in vivo behavior in mice were studied. The Tc-99m labeling was performed by mixing an unreduced fibrinogen (UnFib) or a reduced fibrinogen (ReFib) with Tc-99m pertechnetate in the presence of stannous chloride. In both of them, chelation with Tc-99m resulted in a single radiochemical product. For the in vitro stability studies, Tc-99m labeled fibrinogen (Tc-99m UnFib) was prepared with UnFib, and transchelation with cysteine solution was easy to produce compared to Tc-99m labeled fibrinogen (Tc-99m ReFib) prepared with ReFib. The radioactivity bound to clottable protein for Tc-99m UnFib and Tc-99m ReFib was about 70% and about 69%, respectively. The in vivo behavior of these labeled fibrinogens was studied, and their efficiencies for imaging an abscess and Ehrlich tumor in mice were determined with a gamma camera. Technetium-99m UnFib underwent a rapid partial exchange of the Tc-99m with compounds of the blood buffer system in vivo, resulting in early biologically active and would be incorporated into the abscess and tumor. The uptake in the abscess increased slightly over time with Tc-99m ReFib, but the abscess to blood and abscess to muscle ratios were 0.09 and 2.6 at 5 hr, respectively. Clearly delineated images of abscess were obtained beginning at about 5 hr after injection. The tumor to blood and tumor to muscle ratios were 0.05 and 1.4 at 5 hr, respectively. The Ehrlich tumor image in mice was slightly visible at 10 hr. The short half-life of Tc-99m was inappropriate for fibrinogen with a low pharmacokinetic value, because it was necessary for imaging of the abscess and tumor to take a long time.
Biodistribution and imaging characteristics of Tc-99m-labeled parental mouse and mouse-human chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and ChF11-39, respectively, were evaluated in athymic nude mice bearing the human CEA-producing gastric carcinoma (MKN-45) xenografts. Group F monoclonal antibodies such as F11-39 and ChF11-39 have been found to recognize the protein epitopes present on the domain B3 of the CEA molecule and to discriminate CEA in tumor tissues from the CEA-related antigens. The Tc-99m labeling was performed by immediately mixing a reduced antibody by 2-mercaptoethanol with Tc-99m pertechnetate in the presence of stannous chloride. The labeling yields of the two antibodies were greater than 95% when estimated using gel chromatography. Although these Tc-99m-labeled antibodies were stable in neutral saline solution, Tc-99m from both labeled antibodies was associated with cysteine solution. Technetium-99m ChF11-39 was more susceptible to transchelation than was Tc-99m F11-39. The immunoreactivity of each Tc-99m-labeled antibody was confirmed using MKN-45 cell-binding assay. Biodistribution studies in tumor-bearing mice were performed at 1 h, 5 h, and 20 h after being given IV injections of 3.7 MBq of either Tc-99m F11-39 or Tc-99m ChF11-39. All tumor-to-organ uptake ratios increased with time for both Tc-99m-labeled antibodies. Imaging results also showed selective and progressive accumulation of both Tc-99m antibodies at the tumor site. Both these Tc-99m-labeled antibodies have proved to be good radiotracers giving satisfactory scintigrams of the CEA-producing tumor.
Whole-body autoradiography (WBAR) was used to study the biodistribution of 125I-labeled mouse-human chimeric antibody (Ch F11-39) to carcinoembryonic antigen (CEA) in athymic nude mice bearing the CEA-producing MKN-45 human gastric carcinoma xenografts. Significantly high uptake of 125I-Ch F11-39 in the tumors obtained by tissue-counting technique was confirmed by WBAR of mice of 12, 24, 48, and 96 h postinjection of 125I-Ch F11-39. When compared with histochemical or immunohistochemical staining results of the tumor tissue sections, imaging profiles of 125I-Ch F11-39 obtained by WBARs were topographically correlated with histopathological findings of tissues and immunohistochemical localization of CEA in the tumor tissues, indicating that the accumulation of 125I-Ch F11-39 at the tumor site is based on its specificity for CEA. These results demonstrate that this chimeric antibody may serve as a potential useful diagnostic and/or therapeutic reagent for human CEA-producing cancers.
Nine aminoalkanecarboxylic acid esters of d-alpha-tocopherol were synthesized and evaluated as potential water-soluble prodrugs suitable for parenteral administration. The hydrochloric acid salts of the esters were soluble in water. The kinetics of hydrolysis of the esters was studied in isotonic phosphate buffer, rat plasma, human plasma, and rat liver homogenate at 37 degrees C. The hydrolysis of the esters was proved to be catalyzed by liver esterases. The susceptibility of the esters to undergo liver esterase hydrolysis was affected by the structure of the amino functionality and size of the acyl moiety on the promoiety. The N-methylaminoacetyl and N,N-dimethylaminoacetyl esters of d-alpha-tocopherol were more rapidly hydrolyzed than d-alpha-tocopheryl acetate, a commercially available d-alpha-tocopheryl ester. These results suggested that the salts of the N-methylaminoacetyl and N,N-dimethylaminoacetyl esters are promising prodrug candidates of d-alpha-tocopheryl for parenteral use.
PURPOSE: The hydrochloride salts of the N,N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; and 1,4-bis, 3) were assessed in vivo as prodrug for the systemic site-specific delivery system of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4, vitamin K2(20)). METHODS: The disposition of MK-4 and menaquinone-4 epoxide (MKO) following the intravenous administration of the prodrugs and MK-4 preparation solubilized with surfactant (H-MK-4) were studied in vitamin K cycle inhibited rats. The relative bioavailability of MKH after the administration of the prodrugs was assessed from the area under the plasma concentration of MKO vs. time curve (AUCMKO). The specific delivery of MKH to its active site (liver) and coagulation activity after the administration of selected prodrug 1 were then compared with those of H-MK-4 in warfarin poisoned rats. RESULTS: All compounds showed linear pharmacokinetics, and significant bioavailability of MKH was also observed following the administration of 1 (188%), 2 (87%) and 3 (135%). Prodrug 1 caused the following increases; AUCliver of MKO from 70.7 +/- 5.77 (H-MK-4) to 167 +/- 7.89 nmol.h/g, MRTliver of MKO, from 3.87 +/- 0.307 to 8.57 +/- 0.432 h. The liver accumulation of intrinsic 1 reached a maximum (88% of dose) by 0.25 h. The rapid and liver-selective uptake and liver esterase mediated MKH regeneration characteristics of 1 enhanced the delivery of MKH to its active site and the selective advantage was increased 5.7 fold. The coagulation activity was extended 1.9 fold by 1 administration. CONCLUSIONS: The results indicated that these highly water-soluble and liver-esterase hydrolyzable ester derivatives of MKH are potential candidates for parenteral prodrugs which can thus achieve the systemic site-specific delivery of MKH. Such effective and selective delivery of MKH to its active site can therefore lead to enhanced pharmacological efficacy and can also avoid the toxicity induced by the solubilizing agent used in the H-MK-4 preparation.
The efficacy and toxicity of vitamin K depends on the pathway and the extent of enzymatic reductive activation to vitamin K hydroquinone, which is an essential cofactor for the synthesis of clotting factors. Parenteral use of vitamin K is impaired by its water insolubility. With the aim to improve delivery problems associated with menahydroquinone-4 (MKH, 2), an active form of menaquinone-4, N,N-dimethylglycine esters of 2 (1-mono, 4-mono, and 1,4-bis) were synthesized and assessed as potential water-soluble prodrugs for parenteral use. The esters can deliver the hydroquinone to its active site without a quinone reductive activation step. The hydrochloride salts of the esters were found to be quite soluble in water. The hydrolysis of the esters in 20% rat liver homogenate 9000 x g supernatant, rat plasma and phosphate buffer, pH 7.4, at 37 degrees C was kinetically studied in the presence and absence of an esterase inhibitor. The hydrolysis was catalyzed by esterases located in the rat liver and rat plasma and quantitatively yielded 2. These results suggest that esterification of 2 with N,N-dimethylglycine is a promising way for obtaining water-soluble prodrug forms of 2. Based on the high susceptibility to liver esterase, the esters are potential prodrugs for achieving the site-specific delivery of 2.
UNLABELLED: New cationic technetium-chelating agents containing a pyridinium group have been synthesized and evaluated as potential renal radiopharmaceuticals. METHODS: The pyridinium compounds used in the study are N-methyl pyridoxal chloride, N-ethyl pyridoxal chloride, N-propyl pyridoxal chloride, 1-methyl-3-hydroxy-4-formylpyridinium chloride, 1-methyl-2-formyl-3-hydroxypyridinium chloride and the Schiff's bases of N-methyl pyridoxal chloride with amino acid, amino acid ester and amino acid amide. Complexes of these chelating agents with 99mTc were prepared using a Na2S2O4 or a SnCl2 solution as a reducing agent. The purity of the 99mTc complexes was determined by paper electrophoresis in 0.1 M tris buffer. RESULTS: Electrophoresis indicates slightly positive-charged species. The log P values of these complexes showed a hydrophilic nature. Urinary excretion of the 99mTc N-alkylated pyridoxal derivatives, 99mTc-diethylenetriaminepentaacetic acid, 99mTc-mercaptoacetylglycylglycylglycine (MAG3) and 131I-O-iodohippurate were determined in mice and rats at different time intervals. In a rat model, the pyridoxal-derived 99mTc complexes are rapidly excreted in urine and provide clear renal scintigrams. Hepatobiliary excretion was negligible, reducing scan interference from the intestines. Total clearances were lower than that of 131I-hippurate and 99mTc-MAG3. CONCLUSIONS: The rate of urinary clearance of the new tracers was not significantly faster than 99mTc diethylenetriaminepentaacetic acid and the inhibitor N1-methylnicotinamide had only a minimal effect on the renal behavior. Though the new tracers have cationic properties, the pyridinium group did not contribute largely to the excretion of active transport.
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Machado-Joseph disease (MJD) is an autosomal dominant, multisystem neurodegenerative disorder involving predominantly cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. Although it was first reported in families of Portuguese-Azorean descent, MJD has also been described in non-Azorean families from various countries, being one of the most common hereditary spinocerebellar degenerations. With the use of highly polymorphic microsatellite DNA polymorphisms, we have assigned the gene for MJD to the long arm of chromosome 14 (14q24.3-q32) by genetic linkage to microsatellite loci D14S55 and D14S48 (multipoint lod score Zmax = 9.719).