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H Tone

Publications and source records attributed to H Tone.

At least 55 records · Page 3Linked to original sources
PubMed1986

[General pharmacology of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic].

General pharmacology of (2"R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) was studied in experimental animals. Intravenous administration of THP showed no significant effect on the respiratory and cardiovascular systems, such as blood pressure, heart rate, ECG and respiration in anesthetized rabbits and dogs. But in rats and cats, THP produced a transient decrease in blood pressure resulted from vasodilation. The hypotension was not inhibited by antihistaminics. Contraction of isolated guinea-pig atria was stimulated by THP at high concentrations (10(-4) g/ml). THP inhibited the spontaneous movement of isolated rabbit ileum and rat uterus (virgin and pregnant) at high concentrations (10(-4) g/ml). In some isolated guinea-pig ileum preparations, THP partially (6 approximately 36%) antagonized the contraction inducing by acetylcholine, histamine, serotonin and barium chloride. Urine volume and urinary excretion of electrolytes were increased by intravenous injection of 5.0 mg/kg THP. Vascular permeability was progressed when administered intracutaneously. Hemolytic effect was shown at high concentrations (10(-4) g/ml) but no effect on the coagulation was found. No significant effect of THP was observed on the general behavior and central nervous system, autonomic nervous and peripheral nervous systems. Also, THP had no significant effect on gastrointestinal propulsion in mice, the mucous membranes of the stomach and duodenum of rats, or gastric acid and bile secretion in rats.

Animals↗
PubMed1986

[Effect of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic, on the cardiac function of hamsters].

Cardiovascular effects of (2''R)-4'-O-tetrahydropylanyladriamycin X HCl (THP) and doxorubicin (adriamycin, ADM) were studied in hamsters. In experiments to observe acute effects, THP was administered intravenously at a dose of 12.5, 25.0 or 50.0 mg/kg, and ADM at 1.56, 3.13 or 6.25 mg/kg was given to different subjects. The THP caused slight ECG alterations at a dose of 12.5 mg/kg. At a dose of 25.0 mg/kg or 50.0 mg/kg, THP caused moderate to remarkable alterations in ECG like a widening of PR and PRc interval, A-V block, ST segment depression and T wave flattening. The ADM caused moderate to remarkable alterations in ECG at a dose of 3.13 mg/kg or 6.25 mg/kg, including arrhythmia, bradycardia, A-V block, ST segment changes and T wave flattening. These changes caused by THP and ADM recovered within 5 approximately 10 minutes after injection. Alterations in the ultrastructure of the myocardium caused by THP at a dose of 50.0 mg/kg included some cells with slight changes like swelling of mitochondria, focal intracellular edema, and enlargement of myofibrils. The ADM, at a dose of 3.13 mg/kg, induced severer swelling of mitochondria than THP, dilatation of sarcoplasmic reticulum, intracellular edema, and disorganization of myofilaments. At a dose of 6.25 mg/kg of ADM, these changes became more pronounced. In experiments to observe subacute effects, hamsters were treated with THP or ADM by daily intraperitoneal injections for 15 consecutive days, and then allowed to be recovered for 15 days. Dose levels of THP or ADM were 0.125, 0.25, 0.5 and 1.0 mg/kg. General toxicity, ECG, hematological and blood biochemical analysis, and electron microscopic examination were studied. In the ECG study, THP-treated hamsters showed a reversible elevation of R wave amplitude at a daily dose of 0.5 mg/kg. Widening of PR and PRc interval, elevation of R and S wave amplitude, and reduction of T wave amplitude were observed at a daily dose of 1.0 mg/kg of THP. Hamsters treated with ADM showed increase of heart rate, reduction of T wave amplitude, and shortening of PR and PRc interval at a daily dose of 0.5 mg/kg. Severe changes were observed at a daily dose of 1.0 mg/kg of ADM including an increase of heart rate, elevation of R wave amplitude, reduction of S and T wave amplitude, and shortening of QT interval. The electron microscopic examination revealed that THP-treated hamsters showed separation of intercalated discs, formation of myelin structure, and dilatation of T-tubules at a daily dose of 1.0 mg/kg. Similar changes were caused by ADM at a daily dose of 0.25 to 1.0 mg/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Acute local irritative effect of (2''R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic.

(2"R)-4'-O-Tetrahydropyranyladriamycin hydrochloride (THP), a new antitumor antibiotic, was administered to rabbits at a concentration from 0.02 to 0.5% by instillation, or by intracutaneous, subcutaneous or intramuscular injection to study its local irritative effect. The irritative effect of THP increased with concentration. At a concentration of 0.5%, THP was irritant to the eye, skin and muscle but at a concentration of 0.1% practically no effect was observed. The effect was equal to or lower than that of doxorubicin. An instillation of 0.5% THP caused reversible irritation effect on the eye. Slight conjunctival responses (redness and chemoisis) were observed. Rinsing reduced the irritative effect. Intracutaneous injection of 0.1 ml of 0.5% THP caused well defined, moderate erythema, surface ulceration and dermal necrosis. Cutaneous muscle necrosis also occurred. At a concentration of 0.02%, dermal necrosis and inflammatory cell infiltration were observed. Erythema, as well as muscle necrosis and calcification with giant cell reaction and inflammatory cell infiltration were observed by an intramuscular injection at a concentration of 0.5%. Subcutaneous injection of 0.5% THP showed no irritative effect.

Animals↗
PubMed1986

[Effect of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic, on the bone marrow function of rabbits. (1) Intravenous administration by a single bolus injection].

New Zealand White rabbits were treated with (2"R)-4'-O-tetrahydropyranyladriamycin-HCl (THP), a new antitumor antibiotic, by an intravenous bolus injection at a dose of 1, 2 or 4 mg/kg. The peripheral leucocyte counts decreased markedly at doses of 2 and 4 mg/kg 1 to 7 days after injection, and the lymphocytes and neutrophils were affected. The nucleated cell count decreased in the bone marrow. Especially 3 days after injection, remarkable reductions of erythroids and immatured myelocytes were observed, with a subsequent rise of the matured myelocytes ratio in bone marrow cell constituents. These changes resulted in a marked increase of M/E ratio. Doxorubicin also showed an inhibitory effect on the bone marrow function of rabbits but the effect was slightly lower than THP. These changes of bone marrow cells reverted 7 days after injection and the recovery of the reduced peripheral leucocyte was also observed 14 days after injection. Therefore, it can be concluded that THP showed suppressive but reversible effects on the bone marrow function of rabbits.

Animals↗
PubMed1986

[Effect of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic, on the bone marrow function of rabbits. (2) Repeated intravenous injections].

(2''R)-4'-O-Tetrahydropyranyladriamycin-HCl (THP), a new antitumor antibiotic, was intravenously injected to New Zealand White rabbits at a dose of 2.5 mg/kg every 2 weeks for 6 weeks (3 courses) or at a dose of 0.5 mg/kg/day daily for the first 5 days of a 2-week course for 6 weeks (3 courses). The total dose was 7.5 mg/kg in both dosing schedules. The peripheral leucocyte and erythrocyte counts decreased. The leucocyte count decreased to 57% of the initial count on Day 3 in the first course and then increased gradually. The decrease was smaller in the divided dosing schedule than the single dosing. The nucleated cells, especially immatured myelocytes and erythroids reduced remarkably. Subsequently the matured myelocyte ratio in bone marrow cell constituents increased and the M/E ratio increased. These changes were observed on Day 3 and reverted by Day 9 in each course. The divided dosing schedule resulted in a higher nadir. All the changes in the peripheral blood and the bone marrow reverted even after the 3 course-treatment.

Animals↗
PubMed1986

[Pharmacokinetics and disposition of a new anticancer antibiotic (2''R)-4'-O-tetrahydropyranyladriamycin in rats. Distribution and excretion after a single administration].

Blood levels, tissue distribution and excretion of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in rats received 14C-THP or unlabeled THP at a dose of 5 mg/kg, respectively. The THP disappeared rapidly from the blood and transferred to tissues immediately after an administration. Pharmacokinetic analysis of the plasma level of THP by the simulation according to a three-compartment open model provided large values of apparent volume of distribution in the tissue compartment. The plasma half-lives of THP in alpha, beta and gamma-phases were 0.25 minute, 0.241 hour and 5.11 hours, respectively. The THP was distributed to the lung and spleen at a level about 100 times as high as the plasma level after an intravenous administration. A high level of THP was also found in the lymph node and gland tissues. Concentrations of THP in many tissues decreased to 1 microgram/g or less 24 or 72 hours after an injection of the drug, while the drug remained at higher levels in the thymus, spleen and tumor for a long time. After an injection of THP into the carotid artery, its distribution to the brain was apparent, but the level was lower after an injection to the tail vein. The amount of the drug transferred to a fetus was less than 0.2% of the dose. The major route for the excretion of THP after an intravenous administration was the fecal excretion via bile. Ratios of excretion of the radioactivity in the feces, urine and expired air were 80.3, 5.6 and 9.7% of the dose, respectively, 168 hours after an injection of 14C-THP. About 65% of the radioactivity was excreted in the bile up to 24 hours after injection but THP itself accounted for only 1/6 of the total radioactivity. About 80% of the excreted THP in the bile was in a conjugated form. Enterohepatic circulation of THP was observed mostly as metabolites or decomposed products of THP.

Animals↗
PubMed1986

[Pharmacokinetics and disposition of a new antitumor antibiotic (2''R)-4'-O-tetrahydropyranyladriamycin in rats. Distribution and excretion after multiple administration].

The accumulation of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) was studied in rats received intravenous administration of 14C-THP at a dose of 0.5 mg/kg/day for 14 consecutive days by determining blood and tissue levels and the excretion of the radioactivity. The radioactivity levels in plasma and blood cells after the multiple administration were higher than those after single administration. The half-life of the radioactivity after the multiple administration was longer in the blood cells but not in the plasma than the half-life after a single administration. Tissue levels of the radioactivity after the multiple injection were 2 to 4 times as high as the levels after a single injection except for the brain and testes in which a large accumulation of the radioactivity was observed. However, little accumulation of unlabeled THP was found in most tissues when determined by HPLC. The accumulation of radioactivity in tissues, therefore, was due to metabolites of THP. The disposition of 14C-THP was also examined in rats which had previously received unlabeled THP (0.5 mg/kg/day) for 13 days. The pretreatment did not affect the disposition of 14C-THP seriously, although the pretreatment raised tissue levels slightly and a rebound of plasma level of 14C-THP, and lowered the fecal excretion ratio. No induction of hepatic drug metabolizing enzymes was observed in rats after repeated administrations of THP for consecutive 14 days.

Aminopyrine N-Demethylase↗
PubMed1986

Pharmacokinetics and disposition of (2''R)-4'-O-tetrahydropyranyladriamycin in dogs.

The pharmacokinetics and physiological disposition of a novel anthracyclines, (2''R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in dogs by an HPLC analysis. The THP administered intravenously (1.5 mg/kg) disappeared rapidly from the plasma immediately after an injection of the drug. The plasma level of THP was lowered in a triphasic pattern up to 24 hours and was simulated by a three-compartment open model in which the half-lives of alpha-, beta- and gamma-phase were calculated to be 0.0116 hour, 0.152 hour and 7.02 hours, respectively. The blood cell level of THP was about 10 times as high as the plasma level during the observation. In the study of tissue distribution of THP 2 and 8 hours after the administration, the highest concentration of THP was found in the spleen and lung and these concentrations were diminished quickly. However, in the lymph nodes and bone marrow concentrations of THP increased with a lapse of time. THP and its metabolites were excreted in the bile by 2.7% of dose during 8 hours in the bile-cannulated dogs. Urinary recovery of THP and its metabolites was about 1.3% of the dose up to 72 hours. In these experiment, THP was metabolized to THP-OH and ADM, and to aglycones which were excreted in conjugated forms. The results obtained from a similar study on ADM were compared and discussed.

Animals↗
PubMed1986

[Pharmacokinetic studies of THP-ADM (tetrahydropyranyl adriamycin)].

THP-ADM is a new antitumor agent which belongs to the anthracycline family. This agent has shown a high therapeutic index compared with the mother compound, Adriamycin, in preclinical and clinical studies. This time, a pharmacokinetic study of THP-ADM was performed and the following characteristics of this agent were clarified. Short t1/2 was noted compared with that of Adriamycin in a 3-compartment open model. Leukocyte concentration of THP-ADM was much higher than that of plasma or red blood cells. Renal excretion over 48 hours was 9% and biliary excretion over the same period was 20%. Tissue concentration revealed high THP-ADM and low Adriamycin in all tissues excluding the liver. In liver tissue, a high concentration of Adriamycin and a low concentration of THP-ADM was observed. A small amount of Adriamycin was noted in the plasma following THP-ADM administration. The Adriamycin was most likely related to the small amount of existing Adriamycin in THP-ADM or conversion of THP-ADM to Adriamycin in the liver tissue or both. Poor penetration of THP-ADM was noted into the third space.

Doxorubicin↗
PubMed1985

Pharmacokinetics and disposition of 4'-O-tetrahydropyranyladriamycin in mice by HPLC analysis.

The plasma level of 4'-O-tetrahydropyranyladriamycin (THP) declined rapidly after IV injection to mice, with a t1/2(alpha) of 0.453 min. Only 1.2 micrograms/ml THP was detected 2 min after injection of 5 mg/kg. The drug was immediately transferred to various tissues, where the drug levels were much higher than the plasma concentration. In the lung and spleen, 8.26 and 13.6 micrograms/g THP was present, respectively, 2 h after administration. Major metabolites of THP were 13-dihydro-THP, ADM, 7-deoxyadriamycinone, and 7-deoxy-13-dihydro-adriamycinone. Only 1.12% of the dose had been recovered in the urine by 48 h after injection as THP and its metabolites, according to analysis by HPLC fluorospectroscopy. The observed disposition of THP was compared with that of adriamycin (ADM). The plasma disappearance and tissue transfer of THP were faster than those of ADM. THP levels in the spleen and lung were higher and those in the heart and liver were lower than the corresponding ADM levels. Drug levels declined more quickly in most tissues in the case of THP than of ADM. Tissue distributions after single bolus and multiple injections were also compared and discussed.

Animals↗
PubMed1985

Sensitive enzyme immunoassay for the quantification of aclacinomycin A using beta-D-galactosidase as a label.

A sensitive enzyme immunoassay method (EIA) for an anticancer drug, aclacinomycin A (ACM), has been developed. With a double-antibody technique, ACM at a concentration as low as 100 pg/tube can be detected. An antibody to ACM was obtained by immunizing rabbits with an antigen prepared by coupling ACM with mercaptosuccinylated bovine serum albumin via N-maleoyl aminobutyric acid (MABA) as a coupling agent. Enzyme labeling of ACM was performed with beta-D-galactosidase (beta-Gal; EC 3.2.1.23) via m-maleoyl benzoic acid (MBA). The standard curve of the assay was linear on a logit-log plot over a concentration range of 30 pg to 10 ng. The antibody detected ACM and its metabolites, MA144 M1 (M1), MA144 N1 (N1), MA144 S1 (S1), and aklavin (T1) equally well, but was only minimally reactive with aklavinone (D1) and 7-deoxyaklavinone (C1), thus suggesting that this EIA can detect the total amounts of ACM and its biologically active glycosides among metabolites of ACM. This EIA is practically free from interference by any other anticancer drugs. Using this assay, serum levels of ACM equivalents can be determined accurately after administration of the drug to rats at a single dose of 10 mg/kg. Since ACM is now undergoing clinical trial, the EIA of the drug will be a valuable tool in clinical pharmacological studies.

Aclarubicin↗
PubMed1985

Antitumor activities of (2"R)-4'-O-tetrahydropyranyl-adriamycin (THP) and its combination with other antitumor agents on murine tumors.

(2''R)-4'-O-Tetrahydropyranyladriamycin (THP) is a new derivative of doxorubicin (adriamycin, ADM). The concentrations of THP and ADM required to inhibit by 50% the growth of a cultured L1210 cells was 0.003 microgram/ml and 0.016 microgram/ml, respectively. Various therapeutic designs of combinations of THP with other antitumor agents were investigated in vivo using the L1210 murine leukemia. The combination of THP with cytosine arabinoside (Ara-C), cyclocytidine hydrochloride (Cyclo-C), 6-mercaptopurine (6-MP) and cyclophosphamide (EX) showed a great effectiveness following daily intraperitoneal treatment from days 1 to 10. High therapeutic effects were also obtained with the combinations of THP with Ara-C, Cyclo-C, vincristine (VCR) and EX following intravenous combination therapy one day following implantation of L1210 leukemia. Schedule dependency and its therapeutic efficacy of THP were examined. THP showed almost the same antitumor activity on the solid-type sarcoma-180 or solid-type Ehrlich carcinoma as ADM by intraperitoneal or intravenous treatment. THP showed some superior activity to ADM in the advanced stage of L1210 leukemia. High antitumor activity of THP on murine leukemia L1210 has been reported by Tsuruo et al. (Cancer Res. 42: 1462-1467, 1982) and was also confirmed. THP gave many mice cures, especially in the intravenous treatment.

Animals↗
PubMed1985

Experimental studies on aclacinomycin.

Experimental features of aclacinomycin (ACM), a new antitumour antibiotic of the anthracycline group, are presented. ACM inhibited the growth of experimental mouse tumours and human cancer xenografts from various origins. In CDF1 mice with L1210 cells treated i.p. with ACM in combination with Ara-C for 10 days, a 459% ILS was observed, including 67% of 60-day survivors. The inhibition of RNA and DNA synthesis was examined in L1210 cells. The IC50 values of ACM for incorporations of [14C]-thymidine and [14C]-uridine were 0.30 and 0.038 microgram/ml respectively. The ratio of IC50. DNA/RNA was 7.9, while with adriamycin (ADR) it was 2.5. ACM showed no mutagenic activity in the Ames' test and the rec- assay. The cardiac toxicity of ACM was significantly lower than that of ADR. Lower ECG changes, a return to normal after discontinuation of the drug and slighter ultrastructural modifications of the myocardium were demonstrated in hamsters and rabbits. When administered to hamsters i.v. at 5 mg/kg, ACM was eliminated almost completely from the heart muscle after 2 h, while ADR remained at 8 micrograms/g even after 8 h.

Aclarubicin↗
PubMed1983

A high performance liquid chromatographic method of analysis of 4'-O-tetrahydropyranyladriamycin and their metabolites in biological samples.

A method for measuring 4'-O-tetrahydropyranyladriamycin (THP) and its metabolites in biological samples are described. By reversed-phase high performance liquid chromatography using fluorescence detection, THP and its metabolites were all separated on a single chromatogram within 18 minutes. A linear calibration curve was obtained up to 2,000 ng/ml of THP in plasma. The recovery of THP in the analysis was more than 95% above 5 ng/ml and 87.1% even at 1.25 ng/ml. Thus the lower limit was 1.25 ng/ml in biological samples. Blood levels and urinary excretion in mice and dogs were satisfactory measured by this analytical method.

Animals↗
PubMed1982

Pharmacological studies on carbapenem antibiotics. I. Metabolism of PS-5 in animal tissues.

After injection into mice and dogs, PS-5 showed a very rapid decrease in its blood concentration, compared with cefazolin. Using in vitro experiments with tissue homogenates and acetone powder preparations, the kidney was found to be the primary site of PS-5-inactivation, although the extent of the inactivation varied depending on the species of animals. The comparative stability data of PS-5, NS-5 (deacetylated PS-5), thienamycin and N-formimidoylthienamycin in kidney homogenates of mouse, rabbit, dog and man are presented. Bilateral nephrectomy and the injection of ethylenediaminetetraacetate seemed to prolong the survival time of PS-5 in rats and mice respectively.

Animals↗
PubMed1980

Effect of adenosine-5'-triphosphate-3'-diphosphate and related nucleoside polyphosphates on the spore germination of Streptomyces galilaeus.

Exogenous addition of adenosine- and guanosine 5'-(di- and tri) phosphate 3'-diphosphate (pppApp, ppApp, pppGpp and ppGpp) at the concentration of 0.5 mM inhibits spore germination of Streptomyces galilaeus ATCC 31133. This reversible inhibitory effect appeared to be at the transcriptional level, and also depends on the phase of spore germination; pppApp inhibited more strongly RNA synthesis in the period of the germ tube emergence than the early stage of germination. No inhibitory effect was observed with normal purine and pyrimidine nucleosides, nucleotides, pApp, pGpp, cyclic AMP and pyrophosphoric acid at the concentration of 0.1 - 1.0 mM.

Adenine Nucleotides↗
PubMed1980

A radioimmunoassay for guanosine-5'-diphosphate-3'-diphosphate and adenosine-5'-triphosphate-3'-diphosphate.

A radioimmunoassay for guanosine-5'-diphosphate-3'-diphosphate (ppGpp) and adenosine-5'-triphosphate-3'-diphosphate (pppApp) has been developed. The assay method is based on competition of an unlabeled highly phosphorylated nucleotide with 3H-labeled highly phosphorylated nucleotide for binding sites on a specific antibody. Antibodies to ppGpp and pppApp were obtained by immunizing rabbits with the antigen prepared by conjugating ppGpp with human serum albumin using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and with the antigen prepared by conjugating 8-(6-aminohexyl)amino-adenosine-5'-triphosphate-3'-diphosphate with human serum albumin using glutaraldehyde, respectively. Antibody-bound 3H-labeled highly phosphorylated nucleotides were separated from the free 3H-labeled highly phosphorylated nucleotides by selective adsorption on dextran-coated charcoal. Displacement plots were linear over a concentration range of 5-1,000 pmol/assay tube in a log-probit percentage plot. Application of this method to biological systems offers improved accuracy and convenience compared with the previous 32PO4-labeling technique.

Adenine Nucleotides↗