Anti-inflammatory effects of indomethacin ester incorporated in a lipid microsphere.
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Biomedical subjects
Publications and source records attributed to Y Etoh.
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An autopsy case of postirradiation sarcoma is described. The tumor, a malignant fibrous histiocytoma, occurred in the radiation fied 7 years after postoperative external beam radiation therapy (6000 rad) for squamous cell carcinoma of the cervix. To our knowledge, 11 cases of postirradiation malignant fibrous histiocytoma have been reported in the literature and only one occurrence of this neoplasm after treatment for cervical cancer has been described. We review the literature on postirradiation sarcoma with special attention to malignant fibrous histiocytoma.
Mucor rennin, a milk-clotting acid protease produced by a fungus Mucor pusillus, was inactivated by photo-oxidation mediated by methylene blue according to first order kinetics. The pH profile of the inactivation rate showed that a dissociating group with a pK value of 7.6 was involved in the inactivation. Addition of pepstatin A, an inhibitor specific for acid proteases, caused a marked alkaline shift of the pK value. One of two histidyl residues in the enzyme was destroyed by the photo-oxidation, with complete loss of the enzyme activity. Analysis of inhibitor binding activity and chemical modification with diazoacetyl-DL-norleucine suggested that the photo-oxidized enzyme still retained its original conformation. These results indicated that one histidyl residue in addition to the two essential carboxyl groups is involved in the catalytic function of Mucor rennin.
The location and state of an essential histidyl residue in a milk-clotting acid proteases, Mucor rennin, were investigated by NMR spectroscopy. Assignment of the C2H resonance peak of the essential histidyl residue was possible by comparison of the NMR spectrum of the native enzyme with that of the photo-oxidized enzyme. The pH titration curve for the chemical shift of the C2H proton showed two inflections, a major one with pKa = 7.4 and a minor one with pKa = 3.5 at 30 degrees C. The major inflection, corresponding to an intrinsic protonation of the imidazole ring, shifted toward the alkaline side upon addition of acetyl pepstatin, an inhibitor specific for the acid protease. Modification of an essential carboxyl group in the enzyme with diazoacetyl-DL-norleucine caused disappearance of the minor inflection as well as an acidic shift of the major pKa value. Perturbation effects on the C2H resonance of the lanthanide metals, Pr3+, Eu3+, and Gd3+, suggested their selective binding to a carboxyl group and location of the bound metal atom close to the essential histidyl residue. All data suggested that the essential histidyl residue of Mucor rennin is located close to one of the two essential carboxyl groups in the catalytic site of the enzyme.
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It has been previously reported that acemetacin (ACM), the carboxymethyl ester of indomethacin (IND), is almost completely metabolized to IND in vivo. In the present study, the anti-inflammatory effects of ACM were compared with those of IND. ACM showed inhibitory effects on vascular permeability induced by phenylquinone. ACM inhibited carrageenin, kaolin, and nystatin edema dose-dependently and the ED30 in the carrageenin edema test was 2.8 Mg/kg. Inhibitory effects of ACM on carrageenin edema was not influenced by adrenalectomy or repeated administration of ACM. ACM also inhibited ultraviolet erythema at 5 mg/kg. Furthermore, ACM significantly inhibited granuloma formation at 2.5 mg/kg/day. The ED30 for the therapeutic effect on established adjuvant arthritis was 0.33 mg/kg/day. These anti-inflammatory effects of orally administered ACM were equivalent to or somewhat weaker than those of IND at an equimolar dose. Platelet aggregation was inhibited when ACM was given orally to rats and the activity of ACM was similar to that of IND. On the other hand, the effects of locally administered ACM on carrageenin and kaolin edema were markedly less potent than those of IND. In addition, inhibitory effects on prostaglandin synthesis and platelet aggregation in vitro were significantly weaker than those of IND. These results that the observed anti-inflammatory effects orally administered ACM are not due to its inherent action, but due to its metabolite, IND.
A study was made with the newly developed cefroxadine (CXD) dry syrup by measuring the serum level, urine excretion and recovery rate in 10 children who were orally administered 5, 10 and 20 mg/kg at 1 hour after meals and the following results were gained. Also, its clinical efficacies and side effects were investigated in the following cases who were treated with a mean dose of 33 mg/day divided into 3 to 4 portions for a period of 9 days on the average; viz. a total of 151 cases consisting of 9 cases of pharyngitis, 39 of tonsillitis, 11 of streptococcal infection, i.e. scarlet fever, 7 of bronchitis, 6 of pneumonia, 1 of otitis media, 6 of purulent lymphadenitis, 1 of purulent parotitis, 1 of subcutaneous abscess and 3 of impetigo. 1. The serum level tends to reach its maximum level within 1 hour after administration. The mean concentrations of 5, 10 and 20 mg/kg dose in the foregoing time were 6.35, 9.12 and 21.62 mcg/ml respectively and dose response was observed. CXD showed higher concentration than CEX, CED and CFT. The mean half-life periods of the 3 dose were 72, 84 and 66 minutes respectively and variations were observed, but the drugs maintains a satisfactory serum level. 2. The time which showed highest urine excretion was mainly in the 0 to 2 hours bracket and the average concentrations of 5 , 10 and 20 mg/kg dose in the foregoing time were 381.2, 771.7 and 1,577.7 mcg/ml respectively. The dose response was more evident than in the serum concentrations. The average recovery rates within 6 hours were 93.6, 88.3 and 94.3% respectively and they were similar to those of CEX, CED and CFT. 3. The clinical effects were evaluated were in 148 cases out of the total of 151 and 136 cases, or 91.9% showed good or excellent efficacy response. 4. The daily dose groups of less than 30 mg/kg and 31 to 40 mg/kg formed the majority and there was no difference in the comparison of the clinical effectiveness in these 2 groups. Administration of a daily dose of 20 to 40 mg/kg is sufficient for the treatment of the aforementioned mild diseases except for pneumonia. 5. The clinical effects were compared between the 3 and 4 times a day treatment groups, but there was no difference between these two groups with regard to the foregoing daily dose. The 3 times a day treatment is acceptable, but the 4 times a day treatment is preferable when pharmacokinetics if taken into account. 6. The bacteriological effects in 41 cases, or 97.6% out of the 42 cases were above the efficacy base line and a high efficacy rate was achieved. 7. With regard to side effects, diarrhea developed in 4 cases and eosinophilia in 6 cases, abnormal simultaneous increases in GOT and GPT in 1 case and 1 case each for abnormal values in LDH and BUN were seen in the clinical test values. The foregoing results show that CXD has high efficacy and safety and it can be said that it is a drug required in the pediatric field.
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Anti-inflammatory activities of prednisolone 17-valerate 21-acetate(PVA) were studied in rats and guinea pigs and results compared with data on topical steroids, such as betamethasone 17-valerate(BV) and hydrocortisone 17-butyrate(HB). PVA given subcutaneously inhibited dose-dependently carrageenin- and kaolin-induced edema. These anti-inflammatory activities of PVA were the weakest among the steroids tested. A local administration of PVA into the site of inflammation, however, had the same or more potent activities than BV and HB in carrageenin-induced edema and paper disk granuloma. Topical application of PVA ointment in carrageenin-induced edema exhibited an inhibitory effect which was dependent on the concentrations (0.1-1.0%). The anti-inflammatory activity of 0.3% PVA ointment was equivalent to that of 0.12% BV ointment. For the other experimental models, i.e. exuberant granulation, croton oil-induced ear edema, passive cutaneous anaphylaxis and tuberculin-induced delayed type hypersensitivity, the activity of 0.3% PVA ointment was the same or somewhat more potent than 0.12% BV and 0.1% HB ointments. The thymolytic activity of PVA ointment in the exuberant granulation model was similar to the activity seen with HB ointment and weaker than of BV ointment. Thus, the anti-inflammatory activities of PVA were equivalent to or more potent than those of BV and HB, and with topical application, the systemic effect of PVA was weaker than the other steroids examined.