Antioxidant effects of aminosalicylates and potential new drugs for inflammatory bowel disease: assessment in cell-free systems and inflamed human colorectal biopsies.
BACKGROUND: The therapeutic efficacy of 5-aminosalicylic acid in inflammatory bowel disease may be related to its antioxidant properties. AIM: To compare in vitro the antioxidant effects of conventional drugs (5-aminosalicylic acid, corticosteroids, metronidazole), with new aminosalicylates (4-aminosalicylic acid, balsalazide) and other potential therapies (ascorbate, N-acetylcysteine, glutathione, verapamil). METHODS: Compounds were assessed for efficacy in reducing the in vitro production of reactive oxygen species by cell-free systems (using xanthine/xanthine oxidase, with or without myeloperoxidase) and by colorectal biopsies from patients with ulcerative colitis using luminol-amplified chemiluminescence. RESULTS: 5-aminosalicylic acid and balsalazide were more potent antioxidants than 4-aminosalicylic acid or N-acetyl-5-aminosalicylic acid in cell-free systems. 5-aminosalicylic acid (20 mM) and balsalazide (20 mM) inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively, compared with only 59% inhibition by 4-aminosalicylic acid (20 mM). Hydrocortisone, metronidazole and verapamil had no significant effect on chemiluminescence in any system. Ascorbate (20 mM) inhibited chemiluminescence by 100% in cell-free systems and by 60% in rectal biopsies. N-acetyl cysteine (10 mM), and both oxidized and reduced glutathione (10 mM), completely inhibited chemiluminescence in cell-free systems, but not with rectal biopsies. CONCLUSIONS: The antioxidant effects of compounds varies between cell-free systems and inflamed colorectal biopsies. The effect of drugs on the chemiluminescence produced by these two assay systems is useful for screening potentially new antioxidant treatments for inflammatory bowel disease. Ascorbate seems worth further study as a novel therapy. (+info)
A five-year assessment of controlled trials of in-patient and out-patient treatment and of plaster-of-Paris jackets for tuberculosis of the spine in children on standard chemotherapy. Studies in Masan and Pusan, Korea. Fifth report of the Medical Research Council Working Party on tuberculosis of the spine.
In two centres in Korea 350 patients with a diagnosis of tuberculosis of the thoracic and/or lumbar spine were allocated at random: in Masan to in-patient rest in bed (IP) for six months followed by out-patient treatment or to ambulatory out-patient treatment (OP) from the start; in Pusan to out-patient treatment with a plaster-of-Paris jacket (J) for nine months or to ambulatory treatment without any support (No J). All patients recieved chemotherapy with PAS with isoniazid for eighteen months, either supplemented with streptomycin for the first three months (SPH) or without this supplement (PH), by random allocation. The main analysis of this report concerns 299 patients (eighty-three IP, eighty-three OP, sixty-three J, seventy No J; 143 SPH, 156 PH). Pre-treatment factors were similar in both centres except that the patients in Pusan had, on average, less extensive lesions although in a greater proportion the disease was radiographically active. One patient (J/SPH) died with active spinal disease and three (all No J/SPH) with paraplegia. A fifth patient (IP/PH) who died from cardio respiratory failure also had pulmonary tuberculosis. Twenty-three patients required operation and/or additional chemotherapy for the spinal lesion. A sinus or clinically evident abscess was either present initially or developed during treatment in 41 per cent of patients. Residual lesions persisted in ten patients (four IP, two OP, one J, three No J; six SPH, four PH) at five years. Thirty-two patients had paraparesis on admission or developing later. Complete resolution occurred in twenty on the allocated regimen and in eight after operation or additional chemotherapy or both. Of the remaining four atients, all of whom had operation and additional chemotherapy, three died and one still had paraparesis at five years. Of 295 patients assessed at five years 89 per cent had a favourable status. The proportions of the patients responding favourably were similar in the IP (91 per cent) and OP (89 per cent) series, in the J (90 per cent) and No J (84 per cent) series and in the SPH (86 per cent) and PH (92 per cent) series. (+info)
Five-year assessment of controlled trials of short-course chemotherapy regimens of 6, 9 or 18 months' duration for spinal tuberculosis in patients ambulatory from the start or undergoing radical surgery. Fourteenth report of the Medical Research Council Working Party on Tuberculosis of the Spine.
The five-year assessment of three randomised trials of short course (6, 9 or 18 months) chemotherapy for tuberculosis of the spine is reported. In Hong Kong patients were randomised to isoniazid plus rifampicin (HR) daily for 6 or 9 months, combined with radical surgical resection with bone grafting and streptomycin for 6 months for all patients. In Madras patients were randomised to chemotherapy with HR for 6 or 9 months, or 6 months HR chemotherapy combined with surgical resection. In Korea all patients were ambulatory and were randomised to different regimens of chemotherapy 6 or 9 months HR, or 9 or 18 months isoniazid plus ethambutol. (EH) or isoniazid plus PAS (PH). In all centres the results of the 6- and 9-month regimens of HR were excellent and similar to the 18-month EH and PH regimens. The 9-month EH/PH regimens were clearly inferior. In Hong Kong excellent results were achieved by the radical resection. The disease was however less extensive than in Madras, where the results after surgery were no better than with ambulatory chemotherapy. Chemotherapy is the critical factor in the management of tuberculosis of the spine. Efforts should be concentrated on ensuring that appropriate regimens are given under adequate supervision. (+info)
Activity of a new class of isonicotinoylhydrazones used alone and in combination with isoniazid, rifampicin, ethambutol, para-aminosalicylic acid and clofazimine against Mycobacterium tuberculosis.
The activities of six derivatives of a new class of isonicotinoylhydrazones were investigated in vitro against Mycobacterium tuberculosis H37Rv ATCC 27294, isoniazid-resistant M. tuberculosis ATCC 35822, rifampicin-resistant ATCC 35838, pyrazinamide-resistant ATCC 35828, streptomycin-resistant ATCC 35820 and 16 clinical isolates of M. tuberculosis. Several compounds showed interesting antimycobacterial activity against both ATCC strains and clinical isolates, but were less active against isoniazid-resistant M. tuberculosis. Combinations of five isonicotinoylhydrazone derivatives and rifampicin, ethambutol, para-aminosalicylic acid, isoniazid and clofazimine were also investigated against M. tuberculosis H37Rv ATCC 27294 and against ATCC drug-resistant strains. Addition of sub-MICs of some isonicotinoylhydrazone derivatives resulted in a four- to 16-fold reduction in MICs of ethambutol, para-aminosalicylic acid and rifampicin with fractional inhibitory concentrations (FICs) ranging between 0.17 and 0.37, suggesting a synergic interaction against M. tuberculosis H37Rv. Increased activity was also observed with other combinations (FICs 0.53-0.75), including isoniazid, and a synergic interaction between one of the isonicotinoylhydrazone derivatives and isoniazid (FIC 0.26) was shown against isoniazid-resistant M. tuberculosis ATCC 35822, whereas no effects were observed on combining the isonicotinoylhydrazones with clofazimine. The ability of isonicotinoylhydrazones to inhibit specifically the growth of M. tuberculosis, the high selectivity index and their ability to enhance the activity of standard antituberculous drugs in vitro indicate that they may serve as promising lead compounds for future drug development for the treatment of M. tuberculosis infections. (+info)
Colonic delivery of 4-aminosalicylic acid using amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsules.
BACKGROUND: 4-Aminosalicylic acid has the potential for use in the treatment of diseases of the colon. AIM: To assess the feasibility of delivering 4-aminosalicylic acid directly to the colon using a hydroxypropylmethylcellulose capsule coated with a mixture of amylose, a polysaccharide metabolized by bacterial enzymes in the colon, and ethylcellulose. METHODS: Seven healthy male volunteers received, on three separate occasions, an uncoated or amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsule containing 4-aminosalicylic acid Na (550 mg), or an intravenous injection of 4-aminosalicylic acid Na (135 mg). The capsules were radiolabelled with 99mTc to allow their positions in the gastrointestinal tract to be followed using a gamma camera. Plasma and urine samples were collected and assayed for 4-aminosalicylic acid and metabolite concentrations. RESULTS: The uncoated capsules broke down within 10 min in the stomach, allowing rapid and complete absorption of the drug. The coated capsules remained intact in the upper gastrointestinal tract, and had a median gastric emptying time of 61 min (interquartile range, 77 min) and a median colon arrival time of 363 min (interquartile range, 185 min). For the coated capsules, only the metabolite was detected in the plasma and/or urine after the capsules had reached the colon. CONCLUSIONS: The specific coating protected the drug until the capsule reached the colon, where 4-aminosalicylic acid was slowly released and absorbed. Thus, such a formulation has the potential for use in the treatment of inflammatory bowel disease. (+info)
Management of tuberculosis in childhood.
Statistical evidence documents an overall decrease in incidence of tuberculous infections with continued decline in mortality. Although the number of deaths has decreased in children under 15 years of age, in the city of Los Angeles, the figures suggest a possible increase in total cases during the past two years. Data on 530 cases observed at Los Angeles Children's Hospital from 1934 to 1955 were reviewed with respect to age, race, and mortality under changing methods of management.Available antimicrobial agents are discussed with suggestions for criteria for treatment and for specific treatment schedules. (+info)
Effect of aminophenols (5-ASA and 4-ASA) on colonic interleukin-1 generation.
The effect of 5-ASA and 4-ASA, drugs used for the treatment of inflammatory bowel disease, on modulation of experimental colitis and on colonic generation of interleukin-1 was evaluated. Three weeks of treatment with 5-ASA or 4-ASA (50 micrograms/kg) and one week of treatment with 5-ASA significantly decreased colonic interleukin-1 generation and the extent and severity of inflammation in a rat model of colitis induced by trinitrobenzene sulphonic acid. Colonic biopsies were obtained from patients with active ulcerative colitis and organ cultured 24 hours in the absence or presence of the following drugs: sulphasalazine, sulphapyridine, 5-ASA and 4-ASA (25-100 micrograms/ml). Interleukin-1 content in tissue cultured in the presence of 5-ASA (100 micrograms/ml) was two-thirds of its content in tissue cultured in drug free medium and its release into the medium was decreased by 50%. Sulphasalazine 50 micrograms/ml significantly decreased by 33% the tissue content but did not affect interleukin-1 release and a higher dose was not more effective. Sulphapyridine and 4-ASA in doses up to 100 micrograms/ml did not affect either interleukin-1 colonic content or its release into the culture medium. We conclude that pharmacological suppression of colonic interleukin-1 generation may be one, although not the sole mechanism to explain the therapeutic efficacy of 5-ASA in the treatment of inflammatory bowel disease. (+info)
Competitive relationship between protocatechuic acid and p-aminosalicylic acid for a cellular transport mechanism.
Hubbard, Jerry S. (Oklahoma State University, Stillwater), and Norman N. Durham. Competitive relationship between protocatechuic acid and p-aminosalicylic acid for a cellular transport mechanism. J. Bacteriol. 82:361-369. 1961.-The oxidation of protocatechuic acid by a Flavobacterium is inhibited by p-aminosalicyclic acid regardless of whether the organism is grown on protocatechuic acid or sequentially induced to protocatechuic acid by growth on p-aminobenzoic acid. Depletion of the substrate from the medium by the cell suspension is dependent, within defined limits, on the inhibitor to substrate ratio, and the inhibition can be overcome by addition of excess substrate. However, this competitive effect is not observed in high inhibitor to substrate ratios. p-Aminosalicylic acid did not affect the rate or extent of oxidation, carbon dioxide evolution, or formation of beta-ketoadipic acid during degradation of protocatechuic acid by cell extracts. The results suggest that p-aminosalicylic acid antagonizes the oxidation of protocatechuic acid by the cell suspension by competing with the substrate for a specific transport mechanism, thereby regulating the entry and internal accumulation of the substrate. The lack of a competitive effect in high inhibitor to substrate ratios could be interpreted as an indication that the mechanism for accumulating the substrate may consist of more than one active transport system. (+info)