ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Mesenchymal cells isolated from chick limb-buds, when plated in micromass culture, differentiate into chondrocytes, forming a mineralizable matrix. Because these cells produce prostanoids during differentiation, this system was used to test the hypothesis that E-series prostanoids are involved in chondrocyte-mediated calcification. Prostaglandins E2(PGE2) and E1(PGE1), and the E-series analog, misoprostol (MP), increased chondrocyte cAMP content in the presence of the phosphodiesterase inhibitor IBMX. The increases for PGE1and PGE2at their saturation concentrations were twofold to threefold greater than for MP at its saturation concentration. At culture day 7, 9, or 11 (the day that mineralization commenced), the maximal cyclic adenosine monophosphate (cAMP) production was at a concentration of 250–500 ng/ml PGE2, 500–1000 ng/ml PGE1, and >5000 ng/ml MP. At these concentrations, PGE1and PGE2, but not MP, stimulated chondrocyte differentiation.45Ca accumulation in mineralizing, as compared to nonmineralizing, similarly treated control cultures was not altered by the addition of indomethacin and/or prostanoid when the phosphate source was inorganic phosphate. Because the prostanoids decrease alkaline phosphatase activity, initial β-glycerophosphate-mediated mineralization was inhibited by each of the prostanoids.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The objective of this study was to determine the effects of orally administered misoprostol and diclofenac on inflammation caused by particulates in the rat subcutaneous air-pouch model. Subcutaneous air pouches were formed in male Sprague-Dawley rats. The animals were premedicated by gavage with either saline, diclofenac, misoprostol, or both diclofenac and misoprostol. The air pouches were injected with either polymethyl methacrylate particles or monosodium urate crystals, and the pouch fluids were obtained at 1, 6, 24, 48, and 72 h. Leukocyte influx, tumor necrosis factor, neutral metalloprotease activity, and prostaglandin E2levels were measured. It was determined that leukocyte influx was inhibited by diclofenac in the acute inflammation caused by monosodium urate crystals only. In all animals receiving diclofenac, prostaglandin E2(PGE2) levels were reduced, whereas tumor necrosis factor levels were elevated. The elevation of tumor necrosis factor was prevented by the addition of misoprostol. It is concluded that the oral administration of diclofenac or misoprostol can affect levels of specific mediators involved in particulate-induced inflammation in the subcutaneous air pouch.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Misoprostol, a prostaglandin E1analog, is currently available to manage ulcer disease, being used predominantly in the prophylaxis of nonsteroidal anti-inflammatory drug (NSAID)-induced ulceration, a serious side effect of anti-inflammatory therapy in arthritis. The protective effects of misoprostol have now also been shown to extend to cartilage in a series of experiments using anex vivosystem employing normal human and osteoarthritis (OA) cartilage. Misoprostol reproducibly reverses inhibition of proteoglycan synthesis induced by interleukin-1 and certain NSAIDs, and also stimulates synthesis in OA cartilage. The article reviews these findings and also presents the results obtained in a study of 20 OA cartilages in which synergy was demonstrated between misoprostol (at 50 ng/ml) and diclofenac (0.3 μg/ml) in preventing proteoglycan synthesis. Diclofenac on its own is unusual amongst NSAIDs in exerting virtually no deleterious effect on cartilage. The synergy with misoprostol is of clinical interest in view of the recent introduction of a misoprostol/diclofenac combination product (Arthrotec), the intention of which was to provide antiinflammatory efficacy with a reduced incidence of Gl damage. The implications of these cartilage experiments is that such a combination may also offer improvements in the management of the arthritic process in OA, and methods whereby this would be assessed clinically are discussed.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Skin and skin structure infections are among the most common infectious diagnoses in both the hospital and community settings. If untreated, these infections can produce serious complications. Successful antimicrobial therapy for these infections requires coverage against the causative pathogens, particularlyStaphylococcus aureus.This randomized, single-blind, multcenter study was designed to compare the efficacy and safety of intravenous ceftazidime 2 g given two times daily (BID) with that of intravenous ceftazidime 1 g given three times daily (TID) for the treatment of skin and skin structure infections caused by ceftazidime-sensitive pathogens.Adults (>18 years) were eligible for enrollment if they were hospitalized or in home health care settings and they had a skin or skin structure infection caused by a ceftazidime-sensitive pathogen. Patients were randomly assigned to receive ceftazidime 2 g every 12 h or ceftazidime 1 g every 8 h as an intermittent infusion over 15–30 min. Treatment was continued for 2–3 days beyond the time the patient became asymptomatic or evidence of bacterial eradication was obtained; however, total treatment duration had to be at least 5 days. Patients were assessed for their clinical and bacteriological response at the end of treatment and for their clinical response at follow-up.A total of 806 patients were enrolled in the study, 406 of whom received ceftazidime 2 g BID and 400 of whom received ceftazidime 1 g TID. Both treatments were administered for a mean duration of 9 days. At the end of therapy, 248 of 264 (94%) clinically evaluable patients receiving ceftazidime BID and 258 of 275 (94%) clinically evaluable patients receiving ceftazidime TID achieved clinical cure or improvement (p = 0.953). Pathogens were eradicated or presumed to be eradicated from 217 of 256 (85%) bacteriologically evaluable patients receiving ceftazidime BID and from 228 of 266 (86%) bacteriologically evaluable patients receiving ceftazidime TID (p = 0.760). Of 1131 isolates, the most common pathogens wereS. aureus(30%) andPseudomonas aeruginosa(10%). Both regimens were welltolerated with only 13 patients (3%) in the BID group and 16 patients (4%) in the TID group withdrawing because of an adverse event.These data indicate that ceftazidime 2 g given twice daily is as effective as ceftazidime 1 g given three times daily for the treatment of skin and skin structure infections. In addition, the twice-daily regimen has the advantage of convenience.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Zopolrestat is an aldose reductase inhibitor that may be useful in the treatment of diabetic complications by reducing flux through the polyol pathway. The plasma half-life of zopolrestat in man is approximately 30 h, and approximately 45% of an orally administered 1000-mg dose is eliminated in the urine as unchanged drug. Because active secretion accounts for much of the renal clearance for zopolrestat, a carboxylic acid with a pKaof 5.46, the effect of urinary pH and flow rate on renal clearance of drug was investigated in a series of studies. Renal clearance of zopolrestat following oral administration of 200 mg was determined in normal male volunteers under basal conditions and after treatment with NH4Cl and NaHCO3to alter urinary pH. Plasma concentrations of zopolrestat were similar under basal and NaHCO3treatment but were approximately twofold higher under NH4Cl treatment. However, the half-life of zopolrestat under NH4Cl treatment (29.5 h) was similar to the half-life of zopolrestat in untreated subjects. Renal clearance decreased by a factor of 2.54 for each unit decrease in urinary pH. In a second study, there was no effect of urine flow rate on renal clearance following an oral dose of 400 mg. Renal elimination of zopolrestat and zopolrestat glucuronide was also examined in volunteers with normal urine flow dosed at either 600 or 1000 mg/day. Whereas renal clearance of zopolrestat decreased with decreasing urinary pH, renal elimination of zopolrestal glucuronide was not affected by pH.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effectiveness of an antiarrhythmic drug is judged by the degree of ventricular arrhythmia (VA) suppression. We evaluated the relationship between the degree of VA suppression and survival in a dose-adjusted trial of 110 symptomatic patients treated with amiodarone. Cohorts had leftventricular ejection fraction (LVEF) of 41 ± 18%, ventricular premature contractions (VPCs) of 445 ± 571 h, couplets (C) of 733 ± 149824 h and nonsustained (N) ventricular tachycardia (VT) of 65 ± 21724 h; these conditions were followed for 15 ± 11.5 months. Amiodarone was initiated with an oral loading of 670 + 111.7 mg per day for 10 days and continued on maintenance of 274.9 ± 102 mg per day. Survival rates of responders and nonresponders with VPCsWe conclude that, in patients treated with low-dose amiodarone, the degree of VA suppression of PVCs, C and NVT does not predict survival; the survival of patients with LVEF

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A multicenter study of the treatment of mild and moderate hypertension compared three once-daily regimens for efficacy and safety: Group I, verapamil sustained release (SR) 240 mg; Group II, verapamil SR 480 mg; and Group III, verapamil SR 240 mg plus indapamide 2.5 mg. After a 3-week placebo washout period and a 2-week preliminary treatment period with verapamil SR 240 mg, patients with sitting diastolic blood pressures of 95–115 mm Hg were randomized in a double-blind fashion to one of the three treatment groups for a duration of 16 weeks. (Patients with diastolic BP < 95 mm Hg on this initial treatment were excluded from further study.) Efficacy assessed after 16 weeks or at the end point showed all three treatments significantly reduced sitting diastolic blood pressure from baseline levels. Compared with Group I (low-dose) verapamil SR treatment, there was a reduction in Group III combination therapy of 8.6 mm Hg systolic and 3.0 mm Hg diastolic and a significant reduction in Group II high-dose verapamil SR therapy of 7.6 mm Hg systolic and 3.9 mm Hg diastolic BP. Efficacy results were independent of age or body weight. Patients who were poor responders to lead-in verapamil SR 240 mg daily prior to randomization tended to have a greater response to combination therapy than to high-dose verapamil SR. Adverse experiences leading to withdrawal from the study occurred in 21% of patients receiving high-dose verapamil (Group II), exceeding the withdrawal from the other two treatment groups (8.5% from Group III and 4% from Group I). The most frequent adverse experiences in Group II were constipation and peripheral edema; headache was most common in Groups I and III. This trial demonstrates that adding indapamide to low-dose verapamil SR enhances efficacy and is well tolerated.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Treatments based on mechanistic models of heart failure, although entirely rational, have not succeeded in reducing mortality. A more holistic view, based on the concept that the neurohumoral environment is a common factor, encompasses all the previous theoretical models and extends them to provide a new approach to treatment. Vasodilators, inotropes, and angiotensin-converting enzyme (ACE) inhibitors all modify hemodynamics favorably and improve cardiac performance. Only the vasodilators and ACE inhibitors have been shown to reduce morbidity and mortality. With the ACE inhibitors, this effect is related to changes in the levels of circulating angiotensin II and noradrenaline rather than to improved hemodynamics. There is direct evidence that adrenergic receptor density is reduced in chronic heart failure. Vasodilating β-blockers, like carvedilol, that suppress adrenergic overactivity and reduce preload and afterload, offer a new approach to treatment, but the exploitation of this new opportunity is inhibited by the widely held belief that β-blockers should be avoided in heart failure. This mistaken view is based on the experience of β-blockers in angina pectoris and after myocardial infarction, experience that should not exclude their use in patients with congestive heart failure. Vasodilating β-blockers, introduced at an appropriate dosage, may have an important role to play in the overall management of congestive failure.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Nephrotoxicity manifested by renal insufficiency is a well-known consequence of aminoglycoside administration in hospitalized patients. We report a case of aminoglycoside-induced nephrotoxicity in a young woman with cystic fibrosis that illustrates the classical presentation of nonoliguric renal failure and the risk factors that predispose to the development of aminoglycoside renal toxicity. The incidence of aminoglycoside nephrotoxicity in cystic fibrosis appears to be lower than that expected for a population exposed to prolonged and repetitive courses of therapy with these agents. Cystic fibrosis is a unique disease in which the pharmacokinetic profile of many drugs is abnormal. The pharmacokinetics of aminoglycosides in cystic fibrosis are characterized by an increased drug clearance and a larger volume of distribution; why cystic fibrosis patients should exhibit these abnormalities remains an enigma. If, in fact, patients with cystic fibrosis have a resistant phenotype against aminoglycoside-induced renal damage; further research designed to investigate the complexity of the renal handling of these drugs in these subjects would contribute to unravel the molecular mechanisms of aminoglycoside nephrotoxicity.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID