摘要:

The combination trimethoprim-sulphamethoxazole (co-trimoxazole) is used clinically for the treatment of a variety of infections due to Gram-positive and Gram-negative organisms; particularly for urinary and respiratory tract infections. While both trimethoprim and sulphamethoxazole are mainly bacteriostatic when used alone, their combined effect tends to be bactericidal. Synergism is due to sequential blockade at two separate steps in bacterial folate metabolism, resulting in inhibition of deoxyribonucleic acid synthesis.The optimum concentration ratio of trimethoprim:sulphamethoxazole for a bactericidal effect varies between 1:5 and 1:40, which is consistent with their relative minimum inhibitory concentration (MIC) values against susceptible organisms. The combination is administered principally by the oral route, although it is also given parenterally and rectally. A single oral dose of 160mg trimethoprim and 800mg sulphamethoxazole gives peak serum levels at approximately 4h of 1.2 to 2&mgr;g/ml trimethoprim and 26 to 63&mgr;g/ml sulphamethoxazole. After repeated 12-hourly doses, minimum serum levels are 1.3 to 2.8&mgr;g/ml and 32 to 63&mgr;g/ml for trimethoprim and sulphamethoxazole respectively. The high concentration of sulphamethoxazole in serum relative to that of trimethoprim is due to the greater tissue penetration of trimethoprim. The high sulphamethoxazole:trimethoprim concentration ratio in serum does not always occur in extravascular tissues. However, this is partially compensated for by the high bacteriostatic activity of trimethoprim alone in tissues.The 2 compounds are bound to plasma proteins to similar extents. Both trimethoprim and sulphamethoxazole obey first order absorption, distribution, and elimination kinetics. The disposition of sulphamethoxazole in the body after oral doses has been described in terms of one-compartment model kinetics. while both one-compartment and two-compartment model kinetics have been used to describe the disposition of trimethoprim.Both compounds are cleared from the body predominantly via the kidneys, sulphamethoxazole being excreted mainly in the acetylated form. Average elimination half-lives of trimethoprim and sulphamethoxazole are 11 and 9h respectively, although there is considerable individual variation in these values. The clearance of both compounds is not markedly affected by declining renal function until creatinine clearance falls below 30ml/min. In severe renal failure, the elimination half-lives of both drugs may increase to 45 to 60h and adjustment of dosage is necessary to avoid renal toxicity. Both trimethoprim and sulphamethoxazole appear in bile at concentrations similar to those observed in serum, although the sulphamethoxazole:trimethoprim concentration ratio in bile is somewhat less than that in serum.Trimethoprim and sulphamethoxazole give rise to only occasional side effects, which are characteristic of the individual compounds. Principal reactions are those associated with sulphonamide sensitivity, and renal toxicity in patients with impaired renal function. Anaemia due to impaired folate metabolism may be a problem in some patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Measurement of the plasma concentration of salicylate has been made in the majority of clinical settings where salicylates, mostly in the form of acetylsalicylic acid (aspirin), are used extensively to treat chronic rheumatic conditions. At the same time, studies on the kinetics of salicylates have increased in the specialised literature. Analysis of published papers suggests a surprising difference between principles documented in controlled situations and what happens in routine clinical practice. Recommended dosage regimens are based on a rather narrow amount of data, as relevant studies include few patients and have not used readily comparable protocols.The wealth of information available on the kinetics and metabolism of salicylates has not yet produced generally accepted agreement on how to achieve optimum therapeutic results. Plasma concentration monitoring programmes aim mainly at avoiding side effects and checking compliance, but do not deal specifically with overall evaluation of therapeutic outcome. In the longer term, aspirin may possibly become less favoured as the initial drug of choice for the treatment of chronic rheumatic conditions, and the merits of monitoring plasma salicylate levels could be even less favoured. In the meantime, however, as clinical practice still largely involves use of aspirin, prospective collection of more controlled data on larger population groups seems warranted, not only for the benefit of treated patients but also for the purpose of assessing more thoroughly the clinical relevance of therapeutic drug monitoring in this area.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Adjustment of dosage of a renally excreted drug (or active metabolite) for patients with severe renal failure still causes some difficulties. It is therefore helpful to select, within a given therapeutic group of drugs, a compound that is particularly safe and easy to use and, if possible, does not require adjustment of dosage. This is ‘the drug of choice for renal patients’.Such a drug would ideally meet the following pharmacokinetic criteria: normal urinary excretion less than 30% of the administered dose, predominant biliary and intestinal removal, disposition essentially unaffected by parameters likely to be modified in renal failure (e.g. changes in serum proteins or fluid compartments: receptor sensitivity, etc), and pharmacokinetics not complicated by the formation of active or toxic metabolites that depend on urinary elimination. Above all, the drug should have a wide therapeutic margin and must be free of nephrotoxicity.Examples of drugs of choice for patients with impaired renal function are given for some important therapeutic groups and special emphasis is placed on antibiotics and &bgr;-adrenoceptor blocking agents.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Methotrexate1plasma concentrations were measured repeatedly over 48 hours after each of 5 subsequent intrathecal injections in 14 children and 8 adult patients with acute lymphoblastic leukaemia. Two patterns of concentration profiles were distinguished:a) The plasma concentration reached a rather low maximum, followed by a relatively slow decline (‘slow type’):b) The plasma concentration increased rapidly to a relatively high value after which it declined rather steeply (‘fast type’).The incidence of the ‘fast type’ increased progressively with the number of intrathecal injections.When the plasma concentration-time curves were described by a pharmacokinetic 2-compartment open model with first-order absorption, it was calculated that the transfer of methotrexate from the spinal fluid into the plasma is much slower for the ‘slow type’ compared with the ‘fast type’.Assuming concentration-dependent cytostatic activity, the therapeutic efficacy in the central nervous system is likely to be less for the ‘fast type’ than for the ‘slow type’. Systemic toxicity resulting from the ‘slow type’ is expected to be higher than from the ‘fast type’.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

18 hypertensive patients with a glomerular filtration rate (GFR) between 3.8 and 113ml/min received guanfacine as single intravenous and multiple oral dose treatment. Mean plasma concentrations of guanfacine on the fifth day of oral treatment ranged from 6.5 to 8.6ng/ml in patients with normal renal function (GFR > 90ml/min), as well as in those with a moderate degree of renal impairment (GFR 30 to 10ml/min) and in uraemic patients (GFR <10ml/min). During guanfacine treatment plasma concentrations and fall in blood pressure did not differ in a statistically significant fashion among patients with varying degrees of renal function.Independent of renal function, in all investigated patients the elimination rate constant obtained from serum and urine values were close to 0.05h-1. Mean half-life of guanfacine was calculated to be 14h. The cumulative urinary excretion up to 48h fell from 57% in patients with normal renal function to 7.5% in uraemic patients. Thus, non-renal excretion plays an important role in patients with impaired renal function.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS