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The aim of this investigation was to assess the bioavailability and pharmacokinetics of oxytocin in six male subjects after a sublingual dose of 400 int. units (684 micrograms) and after an intravenous dose of 1 int. unit (1.71 micrograms). After intravenous administration, the pharmacokinetic profile could be described with a two-compartment model. The distribution half-life was 0.049 +/- 0.106 h, the elimination half-life was 0.33 +/- 0.23 h, the total body clearance was 67.1 +/- 13.4 L h-1 and the volume of distribution was 33.2 +/- 28.1 L. After sublingual administration, a poor bioavailability with a 10-fold variation between 0.007 and 0.07% was observed. The pharmacokinetic profile could be described with a one-compartment model. The lag time was subject-dependent and ranged between 0.12 and 0.30 h (40% CV). The absorption half-life was 0.45 +/- 0.29 h, and the apparent elimination half-life 0.69 +/ - 0.26 h. This study showed a very poor and interindividual variability in bioavailability. The sublingual route of administration with its 'long' lag time and 'long' absorption half-life would not seem a reliable route for accurate high dosing for immediate prevention of post-partum haemorrhage.

Objective: To assess and compare the pharmacokinetics and bioavailability of methylergometrine (ME) in men and non-pregnant women., Design: A cross-over design was used for an oral dose of 0.125 mg and an intravenous dose of 0.200 mg of ME in 6 men and 6 non-pregnant women (parallel-design in gender)., Results: After intravenous administration, the pharmacokinetic profile of ME was described with a 2-compartment model. The distribution half-life (t1/2 alpha) in men was 0.19 +/- 0.27 h, in women 0.10 +/- 0.04 h, the elimination half-life (t1/2 beta) 1.85 +/- 0.28 h, respectively, 1.94 +/- 0.34 h and the total body clearance (CL) 33.2 +/- 11.8 l.h-1, and, respectively, 22.18 +/- 3.10 l.h-1. For these intrinsic pharmacokinetic parameters differences between men and women were not statistically significant. After oral administration, the pharmacokinetic profile was described with a 1-compartment model. The lag time was subject dependent and was significantly longer in men 0.33 +/- 0.09 h than in women 0.09 +/- 0.07 h. T1/2 beta in men was 2.08 +/- 0.43 h and was longer than in women 1.42 +/- 0.31 h (p = 0.012). In both men and women a large variation of bioavailability was shown ranging between 22% and 138%., Conclusion: This study with oral methylergometrine showed a comparable large interindividual variability in bioavailability in both men and women.

Some investigators argue that treating epilepsy with several antiepileptic drugs (AEDs) simultaneously (polytherapy) may give rise to more adverse effects than monotherapy, but this argument lacks supporting quantitative data. To reexamine this issue, we recruited a cohort of patients from the outpatients of the Special Centres for Epilepsy in The Netherlands and from the outpatients of the Department of Neurology, Nijmegen University, The Netherlands. Two tools were used for analysis. All daily doses of antiepileptic drugs (AEDs) were standardized by the ratio of prescribed daily dose to defined daily dose (PDD/DDD). The DDD is the assumed average effective daily dose for a drug used for its main indication in adults. The assignment of DDD values is the task of the World Health Organization (WHO) Collaborating Centre for Drugs Statistics Methodology and Nordic Council on Medicines, which regularly publishes Guidelines for Defined Daily Doses. The severity of adverse effects (AE) was assessed by using the Neurotoxicity Index and the Systemic Toxicity Index as developed by the VA Cooperative Study Group for their recent studies comparing the efficacy and tolerability of AEDs. One hundred sixty-one patients received monotherapy; all had a PDD/DDD ratio < or = 2/day; 128 of 262 patients receiving polytherapy also had < or = 2 PDD/DDD ratios/day. The mono- and polytherapy groups were stratified according to the PDD/DDD ratio. The prevalence of neurological AE for patients with similar PDD/DDD ratios was 50-80% for monotherapy patients and 50-82% for polytherapy patients. The difference between the mono- and polytherapy groups was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: This study is part of a programme on reduction of postpartum haemorrhage (PPH). Ergometrine and methylergometrine have a favourable effect on both blood loss and maternal morbidity and mortality and oral preparations were regarded as a possible treatment for use in tropical countries. The stability of oral preparations of the two ergometrine compounds under tropical conditions was unknown and was therefore examined in this study., Study Methods: The 'experimental shelf lives' of ergometrine and methylergometrine tablets were examined by exposing the tablets to seven artificially controlled conditions. Samples were analysed by high performance liquid chromatography at nine different sampling times over a period of 1 year to determine the content of ergometrine and methylergometrine., Results: Under refrigeration (test I), less than 90% of the stated amount of active ingredient was found in the tablets after 14 weeks in the case of ergometrine and 21 weeks in the case of methylergometrine. When stored in the dark at 40 degrees C and 75% relative humidity (test VI), the tablets fall outside accepted specification (= 90-110% of state amount of active ingredient) within 3 weeks in the case of ergometrine and 21 weeks in the case of coated methylergometrine tablets. The stability of uncoated ergometrine tablets was far less than that of coated methylergometrine tablets. Instability worsened under extreme humid conditions (test IV and VI), and hot conditions (test V), for both ergometrine and methylergometrine. From week 31 onwards the coating did not seem to protect the compound anymore, irrespective of the condition of exposure., Conclusions: Tropical conditions make the tablets unstable with humidity as the main adverse factor. The sugar-coated methylergometrine tablets are more stable under humid/hot conditions than the non-coated ergometrine tablets. Under all simulated conditions both oral ergometrine and methylergometrine tablets are unstable.

Objectives: This study is part of a programme on reduction of postpartum haemorrhage. Buccal oxytocin and desamino-oxytocin administration with a favourable effect on both blood loss and maternal morbidity and mortality were regarded as possible treatments for use in tropical countries. The stability of buccal oxytocin and desamino-oxytocin under tropical conditions was unknown and therefore tested in this study., Study Methods: The 'experimental shelf lives' of buccal oxytocin and desamino-oxytocin were examined by exposing the tablets to seven artificially controlled conditions. Samples were analysed by high performance liquid chromatography to determine the content of oxytocin and desamino-oxytocin at nine different times during the period of 1 year., Results: Oxytocin and desamino-oxytocin are fairly stable under refrigeration. Instability for both drugs was detectable after 20 weeks' storage under humid conditions, independent of temperature. Desamino-oxytocin is more sensitive to light exposure; its concentration declines to 55.6% of the stated amount after 1 year of exposure to light compared to 85% in the case of oxytocin. Oxytocin packaged as supplied by the manufacturer were stable for 21 weeks when exposed to simulated humid (75% relative humidity) conditions. At 40 degrees C and 25% relative humidity there is no difference in stability between tablets in sealed aluminium packs as supplied by the manufacturer and unpackaged tablets., Conclusions: Tropical conditions make oxytocin and desamino-oxytocin tablets unstable, with humidity as the most adverse factor. The oxytocin tablets were partially protected from the harmful effect of humidity by sealed aluminium package.

The achievement of treatment objectives for patients with epilepsy, as defined by the treating clinicians, was compared with scoring of clinimetric indexes. Patients with the treatment objectives "complete seizures remission" or "treatment impairment/benefit balance" were included in this study. The clinimetric indexes were also compared with a clinical status rating, as assessed by the clinician. No correlation was observed between clinimetric indexes and achievement of the treatment objective. The difference noted in outcome of treatment objectives and index scores may have resulted because the indexes were group-intended and the clinician's judgment was individual-oriented. The clinician's assessment of clinical status of the patient did correlate with the composite index of impairments (CII), however, a clinimetric scale for severity of impairments caused by epilepsy. The advantage of the CII over the clinical status rating is that the CII is constructed with objective data and shows the cause of change observed during follow-up.

We studied the effects of urinary pH on the kinetics of salicylic acid (SA) with its metabolites and assessed the contribution of alkaline hydrolysis of salicylic acid acyl glucuronide to the renal clearance of salicylic acid. Hydrolysis of SAAG in alkaline urine contributes marginally to the high renal clearance and excretion of salicylic acid, validating alkalinization of a patient with SA overdose. Under acidic urine conditions, salicylic acid (SA) had a terminal plasma t1/2 value of 3.29 +/- 0.52 hours while under alkaline urine conditions this t1/2 was significantly reduced to 2.50 +/- 0.41 hours (p = 0.0156). The total oral body clearance of salicylic acid under acidic conditions (1.38 +/- 0.43 l/h) is significantly lower than under alkaline urine conditions (2.27 +/- 0.83 l/h; p = 0.0410). The Km and Vmax values of SA, and its conjugates salicylic acid phenolic glucuronide (SAPG), salicyluric acid (SU) and salicyluric acid phenolic glucuronide (SUPG) did not differ statistically under acidic and alkaline urine conditions. The protein binding of SA was 93.8 +/- 1.0% and that of SU was 89.7 +/- 2.2% in vivo and in vitro. SUPG had a protein binding of 84.8 +/- 1.8%, while SAPG showed no protein binding at all. The renal excretion of salicylic acid depends strongly on the urinary pH. The percentage of the dose excreted unchanged increased from 2.3 +/- 1.5% under acidic conditions to 30.5 +/- 9.1% under alkaline conditions (p = 0.0006). Alkaline urine lowered by 50% the percentage of the dose excreted as SU (p = 0.0028), SAAG (p = 0.0013), and SUPG (p = 0.0296), while SAPG is only marginally lowered (p = 0.0589).(ABSTRACT TRUNCATED AT 250 WORDS)

To test the feasibility of comparing epilepsy treatment policies and outcome, a secondary and a tertiary epilepsy care facility have been audited in a previous study (1). Marked differences were observed in the treatment policies and outcome and in the distribution of seizure types and duration of epilepsy. For this reason the patients of that study were matched according to seizure type and duration of epilepsy, resulting in two groups each of 32 patients per centre. The outcome of treatment was assessed by using clinimetrical indexes for seizure frequency and severity and toxicity of medication, resulting in the Composite Index of Impairments (CII), reflecting all treatment-related impairments. For the statistical analysis the X2-test and the Kruskal-Wallis test were used. Differences were found to be statistically significant when p < 0.05. No distinct differences were found in the treatment policies of both centres. However, differences were observed in the outcome of treatment. The toxicity ratings in this study were significantly higher for the Epilepsy Centre. Also the Composite Index of Impairments (CII) was significantly higher at the Epilepsy Centre. The number of patients with a CII score of > 100 did not differ significantly for both centres. The finding that pharmacotherapy is similar in both centres, suggests that pharmacotherapy is pushed to its limits in both, and that referral to a tertiary facility is mainly for the non-pharmacotherapeutic care modalities available. For the corroboration of this assumption the use of a quality of life index would be more appropriate than the CII.

Objective: To describe the changes in drug intake during institutionalization in a Dutch psychogeriatric nursing home., Setting: Psychogeriatric nursing home Joachim en Anna in Nijmegen, the Netherlands., Design: Retrospective analysis of medical charts., Patients and Methods: In 390 patients drug intake (sixteen drug groups) at admission, after six weeks, at half yearly intervals and on the day of death was recorded in a longitudinal fashion, as were side effects. Increase or decrease in drug intake was tested by means of linear regression analysis., Results: After an initial decrease there was a gradual increase in mean drug intake during institutionalization. Laxatives and to a lesser degree drugs for the respiratory tract and heart were mostly responsible for this increase. In the other groups no change or even decrease was noted. The degree of dependency and the type of dementia had an influence on these changes. At the day of death analgesics, morphinomimetics and bronchodilators were the most frequent drugs. Neuroleptics caused most of the side effects observed., Conclusion: Prescription of laxatives is mostly responsible for the increase in mean drug intake in this Dutch psychogeriatric nursing home.

A gradient reversed-phase HPLC analysis for the direct measurement of salicylic acid (SA) with the corresponding glycine and glucuronide conjugates in plasma and urine of humans was developed. The glucuronides were isolated by preparative HPLC from human urine samples. The concentration of the glucuronides in the isolated fraction were determined after enzymatic hydrolysis. Salicylic acid acyl glucuronide (SAAG) was not present in plasma. No isoglucuronides were present in acidic and alkaline urine of the volunteer. The limits of quantitation in plasma are: SA 0.2 microgram/ml, salicyluric acid (SU) 0.1 microgram/ml, salicylic acid phenolic glucuronide (SAPG) 0.4 microgram/ml and salicyluric acid phenolic glucuronide (SUPG) 0.2 microgram/ml. The limit of quantitation in urine is for all compounds 5 micrograms/ml. Salicylic acid acyl glucuronide is stable in phosphate buffer pH 4.9 during 8 h at 37 degrees C; thereafter it declines to 80% after 24 h. The subject's urine was therefore acidified by the oral intake of 4 x 1.2 g of ammonium chloride/day. With acidic urine, hardly any salicylic acid is excreted unchanged (0.6%). It is predominantly excreted as salicyluric acid (68.7%).

During a 1-year period, neuroleptic drug utilization was assessed in nonpsychiatric departments of a Dutch university hospital in defined daily doses (DDD), DDD per 100 patients and per 100 bed days. Substantial divergence was found among the nonpsychiatric departments with respect to the quantity as well as the types of neuroleptic used, but there was no relationship between psychiatric consultations and neuroleptic use. In semistructured interviews, the senior consultant at each department stated that neuroleptics were used not only for the treatment of behavior disorders but also for nonpsychiatric indications, such as pain, nausea, and hiccups. In addition, specific neuroleptics were considered to be appropriate for the treatment of specific indications, but the doses anticipated to be effective were in many cases well below the DDDs. It is concluded that substantial quantities of neuroleptics are prescribed for nonpsychiatric use. This is remarkable, because very little is known about nonpsychiatric indications and the effects of neuroleptics, including the unwanted side effects, in patients who are somatically ill.

The aim of this investigation was to assess the pharmacokinetics and bioavailability of ergometrine in six human male subjects after an oral dose of 0.200 mg and after an intravenous dose of 0.075 mg of ergometrine maleate. A large variation in bioavailability of between 34% and 117% in the six volunteers was observed. The lag time was also subject dependent and ranged between 0.0073 h (0.4 min) and 0.47 h (28 min). After intravenous administration, the pharmacokinetic profile can be described by a two-compartment model. The distribution half-life t1/2 alpha is 0.18 +/- 0.20 h, the elimination half-life t1/2 beta is 2.06 +/- 0.90 h, the total body clearance (CL) amounts to 35.9 +/- 13.4 l h-1 and the steady-state volume (Vss) of distribution is 73.4 +/- 22.01. After oral administration, the pharmacokinetic profile can be described by a one-compartment model. The absorption half-life t1/2 abs is 0.19 +/- 0.22 h, and the elimination half-life t1/2 beta 1.90 +/- 0.16 h. This study with oral ergometrine shows such a large interindividual variability in bioavailability that the oral route of administration does not seem not to be the most reliable means of accurate dosing in preventing post-partum haemorrhage.

Of 890 nursing home patients with dementia, admitted between 1980 en 1989 to Dutch nursing home 'Joachim en Anna' in Nijmegen, each episode of psychotropic drug use was retrospectively registered. Drugs were coded by means of the Anatomical Therapeutic Chemical (ATC)-classification system and the daily dose was expressed as the ratio of the prescribed daily dose and the internationally agreed defined daily dose. Side effects were analysed as were changes in prescription patterns throughout the years of patient admittance. A total of 3090 episodes were registered. Neuroleptics, benzodiazepines and antidepressants accounted for 58, 32 and 9% of the prescriptions. In almost every drug-prescription the prescribed daily dose was lower than the defined daily dose. More than 75% of the patients had at least one prescription for a psychotropic drug during institutionalization. Half of those patients who used a neuroleptic showed one or more side effects. Neither the total amount of patients with psychotropics nor the duration of usage changed throughout the years of patient admittance. It is concluded that a majority of these nursing home patients got at least one prescription of a psychotropic drug during institutionalization. Psychotropics were prescribed for long-term usage, but in low doses. Side effects were frequently observed in determining the right dose.

A dose of 1,000 mg probenecid was administered orally to 14 human volunteers in order to quantify the maximal rate of formation and excretion of probenecid acyl glucuronide in the urine. Probenecid showed dose-dependent pharmacokinetics. Plasma protein binding of probenecid was high, being somewhat higher in males (90.7 +/- 1.4%) than in females (87.9 +/- 1.4%; p = 0.0019). It was shown that probenecid is metabolized by cytochrome P-450 into at least two phase I metabolites. Each of the metabolites accounted for less than 12% of the dose administered; the main metabolite probenecid acyl glucuronide, representing 42.9 +/- 13.2% of the dose, was only present in urine and not in plasma. The renal excretion rate-time profile of probenecid acyl glucuronide showed a plateau value in the presence of an acidic urine pH. This plateau value was maintained for about 10 h at the dose of 1,000 mg. The height of the plateau value depended on the individual and varied between 250 and 800 micrograms/min (15-50 mg/h). It was inferred that probenecid acyl glucuronide is formed in the kidney during blood-to-lumen passage through the tubular cells. We conclude that the plateau value in the renal excretion rate of probenecid glucuronide reflects its Vmax of formation.

The aim of this pilot study was to demonstrate the possible inhibitory effect of probenecid on the renal glucuronidation and on the renal clearance of nalidixic acid in a human volunteer. Under acidic urine conditions, hardly any nalidixic acid is excreted unchanged (0.2%). It is excreted as acyl glucuronide (53.4%), 7-hydroxymethylnalidixic acid (10.0%), the latter's acyl glucuronide 30.9%, and 7-carboxynalidixic acid (4.2%). Under probenecid co-medication the renal glucuronidation of nalidixic acid is reduced from 53% to 16%; the renal clearance of both nalidixic acid and 7-hydroxymethylnalidixic acid are reduced (p < 0.001); the intrinsic t1/2 of the metabolite 7-hydroxymethylnalidixic acid increased from 0.48 h to 4.24 h. The amount of acyl glucuronidation of 7-hydroxymethylnalidixic acid was not altered. The in vitro protein binding of both acyl glucuronides was increased, while no effect on the unconjugated compounds was seen. Nalidixic acid had no effect on the maximal renal excretion rate of probenecid acyl glucuronide.

A gradient reversed-phase high pressure liquid chromatographic analysis was developed for the direct measurement of nalidixic acid with its acyl glucuronide, 7-hydroxymethylnalidixic acid with its acyl and ether glucuronides, and 7-carboxynalidixic acid in human plasma and urine. The glucuronides and 7-carboxynalidixic acid were not present in plasma after an oral dose of 1,000 mg nalidixic acid. The acyl glucuronides of 7-carboxynalidixic acid were not present in plasma and urine. The acyl glucuronides are stable in urine at pH 5.0-5.5. The subject's urine must therefore be acidified by the oral intake of 4 x 1 g of ammonium chloride per day. With acidic urine, hardly any nalidixic acid was excreted unchanged (0.2%). It was excreted as acyl glucuronide (53.4% of dose), 7-hydroxymethyl-nalidixic acid (10.0%), the latter's acyl glucuronide (30.9%), and 7-carboxynalidixic acid (4.2%).

In order to test if it is feasible to compare epilepsy treatment policies, a secondary (University Hospital) and a tertiary referral care centre (i.e. an Epilepsy Centre) were compared with respect to their characteristics, the treatment approaches, and the outcome of treatment using clinimetric indexes. At the Epilepsy Centre a greater variety of seizure types was seen than at the University Hospital. At the University Hospital more patients were treated with monotherapy (62.5%) than at the Epilepsy Centre (28.0%). The Composite Index of Impairments (CII), which reflects all treatment related impairments i.e. seizures and adverse events, was significantly higher at the Epilepsy Centre than at the University Hospital. No difference was seen in the groups of patients with a high score of the CII (> 100). Further analysis is needed to obtain an answer as to why differences between the two groups exist.

Objective: To describe the changes in de first six weeks after admission and to consider the factors which influence drug intake., Place: Psychogeriatric nursing home facility Joachim en Anna in Nijmegen, the Netherlands., Design: Retrospective analysis of medical charts., Patients and Methods: Of 356 patients drug intake on the day of admission and six weeks after were registered as well as diagnosis on dementia, domicile before admission, degree of dependence and comorbidity. Medication was divided into sixteen groups. Changes in drug taking were tested by means of the Wilcoxon test. The influence of the factors mentioned was analysed by an analysis of variance and the logistic regression procedure., Results: The mean number of drugs taken per patient decreased from 2.5 at admission to 2.1 at six weeks. In particular psychotropics, diuretics, cardiac drugs and drugs grouped as a 'miscellaneous' were reduced. Domicile before admission, diagnosis of dementia, comorbidity and less significantly the degree of dependence all had an influence on drug intake. Patients admitted from old people's homes or a general hospital had twice as much medication as patients who lived in their own homes. Main differences were seen in the use of psychotropics and diuretics. Patients suffering from Alzheimer's disease used fewer drugs than patients with a multi-infarct dementia. The latter had a higher intake of diuretics, cardiac drugs and laxatives, while Alzheimer patients used more psychotropics. Patients with the highest degree of dependence used more laxatives and fewer psychotropics or diuretics., Conclusion: Reduction of drug intake after admission to a psychogeriatric nursing home is possible. Several factors influence drug intake. These should be considered when comparing different studies.

In two male patients, aged 53 and 21 years, lithium intoxication was suspected. The diagnosis was apparently confirmed by blood testing (the lithium concentrations amounted to 3.68 and 1.82 mmol/l, respectively). Retrospectively however it was found that blood sampling tubes with lithium-heparin as the anticoagulant had been used. No lithium intoxication was present in the patients. Clear instructions in writing are necessary to prevent this error.

To study the utilization of total parenteral nutrition, using methodology recommended by the World Health Organization, classification of components in accordance with the anatomical therapeutic chemical classification and defined daily dose system is necessary. Anatomical therapeutic chemical indices are available but defined daily dose values have not been established yet. In this article, a methodology to study both the total utilization of total parenteral nutrition, the utilization of individual substances and the composition of total parenteral nutrition is presented. To validate the proposed methodology, the utilization of total parenteral nutrition in a teaching hospital is studied, based on pharmacy computer data. The total utilization of total parenteral nutrition in the hospital in 1990 is 1.4 defined daily doses/100 bed-days. The composition of total parenteral nutrition varied greatly between the clusters. In this study we showed that utilization of total parenteral nutrition can be measured with the proposed methodology, using a defined daily dose for total parenteral nutrition in concurrence with a defined daily dose for the individual components.

An isocratic high-performance liquid chromatographic (HPLC) method with fluorescence detection has been developed for the measurement of ergometrine in human plasma. The quantitation limit in plasma was 75 pg/ml. An example of the plasma concentration-time curves obtained after both oral and intravenous administration of ergometrine in one volunteer is shown. This HPLC method makes it possible to describe the pharmacokinetic parameters of oral ergometrine.

Objective: To demonstrate that the human kidney is capable not only of filtering and secreting drugs and their metabolites, but also of carrying out conjugation reactions such as acyl glucuronidation, N-glucuronidation, and glycination., Data Sources: Plasma concentrations and renal excretion rates of drugs are measured and renal clearance is calculated in a series of selected pharmacokinetic studies in healthy human volunteers (some studies were conducted in the authors' laboratory and others were reported in the literature). BACKGROUND THEORY: It is generally agreed that the liver plays the dominant role in drug metabolism, and that the function of the kidneys is limited to excretion of parent drug and metabolites. This can be easily understood when a metabolite is present in both plasma and urine. When the metabolite is present in urine but is not measurable in plasma, then the possibility exists that the metabolite is formed by the kidneys., Results: "Simple" excretion by the kidneys is demonstrated for sulfatroxazole/sulfamethoxazole. Ether glucuronides of codeine are formed in the liver, and the resulting glucuronide is excreted by the kidneys. Possible formation of N1- and N2-glucuronides by the kidneys is demonstrated for sulfadimethoxine, sulfametomidine, and sulfaphenazole. Acyl glucuronidation of probenecid and nalidixic acid is carried out by the kidneys. The acyl glucuronidation of probenecid shows a capacity-limited formation/excretion rate of 46 mg/h, which is subject dependent. During this process, the acyl glucuronidation of co-administered nalidixic acid is reduced from 53 to 16 percent compared with that of nalidixic acid alone. Probenecid and its acyl glucuronidation do not inhibit the ether glucuronidation of codeine in the liver, but only interfere with the active tubular secretion process. The acyl glucuronidation of the nonsteroidal antiinflammatory drug naproxen and its metabolite, O-desmethylnaproxen, may be carried out by the liver and kidneys. Glycination of benzoic acid and salicylic acid is carried out in both the liver and kidneys., Conclusions: It is difficult to recognize renal drug metabolism in the intact human body (in vivo); the glucuronides or conjugates must be measured via direct HPLC analysis. In cases where the metabolite is present in high concentrations in urine but not in blood, there may be an indication that the kidneys are responsible for the formation of the metabolite. Impaired kidney function not only affects renal excretion but may also affect renal metabolism.

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, the t1/2 increased from 3 to 6 h. The Cmax was 14 micrograms/ml with a dosage of 250 mg, 31 micrograms/ml with 500 mg, 70 micrograms/ml with 1,000 mg and 120 micrograms/ml with 1,500 mg. The tmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6-0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34-59%). The protein binding of probenecid glucuronide in vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate--time profile of probenecid glucuronide shows a plateau value of approximately 700 micrograms/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects its Vmax of formation.

In humans sulfa-2-monomethoxine (S) is metabolized by N4-acetylation (39.9 +/- 8.0 per cent). After an oral dose, S is eliminated biphasically (t1/2, 5.2 +/- 1.6 h and 13.2 +/- 3.4 h) which is similar in both fast and slow acetylators. The metabolite N4-acetylsulfa-2-monomethoxine (N4) is eliminated monophasically (t1/2, 30.0 +/- 5.7 h). The intrinsic mean residence time (MRT) of N4 is 33.5 +/- 8.8 h. The mean total body clearance of S is 11.6 +/- 2.7 ml min-1, and the Vdss is 12.3 +/- 1.01. The renal clearance of S during the first day was twice as high as on the following days for two of the six volunteers (8 vs 4 ml min-1). The renal clearance of N4 during the first day, for four out of the six volunteers, was twice as high as on the following days (8 vs 4 ml min-1). The protein binding of S is 95 per cent and that of its conjugate N4 98 per cent. Approximately 80 per cent of the oral dose of S is excreted in the urine as parent drug (41.0 +/- 6.2 per cent) and as N4 acetyl conjugate (39.9 +/- 8.0 per cent).

We will describe the method of cost-identification analysis, which was performed in a Dutch hospital during a review of antimicrobial drugs usage. In the present Dutch hospital budget system, in-patients' drug costs generate no revenues. Efforts to diminish drug costs result in financial benefit for the institution. To maximize cost containment, efforts are to be directed to all cost components. We chose wholesale purchase prices of antimicrobial drugs and national prices for salaries and hospital costs. Global cost comparison shows the most cost effective system of intravenous administration. Push injection is the most economic way to administer intravenous drugs which do not require dilution or prolonged infusion time. For stable solutions, such as metronidazole, ready-to-infuse bags are the most economic system. A global cost calculation is listed for commonly used antimicrobial drugs for in-patients. A cost comparison is given for vancomycin CP and teicoplanin, two antistaphyloccocal drugs, which are probably equieffective. The result of global cost comparison contributes to the decision to include new drugs into the hospital formulary or to replace older ones.

A pharmaco-epidemiologic study in hospitalized patients was carried out in order to establish the place and use of omeprazole (Losec), a new and promising drug in the treatment of acid-related diseases. A comparison is made with cimetidine and ranitidine use. It appeared that prescribed omeprazole doses were high in relation to the established defined daily doses and that substitution of H2 receptor antagonists by omeprazole led to tremendously increased drug costs. From the clinical indication data it could be established that the drug was prescribed appropriately.

Sulfamethomidine metabolism was studied in 6 volunteers. In humans, only N1-glucuronidation and N4-acetylation take place, leading to the final double conjugate N4-acetylsulfamethomidine N1-glucuronide. The N1-glucuronides were directly measured by high pressure liquid chromatography. Fast and slow acetylators show a similar half-life for sulfamethomidine (26 +/- 6 h) and its conjugates sulfamethomidine (26 +/- 6 h) and N4-acetylsulfamethomidine (36 +/- 16 h). Approximately 50-60% of the oral dose of sulfamethomidine is excreted in the urine, leaving 40-50% for excretion into bile and faeces. The main metabolite of sulfamethomidine is its N1-glucuronide, which accounts for 36 +/- 7% of the dose, followed by N4-acetylsulfamethomidine (16 +/- 8%). N1-glucuronidation results in a 75% decrease in protein binding of sulfamethomidine. N4-acetylsulfamethomidine and its N1-glucuronide showed the same high protein binding of 99%. The renal clearance of N4-acetylsulfamethomidine is 7.9 +/- 2.2 ml/min and approximately 20 times as high as that of the parent drug (0.46 +/- 0.16 ml/min). Total body clearance of sulfamethomidine is 4.5 +/- 0.9 ml/min and the volume of distribution in steady state 10.6 +/- 1.7 1. No measurable plasma concentrations of the N1-glucuronides from sulfamethomidine are found in plasma. This may be explained by renal glucuronidation after active tubular reabsorption.

The sulphonamides sulphapyridine and sulphadiazine show novel hydroxy metabolites in the turtle Pseudemys scripta elegans. In the excreta of the turtles the monohydroxy metabolites 4-hydroxy- and 5-hydroxysulphapyridine and the dihydroxy metabolite 4,5-dihydroxysulphapyridine were detected. Of sulphadiazine only dihydroxy metabolites 4,5- and 4,6-dihydroxysulphadiazine were detected. About 70-90% of the dose of sulphapyridine was recovered, while this figure varied between 48 and 69% for sulphadiazine.

In order to study the practicability of rating scales in the regular care of people with epilepsy, indices have been developed and tested on their validity. These indices consist of the Index of Seizures, representing seizure activity, and the Composite Index of Impairment concerning the severity of impairment caused by the seizure type and frequency and the side-effects of anti-epileptic drug treatment. The indices have been applied in a retrospective quantitative evaluation of anti-epileptic drug therapy. The medical records of 250 randomly selected patients registered at an adult out-patient clinic have been reviewed. Their seizures have been classified as generalized tonic-clonic, simple partial and/or complex partial. The distribution of this population according to these indices has been studied, which leads us to the following conclusions: the global indices are valid for clinical application; in 18.6% of the patients studied there was severe impairment and unacceptable seizure control; combined types of seizure are difficult to control; no significant difference is demonstrated between monotherapy and polytherapy regarding the amount of neurotoxicity. The indices can be determined rapidly and therefore may become valuable aids for the physician in an out-patient clinic to support a decision whether or not to revise current anti-epileptic drug therapy.

The amount of additional antibiotics measured by defined daily dose (DDD) methods after 2651 hip and 362 knee replacements was assessed after prophylaxis with one or three doses (1502/1511 patients) of cefuroxime. No differences were observed between the two regimens with respect to total amount, type, indication, and duration of additional antibiotics. The incidence of joint sepsis did not differ significantly between the two trial arms, but the sample was too small for definite conclusions. There were 11.4 DDD/100 bed days of additional antibiotics used in 21% of patients after hip replacement and 15.7 DDD/100 bed days in 31% after knee replacement. For wound problems, 3.8 and 6.9 DDD/100 bed days were given in the hip- and knee-replacement groups. For distant infection, 6.5 DDD/100 bed days was administered in both groups. Duration of therapy varied only in relation to indication. Prescribed were penicillins (43% to 50%), sulfonamides (18%), cephalosporins (10% to 16%), and nitrofurantoin (8% to 13%); drug use was related to the type of infection.

Sulpha-2-monomethoxine is N4-acetylated to an extent of 12% of the dose by Pseudemys scripta elegans; 48% is excreted unchanged. No O-dealkylation of the 2-methoxy group takes place.

After an oral dose of 100 mg of sulphaphenazole, the turtle Pseudemys scripta elegans excretes 27% of the compound unchanged and 3.8% as N4-acetylsulphaphenazole. The expected glucuronide conjugate, sulphaphenazole-N2-glucuronide, is not formed and excreted.

Cefuroxime is well-absorbed and distributed over the human body. This review gives a general summary of published information on tissue concentrations of cefuroxime after an intravenous or intramuscular dose of 750 or 1,500 mg of cefuroxime. Tissue concentrations are given for blister fluid, meninges, eyes, respiratory tract, sputum and bronchi, abdominal and urogenital tract, uterine, ovarian and fallopian tube tissue, myometrium, membranes, placenta, puruloid and healthy human milk, bile, prostate, hip and knee bone. Pharmacokinetics are reviewed in patients with impaired kidney function and in pregnancy.

A direct high pressure liquid chromatographic analysis of sulfaphenazole-N2-glucuronide in urine is described. After an oral dose of 439 mg of sulfaphenazole, 0% is excreted unchanged in the urine, less than 1% is excreted as N4-acetylsulfaphenazole. As N2-glucuronide 49.4% is excreted in one slow acetylator and 84.8% in one fast acetylator.

Sulfamonomethoxine (S) is metabolized by O-dealkylation, N4-acetylation, and N1-glucuronidation. In humans, only N1-glucuronidation (12%) and N4-acetylation (36%) takes place. The N1-glucuronide is directly measured by HPLC. When N4-acetylsulfamonomethoxine (N4) is administered as the parent drug, N1-glucuronidation does not occur. After an oral dose, fast and slow acetylators show a similar t1/2 for S (25.0 +/- 4.6 hr vs. 29.8 +/- 4.8 hr; p = 0.459), and the t1/2 of the N4-acetyl conjugate is also similar in fast and slow acetylators (25.0 +/- 4.64 hr vs. 29.8 +/- 4.8 hr, p = 0.459). The intrinsic mean residence time of N4 is 7.1 +/- 2.3 hr. The mean total body clearance of S is 5.0 +/- 1.3 ml/min, the renal clearance is 0.84 +/- 0.26 ml/min, and the volume of distribution at steady state is 11.7 +/- 3.4 liters. The renal clearance of N4 is 17.89 +/- 4.19 ml/min. No measurable concentrations of the N1-glucuronide of S are found in plasma. The protein binding of S is 92%. N1-glucuronidation results in an 80% reduction in the protein binding of S (11%). N4 shows a high protein binding of 98%. Approximately 60% of the oral dose of S is excreted in the urine.

Drug therapy in patients suffering from various forms of epilepsy aims at the administration of such dosages of antiepileptic drugs as to produce significant reduction of seizures without the occurrence of serious side-effects. To assess these side-effects 75 patients (48 males, 27 females) with epilepsy, attending an out-patient clinic were studied prospectively and data were collected regarding diagnosis, drug use and side-effects. Primarily generalized epilepsy and partial complex epilepsy with secondary generalization are the most prevailing categories. 69% (52) Of the patients are treated with monotherapy, with carbamazepine as the drug most frequently prescribed (30/52). Side-effects were scored after examining and questioning the patient with the help of a standard questionnaire. A distinction was made between groups of side-effects, being systemic, anamnestic, dermatological, neurological or miscellaneous. Also, haematological and biochemical changes were looked for. In the monotherapy group 26/52 (50%) of the patients showed side-effects (23 patients with 1, 2 with 2, 1 with 3 side-effects), and in the polytherapy group 15/23 (65%) (8 patients with 1, 7 with 2 side-effects). Adverse drug reactions were hardly related to the plasma concentration category. Between 50-60% of the patients at sub-therapeutic and low-therapeutic plasma levels complained of side-effects. No clear relationship between the clinical efficacy and the side-effects could be established. The clinical custom, among others, to titrate the dose according to the disappearance or appearance of side-effects seems open for discussion.

Non-steroidal anti-inflammatory drugs represent an important drug class in ambulatory care. A utilization study among half a million persons showed that 8.6% could be identified as having used one or more non-steroidal anti-inflammatory drugs (excluding salicylates) in 1987. Data were drawn from a representative sample of pharmacy records which comprise full medication histories of individual patients. Overall utilization of non-steroidal anti-inflammatory drugs was 10.8 defined daily doses/(1000 persons.day). Approximately three quarters of the patients are 'incidental' users and receive non-steroidal anti-inflammatory drugs for a relatively short time (30 days or less). Patients who were identified as 'regular' (31-210 days of therapy) and 'heavy' (greater than 210 days of therapy) users, accounted for 21.2% respectively 4.8% of all users. 'Heavy' users are responsible for 17.3% of all non-steroidal anti-inflammatory drug prescriptions. Especially the elderly and females are prone to be 'heavy' users. Five drugs account for 90.4% of all prescriptions (diclofenac, ibuprofen, naproxen, piroxicam, indomethacin). A total of 71.1% of the patients with more than one prescription for non-steroidal anti-inflammatory drugs switched in therapy. There are two classes of concomitant drug use especially relevant with respect to detecting non-steroidal anti-inflammatory drugs-associated risks: H2 blockers and antacids (belonging to anatomical therapeutic and chemical anatomic class A) and diuretics (belonging to anatomical therapeutical chemical anatomic class C). More than half of the 'heavy' users showed concomitant use of drugs in these classes.

Sulfadimethoxine is metabolized by O-dealkylation, N4-acetylation and N1-glucuronidation. In man, only N1-glucuronidation and N4-acetylation takes place, leading to the final double conjugate N4-acetylsulfadimethoxine-N1-glucuronide. The N1-glucuronides are directly measured by high pressure liquid chromatography. When N4-acetylsulfadimethoxine is administered as parent drug, 30% of the dose is N1-glucuronidated and excreted. Fast acetylators show a shorter half-life for sulfadimethoxine than slow acetylators (27.8 +/- 4.2 h versus 36.3 +/- 5.4 h; P = 0.013), similarly the half-life of the N4-acetyl conjugate is also shorter in fast acetylators (41.3 +/- 5.2 h versus 53.5 +/- 8.5 h, P = 0.036). No measurable plasma concentrations of the N1-glucuronides from sulfadimethoxine are found in plasma. N1-glucuronidation results in a 75% decrease in protein binding of sulfadimethoxine. N4-acetylsulfadimethoxine and its N1-glucuronide showed the same high protein binding of 99%. Approximately 50-60% of the oral dose of sulfadimethoxine is excreted in the urine, leaving 40-50% for excretion into bile and faeces.

Plasma and urine concentrations of creatinine, sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole were measured in patients with varying degrees of kidney impairment. The plasma elimination half-life of sulphamethoxazole is not influenced by the kidney function, while the half-life of the metabolite is fully dependent on the kidney function. The renal clearances of the metabolites and that of the parent compound under alkaline urine conditions are linearly related to the creatinine clearance. Kidney impairment affects only the renal clearance of the metabolite, whereas sulphamethoxazole is metabolized (acetylated) independently of kidney function.

A review of the recent literature on acute urinary tract infections reveals some unresolved problems and considerable discussion and reappraisal of the current diagnostic and therapeutic methods. In this review, the rationale for the diagnostic confirmation of the presence, extent and site of infection is presented. Recent developments in the treatment of acute urinary tract infections are discussed. Factors affecting the choice of drug and recent studies concerning the duration of therapy are detained. Studies concerning the treatment of urinary tract infections with trimethoprim alone are reviewed and results of the treatment of acute urinary tract infection with a single dose of trimethoprim at St Radboud Hospital are presented.

Nalidixic acid is metabolized by hydroxylation to 7-hydroxymethylnalidixic acid[[ and then by oxidation to 7-carboxynalidixic acid.[[ The half-lives of the two elimination phases of nalidixic acid are 0.75 and 2.5 h. The apparent half-lives of the metabolite 7-hydroxymethylnalidixic acid are 2.5 and 5.5 h. Plasma protein binding of nalidixic acid is 95% and that of 7-hydroxymethylnalidixic acid 65%. The renal clearance of nalidixic acid varies between 2 and 25 ml/min and that of 7-hydroxymethylnalidixic acid between 37 and 162 ml/min. Of nalidixic acid 42% is glucuronidated and 40% hydroxylated. Of the hydroxy metabolite 57% is glucuronidated and 32% excreted unchanged. 7-Carboxynalidixic acid is excreted in the urine and is not glucuronidated. The variations in the glucuronidation/hydroxylation ratio of nalidixic acid and the glucuronidation/renal excretion ratio of the 7-hydroxymethyl metabolite belong to a normal distribution.

Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation, which results in an increase of the T 1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes.

Hydroxylated metabolites of sulphadimidine, sulphamerazine, sulphatroxazole, sulphamethoxazole, and sulphadiazine exhibited antimicrobial activity against Escherichia coli 28 PR 271 test strain ranging from 2.5 to 39.5 per cent of that of the parent drug. Trimethoprim addition potentiated the antimicrobial activity of these metabolites. N4-acetyl sulphonamide metabolites possessed no antimicrobial activity, nor did trimethoprim potentiated them.

An epidemiological analysis was performed of the adult, out-patient epilepsy clinic population of a university hospital during the period from 1 January 1981 through 30 June 1985. The number of patients that could be traced amounted to 590. An at random sample of 207 were retrospectively analysed. Gender distribution was male:female = 1.46. The mean age was 37.4 years. The diagnoses were classified according to the classification of the International League Against Epilepsy (ILAE). A preponderance of partial seizures was present, reflecting the selection in a university out-patient clinic of more difficult to treat forms of epilepsy. Antiepileptic drugs used in the treatment varied; monotherapy was obtained in 46% of the cases and carbamazepine was the most frequently prescribed drug (49%). Changes in seizure severity and factors associated with epilepsy are described. A discrepancy was found between the suspected drug levels, based upon the physician's judgement, and the plasma level measured in those patients in whom drug levels were monitored; factors interfering with clinical judgement are discussed.