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Biomedical subjects

J R Brouwers

Publications and source records attributed to J R Brouwers.

15 recordsLinked to original sources

Technetium-99m carboxymethylcellulose: a newly developed fibre marker for gastric emptying studies.

We report a study of technetium-99m-labelled carboxymethyl-cellulose (99mTc-CMC) as a newly developed non-digestible marker of the solid phase of gastric contents. The radiosynthesis is simple and shows a high labelling efficiency. In vitro and in vivo experiments demonstrated stability of the marker in the gastrointestinal tract during the process of gastric emptying. The gastric half-emptying time in ten healthy volunteers of both sexes was 105 +/- 17 min (mean +/- SD). This rate of gastric emptying is similar to that of non-digestible solid-phase markers such as in vivo labelled 99mTc-chicken liver or radio-iodinated cellulose. In comparison with digestible solid-phase markers such as 99mTc-labelled pancake or 99mTc-cooked egg, gastric emptying of 99mTc-CMC occurred more slowly, confirming the expected behaviour of a non-digestible solid-phase marker. We conclude that 99mTc-CMC has the advantage of a simple and rapid labelling procedure and may be useful for clinical studies of gastric emptying.

Adult

Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature.

This study is intended to alert the clinician to the insidious symptoms of baclofen overdose, its prevention and treatment. In a group of 43 patients suffering from previously intractable spasticity and a total treatment time of 2,422 weeks, 7 events of intrathecal baclofen overdose happened in 5 patients. On two occasions, a bolus injection caused an overdose (dose 50 and 280 micrograms). The 5 events during continuous infusion intoxication only happened in high dosed patients. The overdose symptoms occurred in one patient when she was lying in supine position (800 micrograms/24 h), in another patient after repair of CSF leakage by an autologous epidural bloodpatch (1,920 micrograms/24 h) and in tolerant patients, once during maximal dose adjustments (2,400 micrograms/24 h) and twice ca. 6 hours following reinitiation of the intrathecal baclofen infusion after a "drug holiday" treatment (27 and 55 micrograms/h). We could not confirm the reported similarity of baclofen overdose with the anticholinergic syndrome. Especially, the bradycardia and hypotension are more in accord with the reported clinical picture of oral baclofen overdose. In the absence of a pure baclofen antagonist and the varying symptoms of intrathecal baclofen, intoxication make rational treatment difficult. We observed that the advised physostigmine therapy is not always effective and safe. The occasionally doubtful antidotal benefits of physostigmine must be weighted against major side-effects. The classical approach of decreasing the absorption of a drug by lowering baclofen levels in the CSF by lumbar puncture drainage was successful. This approach together with conservative symptomatic treatment in an intensive care environment is probably a better and safer alternative than physostigmine alone as an antidote.

Adult

Decreased ciprofloxacin absorption with concomitant administration of ferrous fumarate.

The effect of ferrous fumarate on the relative bioavailability of ciprofloxacin after a single 500 mg oral dose of ciprofloxacin was studied in eight healthy males. Blood samples were collected at regular intervals 0-24 h post-dose. Urine was collected during 24 h to determine the cumulative urine excretion of ciprofloxacin. Ciprofloxacin concentrations in serum and urine were determined by high pressure liquid chromatography. Mean area under the serum concentration-time curve decreased significantly (P less than 0.001) after ciprofloxacin was taken with 200 mg ferrous fumarate. The relative bioavailability was 30% when ciprofloxacin was given with ferrous fumarate. The maximum blood level decreased from 2.1 +/- 0.9 (control) to 0.6 +/- 0.2 mg/l (with ferrous fumarate). Further studies are needed to determine if chronic treatment with ferrous fumarate further decreases the relative bioavailability. For the moment administration of ciprofloxacin with ferrous fumarate should therefore be avoided.

Adolescent

A simple high pressure liquid chromatographic method for the determination of fluorouracil to monitor patients on regional infusion for hepatic metastases.

A rapid and sensitive high pressure liquid chromatographic method has been developed for the routine monitoring in serum of the antineoplastic agent fluorouracil, during continuous intraportal administration. Serum spiked with internal standard, bromouracil, was gently shaken for 10 min with ethylacetate at an acidic pH. The evaporated extract was dissolved in the mobile phase containing potassium phosphate buffer. Assays were performed at ambient temperature on a Chrompack LiChrosorb RP 18 column (2 X 100 X 3.0 mm) equipped with a guard column. The retention time of fluorouracil was 2-6 min. The calibration curve was linear from 25 to 2,000 ng/ml. The coefficient of variation was less than or equal to 1.6% for within-run precision and less than or equal to 2.9% for day-to-day precision. The mean recovery of fluorouracil was 57%.

Chromatography, High Pressure Liquid

Regional infusion of fluoropyrimidines for hepatic metastases of colorectal cancer.

Recent reports on regional chemotherapy for hepatic metastases of colorectal origin are reviewed. Because of reported side effects and lack of evidence for its superiority over conventional intravenous administration, intra-arterial administration of fluoropyrimidines cannot be advised for routine use, but should be restricted to centres participating in clinical trials on this subject.

Clinical Trials as Topic

Pharmacokinetics of the newer fluoroquinolones.

A large number of pharmacokinetic studies have been carried out using 4-quinolones in order to estimate total and renal clearance, to examine tissue penetration, to establish suitable dosage regimens and to determine the influence of kidney and liver impairment on the pharmacokinetic behaviour. Although the quinolones are poorly water soluble over the physiological pH range (6-8) they are well absorbed following oral administration. Ofloxacin is almost completely absorbed and ciprofloxacin has been shown to have an absolute bioavailability of 0.70. Plasma protein binding varies greatly from quinolone to quinolone ranging from about 10% in the case of norfloxacin to more than 90% in the case of nalidixic acid. Penetration of the quinolones into the prostate is generally good. Most quinolones, too, have been shown to penetrate blister fluid rapidly and this model has proved useful in distribution studies. Some quinolones, like ofloxacin, are excreted largely unchanged while others like pefloxacin and acrosoxacin, are almost completely metabolized. Conjugation to very water-soluble glucuronides is not common although other types of metabolites have been shown. Little information appears to have been published on the effect of liver disease on the metabolism of the quinolones. This must be an important consideration for this type of drugs which are subject to hepatic transformation. The pharmacokinetic behaviour of quinolones in patients with impaired renal function has been extensively studied. The interaction of food on the absorption does not seem to be great, there is however evidence of a drug interaction between theophylline and some of the newer quinolones. Sucralfate and antacids containing Mg2+ or (and) Al3+-ions can markedly impair the absorption of quinolone antibiotics.

Absorption

Quantitative determination of ofloxacin, ciprofloxacin, norfloxacin and pefloxacin in serum by high pressure liquid chromatography.

A simple sensitive HPLC method for the analysis of ciprofloxacin, norfloxacin, ofloxacin and pefloxacin in serum is described. The quinolones were extracted using dichloromethane under neutral conditions, followed by drying under nitrogen and dissolving in mobile phase before chromatographic analysis. The stationary phase consisted of a stainless steel column with Nucleosil CI8 (5 microns), and a mobile phase of 0.04 M phosphoric acid, tetrabutylammoniumiodide as ion-pairing reagent and methanol (pH 2.2). UV absorbance was used for detection. The method was shown to be linear, quantitative and reproducible in the therapeutic range of each of these quinolones. Serum levels of ofloxacin and ciprofloxacin were determined and compared to those found by a microbiological assay. Good correlation was found for the assay of ciprofloxacin as well as for ofloxacin.

Anti-Infective Agents

Biopharmaceutical properties of liquid and tablet antacids: in vivo studies using the intragastric pH-measurement technique.

Three types of liquid and tablet antacids have been studied in vitro and in vivo: aluminium hydroxide, aluminium hydroxide-magnesium carbonate and hydrotalcite. The effects on gastric pH of antacid suspensions and antacid chewing tablets having identical active ingredients have been studied in 36 volunteers, the sequence of both forms of administration being randomized. Gastric acid secretion was continuously stimulated during the experiment by a pentagastrin infusion. Antacid chewing tablets gave inferior results when compared with the same antacid in liquid. Antacid suspensions are therefore preferred in the treatment of acid-peptic disease.

Antacids

Drug interactions with quinolone antibacterials.

The quinolone antibacterials are prone to many interactions with other drugs. Quinolone absorption is markedly reduced with antacids containing aluminium, magnesium and/or calcium and therapeutic failure may result. Other metallic ion-containing drugs, such as sucralfate, iron salts, and zinc salts, can also reduce absorption. Some of the newer quinolones inhibit the cytochrome P450 system, e.g. enoxacin, pefloxacin and ciprofloxacin. The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Ciprofloxacin, enoxacin and pefloxacin can increase theophylline concentrations to toxic values. The pharmacokinetics of warfarin and cyclosporin are unaffected. Ofloxacin, fleroxacin and temafloxacin have a low inhibitory effect on the cytochrome P450 system and a low interaction potential may result. The affinity of quinolones for the gamma-aminobutyric acid (GABA) receptor may induce CNS adverse effects; these effects are enhanced by some nonsteroidal anti-inflammatory drugs (NSAIDs).

4-Quinolones