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Biomedical subjects

D Westerlund

Publications and source records attributed to D Westerlund.

At least 55 records · Page 3Linked to original sources
PubMed1985

Dose-dependent absorption of amoxycillin and bacampicillin.

The relationship between the relative absorption and increasing oral doses of amoxycillin and bacampicillin, a prodrug of ampicillin, was studied testing the hypothesis that a saturable transport system for aminopenicillins exists in the human gut. Each drug was given in four different doses in a randomized order to 12 fasting subjects. One group of subjects was given amoxycillin in single doses of 375, 750, 1500, and 3000 mg, while the other group received bacampicillin in 400, 800, 1600, and 3200 mg doses. The highest dose was four times larger than that normally used in clinical practice. Amoxycillin, and ampicillin generated from bacampicillin, were determined in plasma and urine by modern column liquid chromatographic methods. With increasing doses of the penicillins, there was a saturable increase in peak plasma concentration, plasma AUC, and urinary recovery. The mean (+/- SD) AUC values after 750, 1500, and 3000 mg amoxycillin were 86% +/- 13%, 70% +/- 16%, and 55% +/- 14% of that expected, when the expected ratio of AUC to dose was that of the 375 mg dose, assuming nonsaturable absorption. The corresponding AUC values after 800, 1600, and 3200 mg bacampicillin were 97% +/- 17%, 89% +/- 19%, and 76% +/- 11% of that expected from the results obtained after the 400 mg dose. The importance of dose of either drug for AUC and urinary recovery was analyzed according to a function implying capacity-limited absorption. The dose-dependency was most pronounced for amoxycillin (P less than 0.001). Renal drug clearance was stable within subjects throughout the dose range. Our results support the concept of capacity-limited absorption of aminopenicillins, probably by carrier-mediated transport. However, limited solubility of the compounds, especially of bacampicillin, may be a confounding factor.

Absorption↗
PubMed1985

Renal excretion of intravenously infused amoxycillin and ampicillin.

The aim of this study was to determine whether concentration-dependent renal clearance of ampicillin and amoxycillin occurs. The drugs were given as single 20 min i.v. infusions in doses ranging from 1.9 to 2.8 g to nine healthy volunteers using a cross-over design. Plasma and urinary concentrations were determined by a selective liquid chromatographic method using frequent sampling up to 10 and 30 h respectively after termination of the infusion. The renal clearance of the drugs was independent of the plasma concentration. The mean (s.d.) renal clearances of ampicillin and amoxycillin were 167 (24) and 157 (20) ml min-1 1.73 m-2 respectively. The net secretion was about 50% of the total renal clearance of both drugs. The plasma concentration and urinary excretion rate versus time curves indicated a polyexponential decline, which could be described by both a biexponential and a triexponential equation. The former proved to be more reliable, especially in the calculation of micro rate constants. There was a tendency to more sustained plasma concentrations after amoxycillin, also illustrated by a significantly lower mean (s.d.) plasma clearance of this drug, viz. 185 (30) ml min-1 1.73 m-2, as compared to ampicillin, 210 (24) ml min-1 1.73 m-2 (P less than 0.04). There were no major differences in the disposition rate constants and the distribution volumes of ampicillin and amoxycillin. The mean (s.d.) plasma half-life was 1.7 (0.3) h for both drugs. The urinary excretion rate indicated a slower terminal disposition rate however, with ampicillin and amoxycillin half-lives of 3.4 (2.0) and 3.9 (1.2) h respectively. The longer half-life in the terminal phase may be due to increased tubular reabsorption at low urinary concentrations. It was not possible to determine in this study whether the half-life was affected by changes in clearance or volume of distribution. The urinary solubility of the drugs was dependent on pH. This could explain the massive macroscopic crystalluria seen in one subject after amoxycillin. Three hours after termination of the infusion, crystals could no longer be found in the sediment. There was no clinical or laboratory evidence of renal damage.

Adult↗
PubMed1984

Direct injection of plasma and urine in automated analysis of catecholamines by coupled-column liquid chromatography with post-column derivatization.

Adrenaline, noradrenaline and dopamine have been quantified by direct injection of plasma and urine in a liquid chromatographic system comprising three columns, one packed with a boronic acid gel and two with reversed-phase material. The catecholamines were selectively adsorbed on the boronic acid gel and separated by ion-pair chromatography on the reversed-phase columns. Dopamine was detected by coulometry, while noradrenaline and adrenaline were detected by fluorimetry as trishydroxyindoles after post-column coulometric oxidation and alkaline rearrangement. The reaction rate constants of the post-column reactions were determined by a flow injection analysis approach. Limits of detection were 0.04, 0.05 and 1.6 pmol for noradrenaline, adrenaline and dopamine, respectively. Endogenous plasma levels of noradrenaline and adrenaline could be quantified with a precision (RSD) of 2-4%.

Journal Article↗
PubMed1984

Rectal bioavailability of bacampicillin hydrochloride in man as determined by reversed-phase liquid chromatography.

The relative bioavailability of bacampicillin hydrochloride, a pro-drug of ampicillin, was compared after rectal and oral administration. Bacampicillin was administered rectally as a microenema . The oral formulation was an aqueous microcapsule suspension. They were given as single doses of 400 mg to 12 healthy volunteers after overnight fasting using a randomized cross-over design. Ampicillin and bacampicillin were determined in plasma and blood, respectively, using HPLC. Bacampicillin was rapidly absorbed from the rectum but to a much smaller degree compared to the oral dose. The median t-max was 0.5 and 0.75 h after the rectal and oral doses, respectively. The mean (SD) Cp-max was 1.2 (0.33) mg/l after rectal and 4.8 (0.98) mg/l after oral administration, respectively. Blood concentrations of bacampicillin were extremely low or undetectable with no indication of differences between the two modes of administration. The 95% confidence limits for the relative bioavailability of the microenema were 22.4-39.2 and 22.5-40.4% based on area under the plasma concentration time curve and urinary recovery, respectively. The rectal dose was followed by distress, diarrhea or pain, in 7 subjects. There were no adverse reactions after the oral dose. Bacampicillin was unaffected by beta-lactamases produced by intestinal bacteria.

Absorption↗
PubMed1983

Plasma protein binding of sulphadiazine, sulphamethoxazole and trimethoprim determined by ultrafiltration.

The plasma protein binding of trimethoprim, sulphadiazine and sulphamethoxazole was studied at 37 degrees C by ultrafiltration. Plasma samples contained steady state levels of the drugs from ten volunteers from a cross-over comparative pharmacokinetic study on co-trimazine and co-trimoxazole. The three compounds were determined in plasma and ultrafiltrate by HPLC, the recoveries being close to 100% in each case. Freezing of spiked samples had no influence on the binding. Trimethoprim was 48.5-52.2% bound (mean 50.0%); sulphadiazine was 50.9-60.6% bound (mean 56.2%); and sulphamethoxazole was 74.3-80.8% bound (mean 76.9%). The significantly lower protein binding of sulphadiazine compared to sulphamethoxazole means that equivalent non-protein bound plasma levels of the two sulphonamides are achieved from smaller doses of co-trimazine than co-trimoxazole. Use of co-trimazine may thus minimize the risk of adverse reactions.

Journal Article↗
PubMed1983

Influence of food intake on the bioavailability of zimeldine and its active metabolite, norzimeldine.

The possible influence of concomitant food intake on the bioavailability of the novel antidepressant zimeldine and its active metabolite norzimeldine was assessed in ten healthy female volunteers, who ingested a single dose of 200 mg zimeldine on an empty stomach and together with a standardized breakfast of 1 840 kJ. The plasma concentrations of zimeldine and norzimeldine were measured by a selective modern liquid chromatographic technique. Neither the peak concentration nor time to reach peak concentration nor elimination half-life nor the total area under the curve (AUC) of zimeldine was affected by concomitant food intake. For norzimeldine, the peak concentration showed a 10% reduction, but there was no change in any other parameter. Thus, the bioavailability of zimeldine and of its active metabolite norzimeldine is unaffected by food intake, suggesting that the drug need not be taken in a strictly defined relation to meals.

Adult↗
PubMed1982

Determination of sulfadiazine and N4-acetylsulfadiazine in biological fluids by liquid chromatography on silica gel with an aqueous buffer as mobile phase.

Sulfadiazine and N4-acetylsulfadiazine were determined in biological fluids by the direct injection (plasma after protein precipitation and urine after dilution 100 times) of 20 microliters on a silica gel column. The mobile phase was an aqueous citrate buffer (pH 4.0) and UV detection was a 264 nm. Chromatographic selectivity was optimized by the silica gel surface and pH of the mobile phase. Detection limits were approximately 0.4 microgram/ml for sulfadiazine in plasma and approximately 5 and 7 micrograms/ml of sulfadiazine and N4-acetylsulfadiazine in urine, respectively. In quantitations by peak heights relative to an internal standard (sulfamerazine), within-run precisions (srel%) for sulfadiazine were 1.7 and 4.0% at 40 and 2 micrograms/ml, respectively, in plasma and 0.76 and 1.7% and 25 micrograms/ml, respectively, in urine.

Buffers↗
PubMed1982

Determination of bacmecillinam, an amdinocillin prodrug, in human and canine whole blood by reversed-phase liquid chromatography.

Bacmecillinam is an amdinocillin prodrug designed to be easily hydrolyzed in biological materials, so special procedures were developed for the collection of blood specimens. Whole blood was collected in tubes containing bacampicillin as an adsorption inhibitor and kept at -70 degrees; the extracting solvent, hexane-methylene chloride (9:1, v/v), was added to the cold tubes, and the extraction was performed during the thawing of the samples. The organic phase was partially evaporated before a reextraction to a small volume of acidic aqueous phase was made. The separation was performed on a microparticulate. C18-alkyl bonded silica packed in glass-lined stainless steel columns. Mobile phase was a buffer (pH 6)-acetonitrile mixture containing N-hexyl-N-methylamine as an adsorption inhibitor. The detection limit was 600 pg/ml of whole blood, and the within-run precision (srel%) was approximately 8% at the 5-ng/ml level.

Amdinocillin↗
PubMed1982

Pharmacokinetics of bacmecillinam and pivmecillinam in volunteers.

The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (+/- SD) peak levels of plasma mecillinam were 1.43 +/- 0.34, 2.73 +/- 0.43, and 4.62 +/- 1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38 +/- 0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21 +/- 0.19, 3.99 +/- 0.63, and 7.74 +/- 1.38 mg . h. l-1 for bacmecillinam and 5.35 +/- 0.93 mg . h. l-1 for pivmecillinam. The elimination half-lives were 0.8-1.1 h for bacmecillinam and 0.7 h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p less than 0.001), AUC (p less than 0.001) and urinary recovery (p less than 0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p less than 0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.

Absorption↗
PubMed1981

Effects of zimelidine and desipramine on serotonin and noradrenaline uptake mechanisms in relation to plasma concentrations and to therapeutic effects during treatment of depression.

The selective inhibitors of neuronal 5-hydroxytryptamine (5-HT) and noradrenaline (NA) uptake, zimelidine and desipramine, were compared in a double blind crossover study of 40 inpatients with endogenous depression. The clinical effects of these two drugs and some biochemical variables related to the monoamine systems were studied during 4 weeks' treatment. Patients with a low pretreatment level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) (less than 20 ng/ml) responded significantly better to zimelidine treatment than those with a high pretreatment level (greater than 20 ng/ml). In the group treated with desipramine no difference in therapeutic outcome was obtained between patients with low and high pretreatments levels of 5-HIAA in the CSF. Attempts to correlate the steady state plasma concentrations of zimelidine, norzimelidine and desipramine with the therapeutic effect were unsuccessful. The plasma concentration of norzimelidine demonstrated a significant (P less than 0.05) positive correlation with age. The mean value of the uptake of 14C-5-HT in the patient's platelets, when measured before the treatment, was significantly (P less than 0.05) lower than found in a control group. Zimelidine, mainly via its metabolite norzimelidine, caused a pronounced inhibition of uptake of 14C-5-HT in platelets, decrease in whole blood 5-HT and inhibition of accumulation of 14C-5-HT in rat hypothalamic synaptosomes incubated in the patients plasma. Desipramine produced a slight inhibition of accumulation of 14C-5-HT in rat synaptosomes, but a marked inhibition of uptake of 14C-5-HT in the patient's platelets and a decrease in whole blood 5-HT. The accumulation of 3H-NA in rat synaptosomes incubated in the patient's plasma was strongly inhibited by desipramine treatment but only slightly affected by zimelidine.

Animals↗
PubMed1980

Simultaneous determination of dopamine, DOPAC and homovanillic acid. Direct injection of supernatants from brain tissue homogenates in a liquid chromatography--electrochemical detection system.

A simple method based on high-performance liquid column chromatography with electro-chemical detection is described for the simultaneous determination of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in discrete brain regions of rats. The supernatant of a tissue homogenate is injected directly onto a liquid chromatograph, thus omitting the commonly adopted adsorption step. Of the four different supports tested Nucleosil C15 (5 micron) was found superior with respect to chromatographic performance. The effects of pH, methanol and the ion-pairing agent hexyl sulfate on the retention were studied. The mobile phase used in the final studies consisted of citrate buffer pH 4.25-methanol (92:8, v/v) containing hexyl sulfate (1.7 . 10(-3) M). Standard curves of dopamine, DOPAC and HVA were found linear up to about 600 pmol per injection for each compound. The precisions of the chromatographic step were (Srel. %): 0.72% (dopamine), 1.26% (DOPAC) and 2.69% (HVA).

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Hydrophobic chromatography and bioanalysis of some polar pyridine derivatives used as antilipolytic agents.

The antilipolytic compound 5-fluoro-3-pyridinecarboxylic acid and 5-fluoro-3-hydroxymethylpyridine have been determined quantitatively in plasma (Srel = 5-7% in the concentration range 1-20 microgram/ml) by liquid chromatography on LiChrosorb RP-8 (5 micrometer) with phosphate buffer pH 3-4 as mobile phase, after precipitation of proteins and direct injection of the supernatant. Detection limits were 0.1-0.2 microgram/ml. The chromatographic retention is explained by adsorption of the uncharged compounds on to the support complemented by ion-pair adsorption with buffer components at extreme pH values.

Chromatography, Liquid↗
PubMed1979

Reversed-phase chromatography of zimelidine and similar dibasic amines. I. Analysis in biological material.

Zimelidine, a new antidepressant, and its pharmacologically active metabolite, norzimelidine, have been determined quantitatively in biological material. The compounds are extracted from alkali-treated body fluid or tissue homogenate into diethyl ether-n-hexane (8:2, v/v), and re-extracted into a small volume of acidic aqueous phase (ca. 100 microliter), which is injected onto the chromatographic column. The chromatographic support is Nucleosil C18 (5 micron) and the mobile phase is phosphate buffer (pH 2)-acetonitrile (91:9, v/v) with the addition of an aliphatic amine, N,N-dimethyl-N-octylamine (4.10(-4) M), which improves the chromatographic performance. By using glass-lined stainless-steel tubes instead of the common precision-bore stainless-steel columns, peak symmetries were improved. Detection limits in plasma are in the range 2.3--4.7 nmol/1 for extractions from 1 ml. It is demonstrated that the quality of the quantitations are improved by use of an internal standard, norzimelidine E-isomer. The precisions obtained for both compounds at the concentration levels of 300 and 1500 nmol/1 are ca. 5--6% and 2% respectively for within-run variations, and 8--9% and 5% respectively for day-to-day-variations.

Animals↗