James E. Axelson

Methadone maintenance: Effect of urinary pH on renal clearance in chronic high and low doses

The subjects were 12 male patients stabilized on methadone for many months or years. A comparison was made of the plasma levels and renal clearance of methadone between patients on “high” doses (80 to 110 mg/day) and those on “low” doses (15 to 40 mg/day). A general trend to higher renal clearance was seen in the “high”‐dose group, but on more detailed examination there was a direct correlation only when the patients were categorized by urinary pH. At low pHs, there was nearly a 3‐fold increase in renal clearance which was associated with a decreased major metabolite to methadone ratio. No evidence for a difference in rate of metabolism between the two groups was found nor were there differences in hepatic function. It was concluded that urinary pH was a major factor in renal clearance of methadone.

Effect of pH-adjustment of bupivacaine on onset and duration of epidural analgesia in parturients.

Previous studies have reported that elevation of the pH of local anaesthetics is associated with enhanced quality and duration of block. This study investigated the effect, on time to onset and duration of analgesia, of pH adjustment of 0.25 per cent bupivacaine immediately prior to injection into the epidural space in parturients. Addition of 0.1 ml of 8.4 per cent sodium bicarbonate to 20 ml of 0.25 per cent bupivacaine consistently raised the pH of the local anaesthetic from 5.65 to 7.26 (mean values).Thirty parturients received an epidural injection of 8 ml of pH-adjusted 0.25 per cent bupivacaine and a control group of 30 parturients received 8 ml of the standardcommercial preparation of 0.25 per cent bupivacaine. Elevation of the pH of the local anaesthetic significantly increased the speed of onset of analgesia from 6.0 minutes to 3.2 minutes and the duration of analgesia was significantly lengthened from 79.4 minutes to 96.5 minutes. There was no significant influence on time to peak effect, nor on mean maternal plasma levels of bupivacaine.RésuméDes étude préliminaires ont rapporté que l’augmentation du pH des anesthésiques locaux est associée avec une amélioration de la qualité et de la durée du bloc. Cette étude investigue l’effet sur le début d’action et la durée de l’analgésie après ajustement du pH de 0.25 pour cent de bupivacaîne immédiatement avant l’injection dans l’espace épidural chez des femmes à terme. L’addition de 0.1 ml de 8.4 pour cent de bicarbonate de soude à 20 ml de 0.25 pour cent de bupivacaîne augmenta le pH de l’anesthésique local de 5.65 à 7.26 (valeurs moyennes).Trente parturientes ont reçu en injection épidurale 8 ml de bupivacaîne 0.25 pour cent à pH ajusté et un groupe contrôle de 30 parturientes a reçu 8 ml de la solution commerciale standard de préparation de 0.25 pour cent de bupivacaîne. L’augmentation du pH de l’ anesthésique local accéléra significativement le début de l’analgésie de 6.0 minutes à 3.2 minutes ainsi que la durée de l’analgésie qui augmenta significativement de 79.4 minutes à 96.5 minutes. It n’y avail aucune influence significative sur le temps d’effet maximal ni sur le niveau plasmatique moyen maternel de bupivacaîne.

Determination of metoclopramide and two of its metabolites using a sensitive and selective gas chromatographic—mass spectrometric assay

A modified gas chromatographic-mass spectrometric (GC-MS) assay has been developed to quantitate metoclopramide (MCP) and two of its metabolites [monodeethylated-MCP (mdMCP), dideethylated-MCP (ddMCP)] in the plasma, bile and urine of sheep. The heptafluorobutyryl derivatives of the compounds were formed and quantitated using electron-impact ionization in the selected-ion monitoring mode (MCP, m/z 86, 380; mdMCP, m/z 380 and ddMCP, m/z 380). No interference was observed from endogenous compounds following the extraction of various biological fluids obtained from non-pregnant sheep. Sample preparation has been simplified and the method is more selective and sensitive (2 fold) than our previous assay using electron-capture detection. The limit of quantitation for MCP, mdMCP and ddMCP was 1 ng/ml in plasma, urine and bile, requiring 0.5 ml of sample. This represents 2.5 pg of the analytes at the detector. The standard curves were linear over a working range of 1-40 ng/ml. Absolute recoveries in plasma ranged from 76.5-94.7%, 79.2-96.8%, 80.3-102.2% for MCP, mdMCP and ddMCP, respectively. In urine, recoveries ranged from 56.5-87.8%, 61.5-87.5%, 62.6-90.2% for MCP, mdMCP and ddMCP, respectively. Recoveries in bile ranged from 83.5-100.9%, 78.5-90.5%, 66.9-79.2% for MCP, mdMCP and ddMCP, respectively. Overall intra-day precision ranged from 2.9% for MCP in plasma to 12.6% for mdMCP in bile. Overall inter-day precision ranged from 5.9% for MCP in urine to 14.9% for ddMCP in bile. Bias was the greatest at the 1 ng/ml concentration in all biological fluids ranging from a low of 2.4% for mdMCP in plasma to a high of 11.9% for ddMCP in urine. Applicability of the assay for pharmacokinetic studies of MCP, mdMCP and ddMCP in the plasma and urine of a non-pregnant ewe is demonstrated.

Placental transport of metoclopramide: Assessment of maternal and neonatal effects

Twenty-three patients undergoing general anaesthesia for Caesarian section for healthy term pregnancies were entered into a double blind study using metoclopramide (MCP) and a normal saline placebo. Of these patients, eight received intravenous metoclopramide, 12 a normal saline placebo and three were lost to clinical follow-up. The maternal gastric volumes were measured and maternal and foetal MCP plasma concentrations were determined by gas-liquid chromatography. The Neurological and Adaptive Capacity Score tests of Amiel, Barrier and Schnider (NACS) were used to attempt evaluation of neonatal responses to MCP Maternal gastric volume was significantly lower (p < 0.05) in the treated patients.There were no marked differences in Apgar scores, cardiovascular parameters or neurobehavioural scores between the treated and untreated groups of neonates. At no time were the foetal metoclopramide plasma concentrations observed to exceed maternal values.RésuméVingt-trois patientes subissant une césarienne sous anesthésie générale pour grossesse non compliquée ont été soumises à une élude à double insu. Huit patientes ont reçu du métoclopramide intraveineux, douze ont reçu du salin 0.9 pour cent, trois n’ont pu être suivies en post-opératoire. Les volumes gastriques maternels ont été mesurés et le métoclopramide maternel et foetal a été dosé par Chromatographie gaz-liquide. Le score au test d’Amiel, Barrier et Schnider (neurotogical and adaptive capacity score ’NCAS’) a été utilisé pour l’évaluation de la réponse du nouveau-né au métoclopramide. Les volumes gastriques maternels étaient significativement plus petits (p < 0.05) dans le groupe traité. Il n’y a pas eu de différence marquée des scores d’Apgar, des paramètres cardiovasculaires ou des scores neurobehavioraux entre les nouveaux-nés des deux groupes. En aucun temps le taux plasmatique du métoclopramide foetal a excédé celui de sa mère.

The effect of pH adjustment of bupi-vacaine on onset and duration of epidural anaesthesia for Caesarean section

Previous studies have reported that elevation of the pH of local anaesthetics results in more rapid onset of action, with enhanced quality and duration of block. This study investigated the effect of pH adjustment of 0.5 per cent bupivacaine immediately prior to epidural anaesthesia for Caesarean section. Addition of 0.1 ml of 8.4 per cent sodium bicarbonate to 20 ml of 0.5 per cent bupivacaine consistently raised the pH of the local anaesthetic from 5.49 to 7.04 (mean values). One hundred patients, presenting for elective Caesarean section under epidural anaesthesia participated in the study. Forty patients received epidural anaesthesia, using pH-adjusted 0.5 per cent bupivacaine, in a dosage adequate to produce block to the T4 level. A control group of 40 patients received the standard commercial preparation of 0.5 per cent bupivacaine. A further ten patients in each group received epidural anaesthesia using 0.5 per cent bupivacaine with the addition of 1:400,000 epinephrine, to study the effect of epinephrine on pH adjustment of the local anaesthetic. Elevation of the pH of the local anaesthetic significantly increased the speed of onset of action from 6.4 minutes to 3.2 minutes and the time to peak effect from 24.8 minutes to 18.1 minutes, while the duration of anaesthesia was increased from 124.8 minutes to 147.3 minutes. The time to S2 segment blockade was also shortened from 13.5 to 8.6 minutes. Addition of 1:400,000 epinephrine to the local anaesthetic did not influence the effect of pH adjustment. Maternal and umbilical cord plasma levels of bupivacaine were not affected by pH adjustment of the local anaesthetic, while MV/UV and UA/UV ratios were unaltered.RésuméDes études antérieures ont démontré que ľélévation du pH des anesthésiques locaux raccourcissait le temps de latence, améliorait la qualité et augmentait la durée du bloc. Cette étude investigue les effets ďun ajustement du pH de 0.5 pour cent de bupivacaïne immédiatement avant ľanesthésie épidurale pour une césarienne. Ľaddition de 0.1 ml de 8.4 pour cent de bicarbonate de soude à 20 ml de 0.5 pour cent de bupivacaïne augmentait immanquablement le pH de ľanesthésique local de 5.49 à 7.04 (valeurs moyennes). Cent patientes se présentant pour une césarienne élective sous anesthésie épidurale ont participé à cette étude. Quarante patientes ont reçu une anesthésie épidurale avec 0.5 pour cent de bupivacaïne à pH ajusté avec une dose adéquate pour produire un bloc T4. Un groupe-contrôle de 40 patientes ont reçu la préparation commerciale standard de 0.5 pour cent de bupivacaïne. D’autre part dix patientes de chaque groupe ont reçu une anesthésie épidurale utilisant 0.5 pour cent de bupivacaïne avec ľaddition de 1:400,000 ďépinéphrine afin ďétudier les effets de ľépinéphrine sur ľajustement du pH de ľanesthésique local. Ľaugmentation du pH de ľanesthésique local a augmenté significativement la rapidité ďinstallation du bloc de 6.4 minutes à 3.2 minutes et le temps pour un effet maximal de 24.8 minutes à 18.1 minutes, alors que la durée de ľanesthésie a augmenté de 124.8 à 147.3 minutes. Le temps de blocage du segment S2 a été aussi raccourci de 13.5 à 8.6 minutes. Ľaddition de 1:400,000 ď épinéphrine à ľanesthésique local n’a pas influencé ľeffet de ľajustement du pH. Les niveaux plasmatiques de bupivacaïne dans le cordon ombilical ainsi que chez la mère n’ont pas été affectés par ľajustement du pH de ľanesthésique local alors que les rapports MV/UV et UA/UV sont demeurés inchangés.

Electron-capture determination of metoclopramide in biological fluids using fused silica capillary columns: application to placental transport studies in sheep and humans

An electron-capture gas-liquid chromatographic assay for metoclopramide using cross-linked fused silica capillary columns which provides improved selectivity and sensitivity is reported. A 25 m X 0.31 mm fused silica capillary column was used for all analyses. Linearity was observed in the range of 4--40 ng of metoclopramide base per 0.25--0.5 ml of plasma. This represents from ca. 0.9--9.0 pg at the detector employing a split ratio of 30:1 and an injection volume of 2 microliters. Applicability of the method is demonstrated by the analysis of human and sheep plasma (maternal, fetal and neonatal) from metoclopramide placental transfer studies.

Intravenous and oral propafenone for treatment of tachycardia in infants and children: pharmacokinetics and clinical response.

To elucidate contribution of an active metabolite to overall clinical responses to propafenone, steady‐state disposition of propafenone and its active metabolite and the clinical responses to treatment were examined in pediatric patients receiving intravenous or oral propafenone. There were more than ten‐fold interindividual differences in apparent clearance, resulting in a wide range of the steady‐state trough plasma concentrations of propafenone. The active metabolite, 5‐hydroxypropafenone, was detected in four of the six patients receiving oral propafenone; however, two neonates receiving oral propafenone and all eight receiving intravenous propafenone had no detectable levels of 5‐hydroxypropafenone in plasma. In nine patients for whom electrocardiographic (ECG) data were available, the PQ interval was significantly increased, whereas the QRS duration and the QTc interval were not. There was no close relationship between plasma concentrations of propafenone or 5‐hydroxypropafenone and ECG parameters. Lack of good correlation between serum concentrations and clinical response precludes using a serum‐concentration targeting strategy with propafenone therapy.

In vitro protein binding of propafenone in normal and uraemic human sera

SummaryThe protein binding of propafenone, a Class I antiarrhythmic agent, was studied in vitro using a selective and sensitive electron-capture detection gas-liquid capillary chromatographic assay method developed in our laboratory.The concentration-dependency of the serum protein binding of propafenone was confirmed in vitro by equilibrium dialysis, using serum obtained from healthy human subjects and patients with chronic renal failure.In normal serum the unbound fraction of propafenone was 0.027 at a propafenone concentration of 0.25 µg · ml−1, 0.041 within the therapeutic concentration range (0.5–2 µg · ml−1), 0.138 at a propafenone concentration of 25 µg · ml−1, and 0.187 when the propafenone concentration was increased to 100 µg · ml−1.There was no evidence of significant concentration-dependent changes in unbound fraction within the propafenone concentration range of 0.5–1.5 µg · ml−1. However, concentration-dependent binding was demonstrated at concentrations greater than 1.5 µg · ml−1.A high-affinity, low-capacity binding site (K1=6.53×105 l · mol−1; n1P1=1.73×10−4 mol · l−1) and a low-affinity, high-capacity binding site (K2=8.77×103 l · mol−1; n2P2=8.57×10−3 mol · ×l−1) were identified.In pooled uraemic serum the unbound fraction of propafenone was approximately 50% of that of normal serum throughout the concentration range studied (1–5 µg · ml−1). In sera from patients with chronic renal failure the increase in propafenone binding ratio or the decrease in unbound fraction was associated with the increase in alpha1-acid glycoprotein concentrations, and there was a correlation (r=0.8302) between alpha1-acid glycoprotein concentration and the propafenone binding ratio.

Stereoselective pharmacokinetics of tocainide in human uraemic patients and in healthy subjects

SummaryThe disposition of tocainide enantiomers were examined in healthy human subjects and uraemic patients following a single i. v. dose (200 mg) of racemic tocainide hydrochloride.In the healthy subjects, the total body clearance of R(−)-tocainide was significantly greater than that of S(+)-tocainide (2.62 vs 1.70 ml·min−1·kg−1). Renal clearance also favoured R(−)-tocainide and appeared to contribute significantly to the stereoselective total body clearance. The volume of distribution of the enantiomers did not differ significantly.Uraemia produced a marked decrease in the total body clearance with no apparent effect on the volume of distribution of both enantiomers. The S/R ratio for total body clearance decreased significantly from 0.66 in healthy subjects to 0.54 in the uraemics, while the ratio for terminal elimination half-life significantly increased from 1.43 to 1.59.These results indicate that uraemia alters the degree of stereoselectivity in the pharmacokinetic parameters of tocainide enantiomers.

Determination of diphenhydramine in biological fluids by capillary gas chromatography using nitrogen—phosphorus detection : Application to placental transfer studies in pregnant sheep

A nitrogen-phosphorus detection-gas chromatographic method, which provides improved sensitivity and selectivity for diphenhydramine, is reported. A 25 m X 0.31 mm cross-linked, 5% phenylmethyl silicone-coated fused-silica capillary column (film thickness 0.52 micron) was used for all analyses. The splitless capillary injection mode was employed with a 2-microliter sample being introduced by an automatic liquid sampler. Standard curves, using orphenadrine as an internal standard, were linear in the range 2-320 ng of diphenhydramine per 0.5 ml of sheep plasma. This represents an amount of diphenhydramine from ca. 40 pg to 6.4 ng at the detector. Chromatographic separation of diphenhydramine and orphenadrine was excellent, with no interference from endogenous plasma constituents. Applicability of the method was demonstrated by a placental transfer study in a chronically instrumented pregnant sheep following a 100 mg intravenous injection of diphenhydramine to the ewe.