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P S Collier

Publications and source records attributed to P S Collier.

At least 19 recordsLinked to original sources
PubMed1995

The effect of three H2 receptor antagonists on the disposition of cyclosporin A in the in situ perfused rat liver model.

The in situ perfused rat liver model was used to investigate the effect of three H2 receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2-receptor antagonist-treated groups) of male Sprague-Dawley rats (300-350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusate and bile samples were collected and assayed for CyA, AM1, and the H2 receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine-treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p < 0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H2 receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H2 receptor antagonists for CYP3A, the isoenzyme responsible for CyA metabolism.

Analysis of Variance↗
PubMed1995

Chiral aspects of the metabolism of ethosuximide.

Ethosuximide is a chiral drug substance primarily indicated for the treatment of absence seizures. This drug is used clinically as the racemate. The urinary metabolites of ethosuximide (following i.p. administration of the racemate or individual enantiomers to rats) have been studied using chiral gas chromatography (GC) and gas chromatography-mass spectroscopy (GCMS). The metabolites identified were unchanged ethosuximide enantiomers, all four stereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide, and a single stereoisomer of 2-ethyl-3-hydroxy-2-methylsuccinimide [derived from (R)-ethosuximide]. Preliminary quantitative studies indicate a degree of stereoselectivity in the fate of ethosuximide since the ratio of (R)- to (S)-ethosuximide in the urine was found to be 0.77:1 (0-24 h sample), 0.64:1 (24-48 h sample), and 0.83:1 (48-72 h sample). This would suggest that the (R)-isomer is preferentially metabolised. Results obtained following the administration of individual enantiomers of ethosuximide indicate that the 2-(1-hydroxyethyl)-2-methylsuccinimide diastereoisomers derived from (R)-ethosuximide are produced in approximately equal proportions [ratio 1.05:1 (0-24 h sample), 1.10:1 (24-48 h sample)], whilst those from (S)-ethosuximide are produced in unequal proportions [ratio 1.65:1 (0-24 h sample), 1.74:1 (24-48 h sample)].

Animals↗
PubMed1994

The effect of three H2-receptor antagonists on the disposition of midazolam in the rat in-situ perfused liver model.

The rat in-situ perfused liver model was used to investigate the effect of three H2-receptor antagonists on the pharmacokinetic disposition of the short-acting benzodiazepine, midazolam. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2-receptor antagonist-treated groups) of male Sprague-Dawley rats (300-350 g). All animals received midazolam 1 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg) or famotidine (0.4 mg). Perfusate and bile samples were collected and assayed for midazolam using gas chromatography. The perfusate data indicated that midazolam disposition was impaired at 10, 50 and 60 min of the experimental period following the addition of cimetidine, whereas ranitidine and famotidine produced an effect at 10 min only; midazolam levels in bile were not affected by the presence of an H2-receptor antagonist. It was concluded that the limited inhibitory effect of cimetidine may be attributed to its lack of specificity for CYP3A, the isoenzyme responsible for the metabolism of midazolam.

Animals↗
PubMed1993

Cyclosporin A and erythromycin: a study of a drug interaction in the in situ perfused rat liver model.

Using the in situ perfused rat liver model, the effect of erythromycin (Ery) on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1, was investigated. Prior to perfusion experiments, oral dosing was carried out for three days on three groups of male Sprague-Dawley rats (300-350 g), involving pretreatment with water (control and H2O/Ery groups) or erythromycin (Ery oral group). On the fourth day, perfusion experiments took place using standard techniques, with the addition of 20 mg Ery to the H2O/Ery and Ery oral groups, and 2.5 mg CyA to all groups. Perfusate and bile samples were collected and assayed for CyA and AM1 by HPLC. Results indicated that inhibition of CyA metabolism had occurred as the CyA concentration in perfusate was significantly higher in both Ery groups at all times compared to the control group, and the levels of AM1 in both perfusate and bile were significantly lower than in the control group. There was also a marked reduction in the apparent metabolic clearance of CyA in the Ery groups. It was concluded that AM1 production had been inhibited by Ery, the most likely mechanism being inhibition of the isoenzyme CYP3A with which Ery forms a stable complex.

Animals↗
PubMed1992

Prediction of netilmicin disposition in neonates.

Multiple regression analyses of data from 33 neonates who received netilmicin therapy showed that concurrent treatment with other drugs (Drg), creatinine clearance (CLcr), gestational age (GA), and an apgar score of less than 6 at 1 min (Agl') were significant determinants of netilmicin clearance. Apparent volume of distribution was significantly affected by postnatal age (PNA), gender, the presence of ascites and/or oedema (A/O), and whether or not the neonate was small for gestational age (SGA). The following formulae were obtained: [formula: see text] The regression formulae were shown to predict netilmicin plasma concentrations with good precision and a non-significant bias in a further 15 neonates studied prospectively.

Apgar Score↗
PubMed1992

The influence of particle size on the bioavailability of inhaled temazepam.

1. Temazepam was administered by aerosol using a standard protocol to healthy volunteers. Two studies are reported in which different dosage formulations were used: a) 30 mg of the 5 mu diameter particle (n = 6); b) 10 mg of the 2 mu diameter particle (n = 6). 2. An open crossover design was followed in each study. On one occasion in both studies subjects used a gargling procedure to remove drug which had been deposited in the mouth and oropharynx. 3. Serial venous blood samples were drawn for a period of 24 h. The mean total AUC of the 5 mu preparation was significantly reduced by gargling (3153 ng ml-1 h to 1066 ng ml-1 h) (F = 0.32). Gargling also had a significant effect on the mean AUC(0-1 h). 4. In contrast gargling had no significant effect on the mean AUC associated with the smaller diameter particle preparation (630 ng ml-1 h) vs 397 ng ml-1 h (F = 0.74). 5. These findings also indicate that temazepam deposition in the pulmonary tree is enhanced by the use of a 2 mu rather than a 5 mu diameter particle. However, the plasma drug concentrations achieved are unlikely to produce a sufficiently marked sedative effect for endoscopic investigations such as gastroscopy.

Administration, Inhalation↗
PubMed1992

Factors affecting quantitative assessment of Pseudomonas aeruginosa adherence to buccal epithelial cells.

The influence of experimental protocol on estimation of adherence of P. aeruginosa to buccal epithelial cells is highlighted. Use of membrane filtration to remove non-adherent bacteria was significantly affected by membrane pore size and rinse volume, but was not affected by inoculum size or test isolate. Even with optimum filtration conditions, over 58% of the non-adherent bacterial population were retained on the filters. Separation of non-adherent bacteria was greatly improved when density centrifugation was employed, with less than 30% of non-adherent bacteria present in the buccal epithelial suspension. Adherence values measured by a radiological and fluorometric method were significantly higher than those determined by microscopic counting. Radiological assays had the lowest variance. Gradient centrifugation was used to prepare a standard suspension of buccal epithelial cells. However, cells collected on different days showed significantly different adherence measurements. Adherence of bacteria to trypsinized buccal epithelial cells and to buccal epithelial cells from cystic fibrosis patients was similar, whereas adherence to normal buccal epithelial cells was significantly lower.

Bacterial Adhesion↗
PubMed1991

Development of resistance to ciprofloxacin in nutrient-rich and nutrient-limited growth conditions in vitro by Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

Five serial exposures of mucoid Pseudomonas aeruginosa from patients with cystic fibrosis to subinhibitory concentrations of ciprofloxacin resulted in stepwise increases in the MIC, with a mean proportional increase of 10. MICs were significantly lower in an iron-limited chemically defined medium than in Iso-Sensitest broth. The mucoid phenotype was maintained in chemically defined medium. Acquired resistance was retained either partially or completely in 85% of the isolates following 10 transfers in drug-free media. In cases in which susceptibility was regained, an increase in the MIC was observed on one further exposure to ciprofloxacin.

Cells, Cultured↗
PubMed1990

Propofol sedation after open heart surgery. A clinical and pharmacokinetic study.

One hundred adult patients who required mechanical ventilation after open heart surgery for coronary revascularisation were studied. All received a standard premedication and a high dose opioid anaesthetic. On arrival in the intensive care unit they were allocated randomly to receive either propofol or midazolam to maintain sedation within a predetermined range. Patients who received propofol underwent extubation of the trachea, using standard criteria, after a mean time (log-transformed) of 7.6 minutes after sedation for approximately 17 hours. The corresponding time was 125 minutes in those given midazolam. There were significantly higher morphine requirements during sedation, and higher arterial carbon dioxide tensions 30 minutes after extubation of the trachea, in patients who received midazolam. Pharmacokinetic analysis in 20 patients showed that the elimination half-life of propofol was prolonged (470 minutes) and clearance was reduced (1.14 litres/minute) compared with subjects who had not undergone cardiopulmonary bypass. The rapid clinical recovery was reflected in a rapid redistribution half-life (13.4 minutes), but this was also longer than the redistribution time of 2-4 minutes in other patients.

Blood Pressure↗
PubMed1989

Does pretreatment with cimetidine and ranitidine affect the disposition of bupivacaine?

Thirty patients who chose extradural analgesia for elective Caesarean section were pretreated, by random selection, with cimetidine 400 mg, ranitidine 150 mg or no H2-blocker. Following the administration of 0.5% bupivacaine, no significant difference was found between peak plasma bupivacaine concentrations or area under the plasma bupivacaine concentration-time curve (AUC) in these three groups. This study shows that a single dose of cimetidine or ranitidine does not affect significantly the disposition of bupivacaine in the obstetric patient.

Adult↗
PubMed1989

Clinical and pharmacokinetic aspects of ciprofloxacin in the treatment of acute exacerbations of pseudomonas infection in cystic fibrosis patients.

Twelve cystic fibrosis patients, aged over 18, who had developed an acute respiratory exacerbation and who had Pseudomonas species isolated from their sputum, were entered into a clinical trial involving ciprofloxacin. The dosage regimen was 100 mg iv followed by 500 mg twice daily orally if less than 40 kg in weight and 200 mg iv followed by 750 mg twice daily orally if greater than 40 kg. Ciprofloxacin was well tolerated with no major side effects, except in one patient who withdrew after onset of headaches and generalized aches and pains. Eleven of the 12 patients showed clinical improvement at the end of the treatment period as determined by weight gain, Shwachman Score, Chrispin Norman Score and pulmonary function tests. MICs of Pseudomonas species isolated from the sputum at the start of the trial were in the range 0.25-4 mg/l. During therapy, sensitivity of isolates decreased and did not return to starting levels at the end of a four week follow-up period. Pharmacokinetic parameters were similar to those reported for fasting healthy volunteers by other workers except for bioavailability which was reduced in the non-fasting patients.

Administration, Oral↗
PubMed1989

Effect of intravenous cimetidine on lignocaine disposition during extradural caesarean section.

We studied whether an intravenous bolus of cimetidine altered the disposition of extradurally administered lignocaine in the parturient. Mothers who requested extradural analgesia for elective Caesarean section were randomly pretreated with either cimetidine 200 mg intravenously (n = 5) or no H2-receptor antagonist (n = 5). No difference was found between peak plasma lignocaine levels or area under the plasma concentration/time curve between the two groups after administration of 6 mg/kg lignocaine 2% with adrenaline 1:200,000. There was no evidence for an effect of a single intravenous dose of cimetidine on lignocaine disposition in the obstetric patient. In addition, the extradural administration of 6 mg/kg lignocaine produces plasma levels well below toxic levels.

Anesthesia, Epidural↗
PubMed1989

Single dose oral H2-antagonists do not affect plasma lidocaine levels in the parturient.

We studied whether a single oral dose of either cimetidine or ranitidine affects the disposition of epidurally administered lidocaine in the parturient. Patients given epidural analgesia for elective caesarean section were randomly pretreated with either cimetidine 400 mg (n = 5), ranitidine 150 mg (n = 7) or no H2 receptor antagonist (n = 5). Following the administration of 400 mg of lidocaine 2% with adrenaline 1:200,000 no difference was found in peak plasma lidocaine levels or area under the plasma concentration/time curve (AUC) between the three groups. A single oral dose of cimetidine or ranitidine does not affect lidocaine disposition in the obstetric patient.

Anesthesia, Epidural↗
PubMed1988

A pharmacokinetic study of midazolam in paediatric patients undergoing cardiac surgery.

Midazolam 0.3 mg kg-1 was given as a single dose to three groups of children undergoing cardiac surgery to determine its pharmacokinetic profile in this situation. The first group, undergoing closed heart surgery, received the midazolam during the operation. The other groups underwent cardiopulmonary bypass (CPB) with and without complete circulatory arrest. Mean clearance was 512 ml kg-1 h-1 and mean elimination half-lives were 3.3 h following CPB, with a tendency to a higher clearance in those children who had not undergone bypass. In a subsequent part of the study, 10 children received an infusion of midazolam 0.05 mg kg-1 h-1, in combination with intermittent doses of morphine, in the postoperative period. Mean plasma midazolam concentrations consistent with adequate sedation were 80-100 ng ml-1 during the infusion. One child who had not undergone CPB had very low plasma concentrations of midazolam with the same rate of infusion, consistent with the tendency for higher clearance in this group in the bolus pharmacokinetic study.

Cardiac Surgical Procedures↗
PubMed1988

Effect of ciprofloxacin in an in-vitro pharmacokinetic model against Pseudomonas aeruginosa isolated during cystic fibrosis lung infection.

An in-vitro pharmacokinetic model was used to simulate ciprofloxacin concentrations in serum observed in vivo following oral doses of 250, 500 and 750 mg, in a culture of Pseudomonas aeruginosa isolated from the sputum of a cystic fibrosis patient. In the 12 h interval following each dose, a period of bactericidal activity was observed, succeeded by bacteriostasis and subsequent bacterial regrowth. In all cases bacterial regrowth was first observed when the ciprofloxacin concentration in the culture flask of the dynamic model fell below the MIC. For the three doses investigated, the surviving bacteria at the end of each 12-h dosing interval showed an increase in MIC compared with that of the culture before ciprofloxacin exposure. The post-antibiotic effect of ciprofloxacin against P. aeruginosa was observed for 1-5 h, and was dose related.

Ciprofloxacin↗
PubMed1987

Cimetidine and ranitidine increase midazolam bioavailability.

Cimetidine has been shown to inhibit the oxidative metabolism of a variety of low- and high-extraction drugs. Despite the findings of initial investigators, there is evidence that ranitidine may exert similar effects. Eight healthy volunteer subjects took part in a within-subject crossover study. They received midazolam, 15 mg, by mouth after pretreatment with cimetidine, ranitidine, or nothing and midazolam, 10 mg, intravenously on separate occasions. Mean absolute bioavailability of midazolam was increased by more than 30% after cimetidine (P less than 0.01) and 26% after ranitidine (P less than 0.05). The data, which agree with a concurrent clinical study indicating greater hypnotic action of midazolam after ranitidine, indicate that this is not a result of enhanced midazolam absorption and that reduced hepatic clearance is the most likely explanation.

Absorption↗
PubMed1987

Midazolam sedation following open heart surgery.

Midazolam given as hourly intermittent injections was compared with the same dose given by infusion for postoperative sedation in patients after cardiopulmonary bypass. A stable concentration was rapidly attained with the infusion whereas 6-8 h was required to attain stable plasma (trough) concentrations in the intermittent injection group. Plasma concentrations decreased rapidly to low values within 6 h of discontinuation of therapy. High plasma concentrations and a long (16 h) half-life were noted in one patient who may be a slow metabolizer of the drug.

Adult↗