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Biomedical subjects

E Doyle

Publications and source records attributed to E Doyle.

At least 37 records · Page 2Linked to original sources
PubMed1999

Oral topotecan: bioavailablity and effect of food co-administration.

The aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m(-2) day(-1) of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m(-2) day(-1)) or i.v. (1.5 mg m(-3) day). They crossed over to receive the alternate regimen on day 2. On days 3-5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93+/-0.23 (90% confidence interval (CI) 0.83-1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6+/-4.4 ng ml(-1)) or without food (9.2+/-4.1 ng ml(-1)) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8-6.1) compared to fasted conditions (2.0 h, range 1.1-8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42+/-13% (90% CI 37-47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9+/-1.0 h) than after i.v. administration (2.7+/-0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption.

Administration, Oral↗
PubMed1999

The intravascular migration of an epidural catheter.

The intravascular migration of an endhole epidural catheter in a child is described. We suggest measures to reduce the risk of inadvertent intravenous administration of local anaesthetic and means of reducing the effects of this with particular relevance to paediatric practice.

Anesthesia, Epidural↗
PubMed1999

Comparison of morphine sulphate and codeine phosphate in children undergoing adenotonsillectomy.

We undertook a double-blind study to evaluate equianalgesic doses of intramuscular morphine sulphate (0.15 mg.kg-1) and codeine phosphate (1.5 mg.kg-1) in 40 healthy children undergoing adenotonsillectomy. There were no significant differences in pain scores, analgesic requirements or sedation scores between the two groups over the following 24 h. More children vomited in the morphine group (60%) than the codeine group (30%) between one and six h after the procedure (P < 0.05). Codeine phosphate is associated with less postoperative vomiting than morphine sulphate while providing comparable postoperative analgesia for adenotonsillectomy.

Adenoidectomy↗
PubMed1999

Search for the PARK3 founder haplotype in a large cohort of patients with Parkinson's disease from northern Germany.

A founder haplotype on chromosome 2p for autosomal dominant Parkinson's disease (PD) has been postulated for two families of Northern European descent, and a new mutation in the alpha-synuclein gene (Ala30Pro) has been found in a German PD family. We evaluated 85 German PD patients and 85 ethnically matched controls for shared markers on chromosome 2p and for the new alpha-synuclein mutation. We found no evidence for linkage disequilibrium, suggesting that the putative founder mutation on chromosome 2p is not a common cause of PD in the local population. Furthermore, no patient carried the Ala30Pro change, supporting earlier findings that mutations in the alpha-synuclein gene are extremely rare.

Aged↗
PubMed1999

Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Adult↗
PubMed1999

The effect of ketamine on 0.25% and 0.125% bupivacaine for caudal epidural blockade in children.

Forty boys aged from one to five years undergoing orchidopexy were randomly allocated to receive one of two solutions for caudal epidural injection. Group A received 1 ml.kg-1 of 0.125% bupivacaine with ketamine 0.5 mg.kg-1 and Group B received 1 ml.kg-1 of bupivacaine 0.25% with ketamine 0.5 mg.kg-1. Postoperative pain was assessed by means of a modified Objective Pain Score and analgesia was administered if this score exceeded four. The median duration of caudal analgesia was 8 h in Group A compared with 9.5 h in Group B (P<0.05). The time taken to recover the ability to walk was a median of two h in Group A and three h in Group B (P<0.05). There were no differences between the groups in the incidence of urinary retention or postoperative sedation.

Acetaminophen↗
PubMed1998

Modifying infant stress responses to major surgery: spinal vs extradural vs opioid analgesia.

Twenty-six infants due to undergo major abdominal or thoracic surgery under general anaesthesia were randomized to receive additional analgesia with group A) spinal/epidural analgesia; B) epidural analgesia or C) opioid analgesia with fentanyl. We wished to determine if spinal analgesia followed by epidural analgesia might result in more complete control of cardiovascular or stress responses than the other two treatment groups. Heart rate and blood pressure were recorded at five min intervals throughout surgery. Blood samples were taken for measurement of catecholamines and whole blood sugar on induction, 45 min after skin incision and at the end of surgery. Heart rate rose significantly at the start of surgery in groups B and C but not group A. Systolic blood pressures were higher in group C compared to A and B. The rise in plasma glucose concentrations was significantly different between the groups in the order C > B > A (P < 0.05). A similar trend was seen in the plasma adrenaline and noradrenaline concentrations but this failed to achieve significance due to the limited sample size.

Abdomen↗
PubMed1998

Pre-emptive effect of multimodal analgesia in thoracic surgery.

Thirty subjects undergoing posterolateral thoracotomy were allocated randomly to receive one of two analgesic regimens: group Pre received i.v. morphine, i.m. diclofenac and intercostal nerve blocks from T2 to T11, 20 min before operation and placebo injections after operation. Group Post received placebo injections before operation, and i.v. morphine, i.m. diclofenac and intercostal nerve blocks from T2 to T11 at the end of surgery, before discontinuation of anaesthesia. Visual analogue pain scores, extent and duration of intercostal nerve block, analgesic consumption and complications were assessed during the postoperative period by a single blinded observer. Subjects were followed-up for a minimum of 12 months to determine the incidence of post-thoracotomy pain syndrome. During the first 48 h after operation there were lower pain scores in group Pre when taking a vital capacity breath but there were no significant differences between the groups in any other measure. The effects of pre-emptive analgesia given before surgery appeared to be relatively modest in terms of analgesia, analgesic consumption and long-term outcome and were of limited clinical significance.

Adult↗
PubMed1998

O-glucuronidation, a newly identified metabolic pathway for topotecan and N-desmethyl topotecan.

During topotecan analysis of clinical urine samples, an additional peak eluting just after the solvent front was observed. This potential metabolite was isolated by chromatographic methods. Mass spectrometry data along with chromatographic retention data and fluorescence characteristics showed that the isolated fractions contained two compounds, i.e. topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide. The concentrations of the metabolites in human urine were relatively low. When topotecan was given as a 30 min infusion at a dosage of 1.5 mg/m2 daily for five consecutive days every 3 weeks, the maximal metabolite concentrations in a 24 h urine sample were approximately 10% of topotecan-O-glucuronide and 3.5% of N-desmethyl topotecan-O-glucuronide with respect to the concentration of topotecan in the urine. This is the first report demonstrating that glucuronide metabolites of topotecan are present in the urine of treated patients.

Antineoplastic Agents↗
PubMed1997

Plasma bupivacaine levels after fascia iliaca compartment block with and without adrenaline.

Twenty children undergoing unilateral surgery on the thigh received a fascia iliaca compartment block using 2 mg.kg-1 of bupivacaine with (Group A) or without (Group P) adrenaline 1/200,000. Venous blood samples were taken as 5, 10, 15, 20, 25, 30, 40, 50 and 60 min after injection and assayed for concentrations of bupivacaine. In all subjects an adequate block was produced. Plasma concentrations of bupivacaine in Group P were significantly higher than those in Group A (P < 0.05). The median maximum plasma concentration (Cmax) was 1.1 micrograms.ml-1 (range 0.54-1.29 micrograms.ml-1) in Group P and 0.35 microgram.ml-1 (range 0.17-0.96 microgram.ml-1) in Group A. The median time taken to attain Cmax (Tmax) was 20 min (range 10-25 min) in Group P and 45 min (range 5-50 min) in Group A. The median time to first analgesia was 9.75 h (range 3-15 h) in Group P and 10.5 h (range 2.5-21 h) in Group A. The study confirmed the efficacy of the fascia iliaca compartment block in children and showed that when performed with 2 mg.kg-1 of bupivacaine it is associated with plasma concentrations of bupivacaine well within acceptable limits. The addition of adrenaline 1/200,000 to the local anaesthetic solution reduces the maximum plasma concentration reached.

Adolescent↗
PubMed1997

Comparison of caudal block using bupivacaine and ketamine with ilioinguinal nerve block for orchidopexy in children.

Forty boys weighing less than 25 kg undergoing unilateral orchidopexy were randomly allocated to receive one of two analgesic regimens. Group C received a caudal epidural block with 0.25% bupivacaine 1 ml.kg-1 and preservative-free ketamine 0.5 mg.kg-1; Group L received an ilioinguinal nerve block with 0.25% bupivacaine 0.5 ml.kg-1 and infiltration of the wound with 0.25% bupivacaine 0.5 ml.kg-1. All subjects received diclofenac sodium 1-2 mg.kg-1 as a rectal suppository. Postoperative pain was assessed by means of a modified Objective Pain Score and analgesia was administered if this exceeded a value of 4. The median duration of analgesia was 10 h (range 2.6 to > 24 h) in Group C and 2.9 h (range 0.7 to > 24 h) in Group L (p < 0.05). There were no differences between groups in the incidence of motor block, urinary retention, postoperative vomiting or postoperative sedation. Subjects in Group L required significantly more doses of postoperative analgesia than those in Group C (p < 0.05).

Acetaminophen↗
PubMed1997

A risk-benefit assessment of topical percutaneous local anaesthetics in children.

Since its introduction, eutectic lidocaine-prilocaine cream ('EMLA')1 has been found to be an effective topical anaesthetic agent, with a high degree of efficacy, particularly for venepuncture and venous cannulation, and an impressive tolerability profile. Reports of adverse effects are remarkable for their rarity. The only problems that are likely to be encountered are oral ingestion of the cream (which may lead to anaesthesia of the oropharynx and possible toxicity secondary to rapid absorption of local anaesthetic from oral mucous membranes) and methaemoglobinaemia following repeated applications in neonates and infants. Analysis of the risks and benefits associated with its use comes down heavily in favour of the preparation. More recently, a preparation of tetracaine (amethocaine) has been marketed as a gel. Its advantages are a faster onset, and longer duration, of action than 'EMLA'. Although less widely used, it too has an impressive tolerability record. Concerns over the potential for anaphylactic type reactions due to its ester structure have not been realised in clinical practice. Of the other available preparations, lidocaine (lignocaine), applied iontophoretically, is unlikely to become popular because of the complexity of administration. A paste made of tetracaine, epinephrine (adrenaline) and cocaine (TAC) appears to be a far more toxic preparation on theoretical grounds, and this has been borne out in clinical practice; it is not as well tolerated as 'EMLA' or tetracaine gel. Ethyl chloride, although not a local anaesthetic, can safely provide cutaneous analgesia in children in circumstances when it is impractical to wait for a local anaesthetic preparation to take effect.

Administration, Cutaneous↗
PubMed1996

Nefiracetam (DM-9384) reverses apomorphine-induced amnesia of a passive avoidance response: delayed emergence of the memory retention effects.

Nefiracetam is a novel pyrrolidone derivative which attenuates scopolamine-induced learning and post-training consolidation deficits. Given that apomorphine inhibits passive avoidance retention when given during training or in a defined 10-12h post-training period, we evaluated the ability of nefiracetam to attenuate amnesia induced by dopaminergic agonism. A step-down passive avoidance paradigm was employed and nefiracetam (3 mg/kg) and apomorphine (0.5 mg/kg) were given alone or in combination during training and at the 10-12h post-training period of consolidation. Co-administration of nefiracetam and apomorphine during training or 10h thereafter produced no significant anti-amnesic effect. However, administration of nefiracetam during training completely reversed the amnesia induced by apomorphine at the 10h post-training time and the converse was also true. These effects were not mediated by a dopaminergic mechanism as nefiracetam, at millimolar concentrations, failed to displace either [3H]SCH 23390 or [3H]spiperone binding from D1 or D2 dopamine receptor subtypes, respectively. It is suggested that nefiracetam augments molecular processes in the early stages of events which ultimately lead to consolidation of memory.

Animals↗
PubMed1996

The single and multiple dose pharmacokinetics of pranlukast in healthy volunteers.

OBJECTIVE: The pharmacokinetics of pranlukast, a leukotriene LTD4 antagonist, were studied in 48 young, healthy subjects after single and repeated oral doses (given every 12 h) ranging from 112.5 to 675 mg. The doses were administered 30 minutes after a light breakfast. RESULTS: Maximal drug concentrations generally occurred between 2 and 6 h after dosing, and there was some evidence of an absorption lag-time. Secondary peaks were observed in the plasma concentration vs. time profiles of many of the study subjects after both single and repeated doses, particularly during the period of maximum drug absorption. In general, after both single and repeated doses, there were related increases in the corresponding Cmax and AUC with a rise in dose, although the increase was diminished at doses above 450 mg. With repeated dosing of pranlukast the mean AUC was generally higher (up to 1.6-fold), and the higher plasma concentrations allowed characterisation of a longer mean t 1/2 than after single dose administration. The mean steady-state trough plasma concentrations attained after evening doses were considerably higher (up to 14-fold) than those obtained after the morning dose. CONCLUSION: The data suggested that the pharmacokinetics of pranlukast are influenced by the time of dosing. Based on analysis of urinary 6 beta-hydroxycortisol excretion, there was no evidence that pranlukast modified the metabolic activity of cytochrome P-450 3A isoenzymes.

Adolescent↗