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Biomedical subjects

E J Triggs

Publications and source records attributed to E J Triggs.

At least 19 recordsLinked to original sources
PubMed1998

Effect of oral levodopa treatment on articulatory function in Parkinson's disease: preliminary results.

To quantify lip function in 16 patients with Parkinson's disease, a computerized semiconductor lip pressure transducer system was used prior to subjects being administered oral levodopa and at approximately 0.5 hr, 1.5 hr, and 3.0 hr postmedication. Two blood samples were taken from each subject at varying times during the levodopa dosage interval, and the exact time and dosage of levodopa were noted. Lip function measurements were expressed as percentage changes from baseline and were plotted for each subject against time and levodopa concentrations to determine the effects of levodopa therapy on articulatory function. The results supported the effectiveness of levodopa therapy in improving lip function. In particular, lip pressures recorded during both speech and nonspeech tasks tended to improve after levodopa administration, the lip measures improving somewhat in parallel with the rise and fall of blood plasma levodopa concentrations. Evidence of a hysteresis effect was noted.

Aged↗
PubMed1996

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients.

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, non-linear mixed effect modelling with the program NON-MEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid EMax representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. RESULTS: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. CONCLUSION: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).

Administration, Oral↗
PubMed1996

Rate of motor response to oral levodopa and the clinical progression of Parkinson's disease.

We investigated the relationship between the rate of motor response after a standard levodopa oral dose and drug dynamic variables and disease-related factors in 66 patients with Parkinson's disease. Time to maximum finger tapping effect was positively correlated with matched duration of levodopa dose response and fell from a median 120 minutes in patients at Hoehn and Yahr stage I and II to 60 minutes in stage IV patients (p < 0.001). The accelerated response to levodopa dose with the advancement of disease was also apparent as an increased steepness of the tapping effect versus time curve, with a shift from a hyperbolic to a sigmoid profile. The rate of motor response to oral levodopa may reflect the rate of dopamine interaction with the postsynaptic receptors, providing an indirect objective index of presynaptic dopaminergic homeostasis.

Administration, Oral↗
PubMed1996

Use of methotrexate in older patients. A risk-benefit assessment.

Methotrexate is eliminated almost entirely by the kidneys. The risk of methotrexate toxicity is therefore increased in patients with poor renal function, most likely as a result of drug accumulation. Declining renal function with age may thus be an important predictor of toxicity to methotrexate. Up to 60% of all patients who receive methotrexate for rheumatoid arthritis (RA) discontinue taking it because of adverse effects, most of which occur during the first year of therapy. Gastrointestinal complications are the most common adverse effects of methotrexate, but hepatotoxicity, haematological toxicity, pulmonary toxicity, lymphoproliferative disorders and exacerbation of rheumatic nodules have all been reported. Decreased renal function as a result of disease and/or aging appears to be an important determinant of hepatic, lymphoproli ferative and haematological toxicity. Concomitant use of low doses of folic acid has been recommended as an approach to limiting toxicity. Interactions between methotrexate and several nonsteroidal anti-inflammatory drugs have been reported, but they may not be clinically significant. However, caution is advised in the use of such combinations in patients with reduced renal function. More serious toxicities (e.g. pancytopenia) may result when other inhibitors of folate utilisation [e.g. cotrimoxazole (trimethoprim-sulfamethoxazole)] or inhibitors of renal tubular secretion (e.g. probenecid) are combined with methotrexate. Before starting low dose methotrexate therapy in patients with RA, a full blood count, liver function tests, renal function tests and chest radiography should be performed. Blood counts and liver function tests should be repeated at regular intervals. Therapeutic drug monitoring of methotrexate has also been suggested as a means of limiting toxicity. Patients with RA usually respond very favourably to low dose methotrexate therapy, and the probability of patients continuing their treatment beyond 5 years is greater than for other slow-acting antirheumatic drugs. Thus, given its sustained clinical utility and relatively predictable toxicity profile, low dose methotrexate is a useful addition to the therapy of RA.

Aged↗
PubMed1994

Gentamicin dosing in elderly patients based on bioelectrical impedance analysis.

The relationship between gentamicin pharmacokinetics and measures of bioelectrical impedance (BI) in elderly patients was investigated with the aim of developing a potential noninvasive means of individualising gentamicin dosage. Linear regression analyses identified height/resistance2 as a statistically significant predictor of gentamicin distribution volume, V, [adjusted (adj)r2 = 0.53, coefficient of variation (CV) = 15.2%], and resistance/reactance and creatinine clearance (CLcr) as predictors of total systemic clearance, CL, adj r2 = 0.52, CV = 20.1%. Individualisation of gentamicin dosage regimens based on these relationships to achieve steady-state (SS), peak gentamicin concentrations, Css,max, and SS trough concentrations, Css,min, of 7.0 and 1.0 micrograms/ml, respectively, in an independent group of elderly patients resulted in serum gentamicin levels of 5.9 +/- 0.7 and 0.8 +/- 0.4 micrograms/ml. Mean absolute prediction errors averaged 0.7 +/- 0.5 micrograms/ml for Css,max and 0.5 +/- 0.3 micrograms/ml for Css,min. Measures of BI provided the best predictions of Css,max, whereas models based on CLcr alone were the best predictors of Css,min. This technique provides a means of complementing routine pharmacokinetic monitoring of gentamicin pharmacotherapy in the elderly hospitalised patient with reductions in patient discomfort and potential savings in time and cost.

Aged↗
PubMed1993

Assessment of bioelectrical impedance for individualizing gentamicin therapy in neonates.

The use of bioelectrical impedance (BI) analysis as a non-invasive approach for individualizing gentamicin therapy in newborn infants has been investigated in a two phase study. In Phase I, 1/impedance and length were identified as statistically significant predictors of the distribution volume of gentamicin (Adj R2 = 0.78, CV = 12.42%), and length/impedance and post-conceptual age were predictors of total systemic clearance (Adj R2 = 0.83, CV = 14.5%), following the administration of 2.5 mg.kg-1 gentamicin to 17 neonates (gestational age (GA) 27 to 36 weeks). In a prospective validation of these relationships in an independent (Phase II) group of 27 infants (GA 26 to 41 weeks), predicted serum gentamicin concentrations were close to those achieved. Several instances of high prediction errors (predicted minus achieved levels) were observed in infants with known or suspected renal impairment and they caused significant (P < 0.05) perturbation in the bias and accuracy of the models. Daily BI measures over a four to five day period were able to detect individual changes in the fat-free body compartments, which were translated into alterations in gentamicin regimens. This simple, non-invasive and relatively inexpensive bedside technique provides a potentially valuable means to individualize gentamicin therapy without relying on the measurement of serum gentamicin concentration.

Electric Impedance↗
PubMed1993

Plasma concentrations of bupivacaine after wound infiltration of an 0.5% solution after inguinal herniorrhaphy: a preliminary study.

After routine inguinal herniorrhaphy we gave 12 patients a wound infiltration regimen of bolus doses of 20 ml of 0.5% bupivacaine via a catheter within the wound and rectally administered indomethacin (100 mg). Peak venous plasma bupivacaine concentrations ranged from 0.07 mg.l-1 to 1.14 mg.l-1 (mean (SD) 0.47 (0.33) mg.l-1), and occurred at between 0.25 and 2 h after the first dose. Plasma concentrations were well below the toxic threshold of 4 mg.l-1 and there was no accumulation. The regimen provided satisfactory analgesia. There were no wound infections nor signs of toxicity.

Adult↗
PubMed1993

Individual theophylline dosing based on bioelectrical impedance analysis.

The role of bioelectrical impedance (BI) analysis in determining slow-release theophylline dosage was evaluated in fifteen healthy subjects given a standard 200 mg dose. Reactance and l/resistance were identified as the most significant predictors of pre-dose, steady-state theophylline concentrations (Css,pre). Compared with doses based on body weight (8.8 mg kg-1 day-1), theophylline doses determined by BI analysis (9.6 +/- 2.4 mg kg-1 day-1) resulted in less biased (mean prediction error = 0.6 vs 1.4) though slightly less precise (mean squared error = 7.1 vs 6.3) Css,pre values. These differences were statistically insignificant (P > 0.05).

Adolescent↗
PubMed1992

High-performance liquid chromatographic method for the quantitation of bupivacaine, 2,6-pipecoloxylidide and 4'-hydroxybupivacaine in plasma and urine.

A high-performance liquid chromatographic method with ultraviolet detection at 210 nm for quantitation of bupivacaine and two of its metabolites from plasma and urine is described. The compounds are extracted into n-hexane-isopropanol (5:1), evaporated and the reconstituted residue injected onto a reversed phase C18 column. Standard curves for all compounds were linear (r2 greater than 0.999) in the range 20-2000 ng/ml, with a limit of detection of 10 ng/ml. The inter-day coefficients of variation ranged between 2.7 and 12.2%. The method was applied to analyse bupivacaine and metabolite concentrations in patients on long-term epidural bupivacaine-fentanyl infusions.

Bupivacaine↗
PubMed1991

The disposition of bupivacaine following a 72 h interpleural infusion in cholecystectomy patients.

The disposition of bupivacaine and degree of analgesia following a 72 h interpleural infusion was investigated in 12 adult patients undergoing elective cholecystectomy. The infusion regimen of an initial interpleural bolus dose of 20 ml of 0.5% bupivacaine HCl with adrenaline (1:200,000) followed by continuous infusion at a rate of 8 ml h-1 of 0.25% plain bupivacaine HCl was designed to achieve continuous post-operative pain relief for 72 h. In practice an additional bolus dose (identical to the first) administered 5 h after infusion commencement was required to achieve adequate pain relief on the first postoperative day. The mean measured steady-state plasma bupivacaine concentration was 2.1 mg l-1 (s.d. +/- 0.54, range 1.3-3.2 mg l-1). Disposition parameters for bupivacaine measured for the infusion were calculated by non-compartmental methods and compared with previous values obtained after single and multiple interpleural bolus dose administration. No statistically significant differences were noted and, in particular, the systemic clearance of bupivacaine (mean 10.2 l h-1 s.d +/- 3.0; range 6.3-16.0 1 h-1) remained unchanged following the long-term interpleural infusion. Analgesia was deemed satisfactory throughout the entire post-operative period.

Adult↗
PubMed1991

Interpleural bupivacaine infusion compared with intravenous pethidine infusion after cholecystectomy.

Twenty-six cholecystectomy patients received either an interpleural infusion of bupivacaine (Group B, n = 12) or an intravenous infusion of pethidine (Group P, n = 14) for management of postoperative pain over a three-day period. Patients in Group P experienced a significantly (P less than 0.05) greater incidence of total side-effects (146) than patients in Group B (66). Pain scores (VAS) and responses to a pain questionnaire were similar for both groups; however, within Group B improvement in mean VAS scores at rest with time were more sustained. Similar reductions in FEV1 and FVC from preoperative values occurred for both groups, while for Group P there were significant (P less than 0.05) changes in arterial blood gases (increase in PCO2, decrease in PO2) over two days postoperatively. Patients in Group P recorded longer times to passing flatus and unaided mobilisation (P less than 0.05), and required a significantly greater number of additional medications (anti-emetics and analgesics) over the postoperative period (41 vs 29, P less than 0.05).

Adult↗
PubMed1990

Pharmacokinetics of interpleural bupivacaine in patients undergoing cholecystectomy.

Arterial and venous plasma concentrations of bupivacaine were measured following interpleural administration of 20 ml of 0.5% solution with adrenaline in patients undergoing cholecystectomy. Mean maximum arterial and venous concentrations in eight of 11 patients were 1.90 (SD 0.36) and 1.65 (0.48) mg litre-1 and occurred at 22 (10) min and 25 (10) min, respectively. An arteriovenous difference for bupivacaine of approximately 20% was noted during the first 45-60 min after administration. Mean systemic venous plasma clearance (0.15 (0.08) litre h-1 kg-1) was less and the mean elimination half-life (6.85 (2.29) h) and mean body residence time (9.99 (3.00) h) were longer than reported previously for interpleural bupivacaine--possibly because of continued slow absorption of the drug from its absorption site.

Adult↗
PubMed1990

Steady-state pharmacokinetics of interpleural bupivacaine in patients after cholecystectomy.

Venous plasma concentrations of bupivacaine were determined in eight cholecystectomy patients following multiple interpleural bolus instillations of bupivacaine 20 ml 0.5% with adrenaline (5 mg/l) administered at six- to eight-hour intervals. The mean steady-state peak plasma concentration was 2.3 mg/l (range 1.2-3.1 mg/l); however, in three of the eight patients peak plasma concentrations were greater than 3 mg/l. The mean accumulation ratio was found to be 1.6 (range 0.99-2.49), with steady-state occurring within the first 24 hours of drug administration. Mean apparent systemic plasma clearance was 0.16 +/- 0.07 l/kg/h with a mean terminal half-life of 5.8 +/- 2.3 hours measured at steady-state, values which were not significantly different (P greater than 0.05) from those values obtained following single interpleural bolus dose administration.

Adult↗
PubMed1989

The pharmacokinetics of amiloride-hydrochlorothiazide combination in the young and elderly.

The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics. The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml.min-1, amiloride; and from 418 to 157 ml.min-1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng.ml-1, Css,max; from 2 to 8 ng.ml-1, Css,min; and from 4 to 14 ng.ml-1, Cav; Hydrochlorothiazide: from 184 to 651 ng.ml-1, Css,max; from 31 to 121 ng.ml-1, Css,min; and from 89 to 273 ng.ml-1, Cav). The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r = 0.62, young; r = 0.72, elderly). As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination.

Adult↗
PubMed1989

Disposition of cefotaxime and its metabolite, desacetylcefotaxime, in rat: application of a pharmacokinetic-protein binding model.

1. The pharmacokinetics and protein binding of cefotaxime and desacetylcefotaxime were studied in rat. 2. After i.v. dosing of cefotaxime (100 mg/kg) the concentration-time profiles of cefotaxime and its metabolite desacetylcefotaxime followed biphasic decays, giving the kinetic parameters for cefotaxime: VTss and AUC of 127 ml/kg and 8.2 mg/min per ml, respectively. The beta-elimination half-life was 17 min with Cls of 13.1 ml/min per kg. The average association constant (K x 10(3) M-1) and total protein binding site concentration (Pt x 10(-3) M) for cefotaxime were 3.87 and 0.68, respectively, with saturation of plasma protein binding occurring at about 30 micrograms/ml. The average free fraction of cefotaxime in plasma (Fp) was 0.48. 3. The metabolite desacetylcefotaxime had a plasma Cmax of 74.4 micrograms/ml (35 min). The respective elimination half-life and AUC were 53 min and 7.2 mg/min per ml. The binding profile, unlike that of cefotaxime, was non-saturable with a K value of 13.90M-1. The Fp of desacetylcefotaxime was 0.89. 4. The concentration-time behaviour of total and free desacetylcefotaxime (i.v. bolus, 50 mg/kg) declined biexponentially with respective VTss and AUC of 125 ml/kg and 19.4 mg/min per ml (total drug), and 192 ml/kg and 13.9 mg/min per ml (free drug). The beta-phase half-life of total and free drug was about 36 min, whereas CLs (ml/min per kg) were 2.7 (total) and 3.7 (free). The binding characteristics were in good agreement with those of the metabolite produced in vivo, with a K value of 8.58 M-1. The Fp value of desacetylcefotaxime in plasma was 0.73.

Animals↗
PubMed1989

Disposition of ceftriaxone in rat: application of a pharmacokinetic-protein binding model and comparison with cefotaxime.

1. The pharmacokinetic profile and protein binding parameters of ceftriaxone were determined in rat, and compared with those of cefotaxime. 2. Plasma concentration-time curves of ceftriaxone and cefotaxime (single i.v. bolus; 100 mg/kg each) were described by a two-compartment, protein-binding model. 3. The corrected VTss (ml/kg) of ceftriaxone was lower than that of cefotaxime. The AUCs of both drugs were similar. The t1/2 beta of the two drugs differed significantly, being 29 min for ceftriaxone and 17 min for cefotaxime. 4. In vivo protein binding constants of both drugs were similar, but the concentrations of protein binding sites differed significantly. The average free fractions in plasma (Fp) of ceftriaxone and cefotaxime were 0.22 and 0.48 respectively. 5. Saturation of the binding site for cefotaxime was estimated to occur at about 30 micrograms/ml in plasma, whereas saturation for ceftriaxone was seen at lower concentrations.

Animals↗