Biomedical subjects

O N Keene

Publications and source records attributed to O N Keene.

16 recordsLinked to original sources

PubMed2000

Impact of zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults.

BACKGROUND: Influenza infections commonly lead to respiratory tract complications that result in antibiotic treatment. OBJECTIVES: To determine frequency of respiratory events leading to antibiotic use following influenza illness in adolescents and adults, and to assess whether treatment with topical zanamivir prevents these complications. METHODS: Meta-analysis of 7 randomized, double-blind, placebo-controlled trials; 3815 mainly healthy adolescents and adults (mean age, 34 years) with an influenzalike illness of less than 2 days' duration were randomly assigned to receive combined inhaled and intranasal zanamivir, inhaled zanamivir, or corresponding placebos. Twelve percent of enrolled subjects were high-risk patients. The main outcome was the incidence of respiratory events leading to antibiotic prescriptions in patients with proven influenza. RESULTS: Influenza infections were laboratory confirmed in 2499 (66%) of 3815 patients (influenza A in 88% and B in 12%). Placebo recipients developed a respiratory event leading to antibiotic use in 17% of cases, mainly for acute bronchitis or acute sinusitis. Among zanamivir-treated patients (n = 1494) the incidence of respiratory events leading to the use of antimicrobials was 11% (relative risk [RR] compared with placebo, 0.69; 95% confidence interval [CI], 0.57-0.84). Intranasal and inhaled zanamivir seemed to reduce the number of upper (RR, 0.59; 95% CI, 0.36-0.97) and lower respiratory tract events (RR, 0.64; 95% CI, 0.38-1.08). Inhaled zanamivir reduced the number of lower respiratory tract events (RR, 0.60; 95% CI, 0.42-0.85), but the reduction in the number of upper respiratory tract events was not statistically significant (RR, 0.90; 95% CI, 0.63-1.27). CONCLUSIONS: Respiratory complications or worsening of symptoms leading to antibiotic use occurred in about 17% of adolescents or adults with influenza infection. Early treatment of influenza illness with zanamivir reduced the number of these antibiotic prescriptions. Arch Intern Med. 2000;160:3234-3240.

Acute Disease↗

PubMed2000

Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study.

OBJECTIVES: To assess the clinical efficacy and safety of orally inhaled zanamivir in the treatment of influenza in a European primary care setting. METHODS: This was a randomized, double-blind, placebo-controlled trial in primary care and hospital clinics in 11 European countries. Patients aged > or = 12 years were recruited within 2 days of onset of typical influenza symptoms and received orally inhaled zanamivir 10 mg via a Diskhaler twice daily for 5 days or matching placebo. Influenza symptoms and temperature were recorded daily for 14 days. The primary endpoint was time to alleviation of clinically significant symptoms of influenza. Other endpoints included symptom severity, use of relief medications, time to return to normal activities, complications and investigator's assessment of symptoms. RESULTS: A total of 356 patients were recruited; 277 (78%) had laboratory-confirmed influenza and 32 (9%) were considered high-risk (i.e. elderly or with underlying medical conditions). Zanamivir significantly reduced the time to alleviation of symptoms versus placebo (median 5 days versus 7.5 days, P<0.001), a 33% reduction in duration of illness. Zanamivir significantly reduced the severity of several symptoms; improvements versus placebo were discernible after approximately 24 h. The proportion of patients who were afebrile after 24 h increased by 46% versus placebo. Similar treatment benefits were observed in the high-risk patients. Zanamivir was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: Zanamivir is effective in reducing the duration and severity of influenza illness and is well tolerated. Zanamivir should therefore be a clinically valuable intervention in the management of influenza.

Adolescent↗

PubMed1999

Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections.

The efficacy and safety of zanamivir, administered 2x or 4x daily over 5 days, was evaluated in the treatment of influenza infections. A total of 1256 patients entered the study; 57% of those randomized had laboratory-confirmed influenza infection. The primary end point, "alleviation of major symptoms," was created to evaluate differences in clinical impact. In the overall population with or without influenza infection, zanamivir reduced the median number of days to reach this end point by 1 day (P=.012 2x daily vs. placebo; P=.014 4x daily vs. placebo). The reduction was greater in patients treated within 30 h of symptom onset, febrile at study entry, and in defined high-risk groups. Zanamivir reduced nights of disturbed sleep, time to resumption of normal activities, and use of symptom relief medications. It was well tolerated. These results suggest that zanamivir can significantly reduce the duration and overall symptomatic effect of influenza.

Adult↗

PubMed1998

Evaluation of different partial AUCs as indirect measures of rate of drug absorption in comparative pharmacokinetic studies.

The performance of different partial AUCs, including partial AUC from zero to t(max) of the reference formulation (AUC(r)) and partial AUC from zero to tmax of test or reference formulation, whichever occurs earliest (AUC(e), as indirect measures of rate of absorption have been evaluated using simulated experiments. The performance of these metrics relative to C(max), t(max) and C(max)/AUC(infinity) was further assessed using the results of actual studies involving a Glaxo drug. The normalised metrics AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) have also been evaluated. Our provisional conclusions were: (1) AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) had greater statistical power than C(max) and the non-normalised partial AUCs at detecting true differences in rate of absorption. Using real data, the performance of AUC(e)/AUC(infinity) was poor, however, the performance of AUC(r)/AUC(infinity) was good; (2) C(max)/AUC(infinity) was more precisely estimated than AUC(r)/AUC(infinity) or AUC(e)/AUC(infinity) and may be a superior metric for assessing absorption rates of highly variable drugs.

Area Under Curve↗

PubMed1997

Common noncompartmental pharmacokinetic variables: are they normally or log-normally distributed?

We investigated the hypothesis that distributions of continuous pharmacokinetic variables are positively skewed in nature and that logarithmic transformation of these variables restores normality. The distributions of common continuous noncompartmental pharmacokinetic variables were investigated for four different Glaxo Wellcome compounds, administered by three different routes of administration: ranitidine (po), sumatriptan (sc), ondansetron (iv), and bismuth, from ranitidine bismuth citrate (po). The distributions of all the investigated noncompartmental pharmacokinetic variables were adequately described by a log-normal distribution, whereas statistically significant departures from normality occurred in the majority of cases. Thus, unless there is strong and consistent evidence for a departure from log-normality, the parametric statistical analysis of common noncompartmental pharmacokinetic variables should be carried out after a priori log transformation.

Bismuth↗

PubMed1996

The effect of ondansetron on the pharmacokinetics and pharmacodynamics of temazepam.

The objective of this study was to determine the effects of ondansetron on the pharmacokinetics of temazepam and on pharmacodynamics relevant to its use as oral premedication. Twenty-four healthy volunteers (12 of each sex) were administered the following oral treatments in a randomised, double-blind crossover design: temazepam 20 mg plus placebo; or temazepam 20 mg plus ondansetron 8 mg. Blood samples were taken for plasma temazepam assay at intervals up to 32 h after administration. In addition, a brief battery of psychomotor tests was administered 1 h prior to dosing and 1 and 4 h after dosing. Analysis of the derived pharmacokinetic parameters showed no differences between the treatments described above. Analysis of data from the dynamic measures likewise showed no difference between the treatments. It was concluded that the co-administration of ondansetron did not influence the pharmacokinetics or pharmacodynamic actions of temazepam.

Adult↗

PubMed1995

The log transformation is special.

The logarithmic (log) transformation is a simple yet controversial step in the analysis of positive continuous data measured on an interval scale. Situations where a log transformation is indicated will be reviewed. This paper contends that the log transformation should not be classed with other transformations as it has particular advantages. Problems with using the data themselves to decide whether or not to transform will be discussed. It is recommended that log transformed analyses should frequently be preferred to untransformed analyses and that careful consideration should be given to use of a log transformation at the protocol design stage.

Analysis of Variance↗

PubMed1995

Evaluation of different metrics as indirect measures of rate of drug absorption from extended release dosage forms at steady-state.

Bioequivalence assessment of extended release (ER) dosage forms is usually carried out at steady-state, using area under the curve (AUC) to evaluate extent of absorption and maximum concentration (Cmax) and % peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. Other metrics such as Cmax/AUC and partial AUCs have recently been proposed as alternatives for assessing the absorption rate of drugs from immediate release (IR) dosage forms under single dose conditions. The performances of these metrics were assessed using the results of two sets of simulated experiments of ER dosage forms at steady-state and 2 actual pharmacokinetic studies involving ER dosage forms of a Glaxo drug. In the first set of simulations there was no difference in bioavailability between the two formulations; in the second set of simulations the test formulation had a 50% greater absorption rate-constant (ka) than the reference formulation. The following conclusions were reached: 1. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, resulted in much smaller increases than the underlying 50% increase in ka. Although, %PTF gave the largest effect it was also the most imprecisely estimated. 2. In our studies, none of the metrics tested provided reliable information about changes in the underlying rate of absorption from ER dosage forms under steady-state conditions. 3. The current practice of comparing rate of absorption from ER dosage forms using steady-state Cmax is inappropriate due to lack of sensitivity. The use of %PTF may require a widening in the currently accepted 80-125% permissible range set for Cmax and AUC.

Absorption↗

PubMed1994

Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies.

As indirect measures of rate of drug absorption (metrics), maximum plasma concentration (Cmax) is confounded by extent of drug absorption and the time to reach Cmax (tmax) is a discrete variable, dependent on blood sampling frequency. Building on the work of Endrenyi et al., we have compared different metrics, including Cmax/area under the curve of concentration versus time from time zero to infinity (AUC infinity), partial AUC from zero to tmax (AUCp), and Cmax.tmax with simulated experiments. Importantly, the performance of these metrics was assessed with the results of actual pharmacokinetic studies involving Glaxo drugs. The results of the simulated and real experiments were consistent and produced the following unambiguous findings: (1) Cmax/AUC infinity is a more powerful metric than Cmax in establishing bioequivalence when the formulations are truly bioequivalent; (2) Cmax/AUC infinity is more sensitive than Cmax at detecting differences in rate of absorption when they exist; and (3) the treatment ratios for AUCp, AUCp/AUC infinity, and Cmax.tmax are very imprecisely estimated and are of no practical value as measures of rate of absorption. Of the metrics examined, Cmax/AUC infinity is the most sensitive and powerful indirect measure of rate of drug absorption in comparative pharmacokinetic studies involving immediate-release dosage forms and should be used instead of Cmax in bioequivalence testing.

Absorption↗

PubMed1994

Comparative pharmacokinetics of bismuth from ranitidine bismuth citrate (GR122311X), a novel anti-ulcerant and tripotassium dicitrato bismuthate (TDB).

GR122311X (ranitidine bismuth citrate, Glaxo Group Research Ltd.) is a salt of ranitidine with a complex of bismuth and citric acid which is being developed for the treatment of peptic ulceration. In this study, 4 groups of 12 healthy male subjects were dosed for 10 days with either GR122311X 500 mg bid (301 mg bismuth per day), GR122311X 1.0 g bid (602 mg bismuth per day), tripotassium dicitrato bismuthate (TDB, DeNoltab, Gist Brocades Ltd., Weybridge, England) 240 mg bid (431 mg bismuth per day) or placebo. After the last dose the geometric mean for Cmax for 500 mg bid of GR122311X was 5 ng.g-1, for 1.0 g bid GR122311X it was 12 ng.g-1 and it was 21 ng.g-1 for 240 mg TDB bid. The corresponding trough plasma levels were 2 ng.g-1, 4 ng.g-1 and 4 ng.g-1, respectively. The AUC over a dosing interval after the last dose (AUC tau) were 34 ng.h.g-1, 71 ng.h.g-1 and 79 ng.h.g-1, respectively. The bismuth urinary recoveries over the last dosing interval (Ae tau) were 97 micrograms, 227 micrograms and 309 micrograms, respectively, which is less than 1% of the administered doses. The renal clearance of bismuth was less than the glomerular filtration rate. After adjustment for bismuth dose, the Cmax for GR122311X 500 mg was 35% that of TDB, while for GR122311X 1.0 g the Cmax was 42% that of TDB. Similar differences were observed for Ae tau. In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Ae tau and Cmax, with a much narrower Cmax range than those observed for TDB.

Adolescent↗

PubMed1994

Does tachyphylaxis occur to the non-pulmonary effects of salmeterol?

1. The potential for tachyphylaxis to the non-pulmonary effects of salmeterol, a long-acting selective beta 2-adrenoceptor agonist was investigated in 12 healthy male subjects in a double-blind two period crossover study design. 2. Subjects received cumulative doses of up to 400 micrograms (50 + 50 + 100 + 100 + 100 micrograms at 45 min intervals) inhaled salmeterol prior to a 13 day dosing schedule of twice-daily inhaled salmeterol 100 micrograms or placebo. Twelve hours after the last dose of salmeterol or placebo, subjects again received cumulative doses of up to 400 micrograms inhaled salmeterol. 3. Pulse rate, blood pressure, 12-lead ECG, physiological tremor and peak expiratory flow rate (PEFR) were measured before administration of cumulative doses of salmeterol, at 10, 20, 30 and 40 min after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesium, non-esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4. Eleven subjects completed the study. One subject withdrew due to beta 2-adrenoceptor related adverse events. All other adverse events reported were mild in nature. 5. Dose-related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucose and plasma potassium were seen, but there was no dose-related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6. Tachyphylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1992

Effect of sumatriptan, a new selective 5HT1-like agonist, on liquid gastric emptying in man.

Paired studies were carried out on 12 healthy male subjects to compare the effect of intravenous doses of the 5-HT1-like agonist sumatriptan (GR43175; 3 mg), 10 mg metoclopramide and saline control on the rate of gastric emptying of a radiolabelled liquid test-meal. Intravenous administration of metoclopramide accelerated gastric emptying by decreasing the lag period, while intravenous administration of sumatriptan delayed gastric emptying by increasing the lag period. The observation that sumatriptan causes a delay in gastric emptying in normal healthy volunteers, but relieves nausea and vomiting during migraine attacks, suggests that sumatriptan may be acting via a central mechanism to relieve symptoms of nausea and vomiting associated with migraine.

Adult↗

PubMed1991

Peripheral and intracardiac levels of atrial natriuretic factor during cardiothoracic surgery.

Immunoreactive atrial natriuretic factor (ANF) levels were measured in blood taken from superior vena cava, right atrium, pulmonary artery, pulmonary vein, left atrium, and radial arteries in patients undergoing cardiac surgery. Significant (p less than 0.05) differences were seen between sites. Levels of atrial natriuretic factor were seen to rise from superior vena cava (27.5 pmol/L) to right atrium (54.3 pmol/L) and then fall in pulmonary artery (38.5 pmol/L). A further significant fall was seen in pulmonary vein (32.7 pmol/L) samples. There was no significant change in levels in left atrium (32.1 pmol/L) or radial artery (30 pmol/L). The fall between radial artery levels and superior vena caval levels was also significant. The rise from superior vena cava to right atrium is to be expected as this represents the major site of addition of atrial natriuretic factor to the circulation. We propose that the fall in levels from right atrium to pulmonary artery and from pulmonary artery to pulmonary vein suggests uptake and therefore possible local hormonal action on both right ventricle and pulmonary vasculature. The fall from radial artery to vena cava would be in keeping with atrial natriuretic factor's known systemic uptake and action.

Arm↗

PubMed1991

The pharmacokinetic and pharmacodynamic interaction between lacidipine and propranolol in healthy volunteers.

The pharmacokinetic and pharmacodynamic profiles of lacidipine, a 1,4-dihydropyridine calcium antagonist, and the beta-adrenoceptor blocker propranolol were determined alone and in combination in 24 healthy male volunteers. One group (I) of 12 subjects received a single oral dose of 4 mg lacidipine on two separate occasions, which was taken together with a single oral dose of either 160 mg propranolol or placebo; a second group (II) of 12 subjects received propranolol on two occasions, taken with either lacidipine or placebo. Propranolol significantly decreased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of lacidipine (by 38% and 42%, respectively) whereas lacidipine significantly increased the Cmax and AUC of propranolol (by 35% and 26%, respectively); neither the time to maximum plasma concentration (tmax) nor the terminal half-life (t 1/2) were affected. With regard to the pharmacodynamics, in Group I, there was a greater reduction in supine systolic blood pressure (6 mm Hg) and diastolic blood pressure (4 mm Hg) compared to the reduction produced by lacidipine alone, and pulse rate was approximately 5 beats/min less. In Group II, a significantly greater reduction (6 mm Hg) in supine systolic blood pressure compared to the reduction produced by propranolol alone occurred, but there was no marked difference in supine diastolic blood pressure and pulse rate. In conclusion, a modest pharmacokinetic and pharmacodynamic interaction is evident and should be evaluated further in patients with hypertension.

Administration, Oral↗

PubMed1991

The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan.

Clinical pharmacology studies were undertaken in young healthy volunteers, in a small number of elderly subjects and in migraine subjects during and between attacks. Absorption after subcutaneous and oral administration was rapid. Bioavailability was nearly 100% after subcutaneous administration and averaged 14% after oral administration. Elimination was predominantly by metabolism to a non-active indoleacetic acid analogue. The plasma half-lives of sumatriptan and the metabolite were about 2 h. Pharmacokinetic and pharmacodynamic variables were similar in all groups studied and were not altered by the presence of food, alcohol, dihydroergotamine or prophylactic migraine treatments. Sumatriptan produced a number of minor adverse events, but had no clinically significant effect on routine haematological or biochemical investigations using the intravenous, subcutaneous or oral routes. Transient rises in blood pressure were observed which were no greater than those that would be anticipated during moderate exercise. The physician-administered subcutaneous injection resulted in transient stinging at the site of injection in many subjects; administration using the auto-injector was better tolerated.

Aged↗

PubMed1990

Atrial natriuretic factor release in postoperative cardiothoracic surgical patients.

Immunoreactive atrial natriuretic factor (ANF) levels were measured preoperatively and for 5 days postoperatively in 22 patients undergoing cardiothoracic surgery. They were studied in 4 groups according to surgical procedure (mitral valve replacement, aortic valve replacement, coronary artery bypass grafting, and lung resection). The highest preoperative ANF levels were observed in the aortic valve group (mean 40.9 pmol/L) which were 2.5 (95% CI: 0.7 to 8.6) to 3.5 (95% CI: 0.9 to 13.9) times higher than the other groups. Values tended to peak on the 3rd and 4th postoperative days in all groups, although significantly elevated postoperative ANF concentrations occurred only in the coronary artery bypass group where the levels increased by a factor of 3.2 (95% CI: 1.3 to 7.5). As a separate part of the study, measurement of ANF release before, during, and after cardiopulmonary bypass in 6 patients tended to show a fall in ANF levels when on bypass, with a return to baseline levels on cessation of bypass.

Atrial Natriuretic Factor↗