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Biomedical subjects

K J Cooper

Publications and source records attributed to K J Cooper.

At least 19 recordsLinked to original sources
PubMed2006

Lack of immunogenicity of ice structuring protein type III HPLC12 preparation administered by the oral route to human volunteers.

Before a novel protein can be used in foods, its potential allergenicity must be assessed. In this study, healthy volunteers consumed ice structuring protein (ISP) Type III preparation or a control material 5 days a week for a total of 8 weeks. General measures of health were recorded during the study, and the immunogenicity of the protein was assessed by monitoring the levels of IgG and IgE antibodies specific for ISP Type III. The participants remained in good health throughout the study and during the 4 week follow-up period. No IgG or IgE antibodies specific for ISP Type III were detected in the blood of the participants. Investigations of immunogenicity in man have not been previously applied in the context of safety evaluation and they do not form part of the regimens proposed for the evaluation of protein allergenicity. Consequently no standardised protocols exist for such studies, nor any background against which to interpret the results. Nevertheless, the absence of an immune response using a protocol which could have been expected to result in a response with a strongly immunogenic protein, confirms the conclusions of earlier published work, and attests to the lack of allergenicity of ISP Type III preparation.

Adjuvants, Immunologic↗
PubMed2003

The effect of erythromycin on the pharmacokinetics of rosuvastatin.

RATIONALE OBJECTIVE: To examine in vivo the effect of erythromycin on the pharmacokinetics of rosuvastatin [an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase]. Erythromycin is a potent inhibitor of CYP3A4 that markedly increases circulating levels of some other HMG-CoA reductase inhibitors. METHODS: In this randomised, double-blind, two-way cross-over, placebo-controlled trial 14 healthy volunteers were given 500 mg erythromycin or placebo four times daily for 7 days. A single dose of 80 mg rosuvastatin was co-administered on day 4 of dosing. Plasma concentrations of rosuvastatin and active and total HMG-CoA reductase inhibitors were measured up to 96 h after dosing. RESULTS: Eleven volunteers had data available from both dosing periods. There was no increase in rosuvastatin plasma exposure following co-administration with erythromycin compared to placebo. In fact, following co-administration with erythromycin, rosuvastatin geometric least square mean AUC((0-t)) and C(max) were 20% and 31%, respectively, lower than with placebo. Individual treatment ratios for AUC((0-t)) ranged from 0.48 to 1.17, and for C(max) ranged from 0.33 to 2.19. Essentially all of the circulating active HMG-CoA reductase inhibitors and most (>94%) of the total inhibitors were accounted for by rosuvastatin. Erythromycin did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Erythromycin did not produce any increase in rosuvastatin plasma exposure. This indicates that CYP3A4 metabolism is not an important clearance mechanism for rosuvastatin, a result consistent with previous findings. The small decreases in rosuvastatin AUC((0-t)) and C(max) that occurred as a consequence of short-term treatment with erythromycin are unlikely to have relevance to long-term treatment with rosuvastatin.

Adult↗
PubMed2002

The effect of fluconazole on the pharmacokinetics of rosuvastatin.

OBJECTIVE: To examine the effect of fluconazole, a potent inhibitor of CYP2C9 and CYP2C19, on the pharmacokinetics of rosuvastatin in healthy volunteers. Significantly increased plasma concentrations of fluvastatin have been observed following co-administration with fluconazole. METHODS: This was a randomised, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers ( n=14) were given fluconazole 200 mg or matching placebo once daily for 11 days; rosuvastatin 80 mg was co-administered on day 8 of dosing. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 96 h post-dose. RESULTS: Following co-administration with fluconazole, rosuvastatin geometric least-square mean area under the plasma concentration-time curve (AUC(0-t)) and peak plasma concentration (C(max)) were increased by 14% and 9%, respectively, compared with placebo (90% confidence intervals for the treatment ratios: 0.967 to 1.341 and 0.874 to 1.355, respectively). Individual treatment ratios for AUC(0-t) ranged from 0.59 to 2.23, and for C(max) ranged from 0.52 to 2.28. The limited data available for the N-desmethyl metabolite show that geometric mean C(max) was decreased by approximately 25% compared with placebo. Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (>90%) of the total inhibitors. Fluconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Fluconazole produced only small increases in rosuvastatin AUC(0-t) and C(max), which were not considered to be of clinical relevance. The results support previous in-vitro findings that CYP2C9 and CYP2C19 metabolism is not an important clearance mechanism for rosuvastatin.

Administration, Oral↗
PubMed2001

Prediction of ocular irritancy of prototype shampoo formulations by the isolated rabbit eye (IRE) test and bovine corneal opacity and permeability (BCOP) assay.

The isolated rabbit eye (IRE) test and bovine corneal opacity and permeability (BCOP) assay were evaluated for their ability to predict the eye irritation potential of a range of hair shampoo formulations, some containing a novel non-surfactant ingredient known to be an ocular irritant. The additional endpoints of corneal swelling and histological examination were incorporated into the standard BCOP protocol. Historic Draize data were available for several of the formulations and served as a reference. The standard BCOP assay (without histology) failed to distinguish between shampoos of low and high irritant potential, when exposure times of 10 and 60 min were employed (for undiluted and 10% dilution of the shampoos, respectively) and the in vitro score classified the majority of formulations as mild. The incorporation of the histological endpoint to the BCOP protocol allowed discrimination between formulations of differing irritancy, and should be included to augment the standard BCOP protocol. Corneal swelling values did not, however, correlate with the irritant potential of the shampoos tested. The IRE which includes the endpoints of corneal swelling and histopathological scoring produced classifications of irritancy that were fairly consistent with in vivo data and distinguished between the high and low irritant potential shampoos.

Animal Testing Alternatives↗
PubMed1999

Identification of metal allergens in the local lymph node assay.

BACKGROUND: The murine local lymph node assay (LLNA) has recently been endorsed as a validated alternative to guinea pig methods for the identification of skin sensitization hazard. Nevertheless, there has been some debate regarding the utility of this method for the detection of metal contact allergens. OBJECTIVE: In these investigations, we have used the LLNA to determine the skin sensitization potential of 13 metal salts, 8 of which were considered to possess a significant ability to sensitize man, whereas the remaining 5 were judged to lack such potential. RESULTS: The predictions from the LLNA were correct for 7 of the 8 (88%) sensitizing metals and for 4 of the 5 (80%) nonsensitizers when considered against the experience of these metals as human skin sensitizers. Thus, the overall predictive accuracy of the LLNA in relation to metals was 11/13 (85%), which is very similar to the accuracy of approximately 88% in relation to a much larger number of low-molecular-weight organic chemicals, as reported previously. CONCLUSION: These data provide support for the potential utility of the LLNA in hazard identification of metal contact allergens.

Allergens↗
PubMed1997

The effect of food on the pharmacokinetics of the bicalutamide ('Casodex') enantiomers.

'Casodex' (bicalutamide) is an orally active, non-steroidal, pure antiandrogen; it is a racemate with antiandrogenic activity residing predominantly in the (R)-enantiomer. Healthy male volunteers (n = 15) were administered single oral doses of bicalutamide (50 mg) after food and after fasting as part of a three-treatment, three-period, randomized cross-over study, with a 9 week washout. After fasting, plasma concentrations of (R)-bicalutamide were much higher than those of (S)-bicalutamide; the mean (R)-enantiomer Cmax (734 ng mL-1) was about nine times higher than the (S)-enantiomer value (84 ng mL-1). The corresponding tmax values were 19 and 3 h for (R)- and (S)-bicalutamide, respectively. Elimination of (R)-bicalutamide from plasma was monoexponential and slow (t1/2 = 5.8 d). Elimination of (S)-bicalutamide was biphasic in some volunteers but monophasic in others (terminal t1/2 =1.2 d; n = 11). There was no significant effect of food on AUC, tmax, or t1/2 data for either enantiomer. The observed slightly higher values of Cmax for (R)-bicalutamide (14%) and (S)-bicalutamide (19%), when dosing with food, achieved statistical significance. However, differences of this magnitude are unlikely to to be of any clinical relevance. These data indicate that 'Casodex' can be taken without reference to meal times; this may be of particular relevance for its indication in a disease of the elderly.

Administration, Oral↗
PubMed1995

Enantioselective metabolism and pharmacokinetics of Casodex in the male rat.

1. Casodex, a non-steroidal antiandrogen, is a racemic mixture of R-Casodex, the pharmacologically active (-)-enantiomer, and S-Casodex, the inactive (+)-enantiomer. Single oral doses of pseudo-racemic 14C-Casodex (10 mg/kg), prepared from mixtures of either 14C-labelled R-Casodex and unlabelled S-Casodex, or 14C-S-Casodex and unlabelled R-Casodex, were administered to the intact and bile duct-cannulated male rat. 2. Neither enantiomer underwent stereochemical inversion, but the pharmacokinetics of Casodex showed marked enantioselectivity. 3. After dosing R-labelled Casodex, plasma concentrations of R-Casodex increased slowly to reach a peak of 3.50 +/- 0.05 micrograms/ml (mean +/- SEM) at 12 h and, thereafter, declined monoexponentially with an elimination half-life of 24 h. Plasma concentrations of S-Casodex rose rapidly to reach a much lower peak of 0.97 +/- 0.06 microgram/ml at 3 h and, thereafter, declined rapidly, although there were insufficient data to determine the half-life. R-Casodex had a much higher AUC0-24 (66 micrograms.h/ml) than S-Casodex (12 micrograms.h/ml). Plasma drug concentrations measured using an achiral assay were in very good agreement with the sum of the enantiomer concentrations throughout the profile. R-Casodex comprised 94% of the total plasma radioactivity at 12 h, decreasing to 75% at 120 h. 4. Plasma concentration data generated after administration of S-Casodex were similar to those observed after dosing R-labelled Casodex. S-Casodex comprised about 74% of the total plasma radioactivity at 6 h and only 41% at 24 h. 5. The urine of intact animals contained 36 +/- 2 and 48 +/- 3% of the dose respectively up to 48 and 120 h after dosing with R-labelled Casodex, and 33 +/- 4 and 34 +/- 4% respectively after dosing with S-labelled Casodex. The urine and bile of the cannulated rat contained 43 +/- 2 and 21 +/- 2% of the dose respectively up to 48 h after dosing with R-labelled Casodex and 37 (n = 2) and 50% respectively after dosing with S-labelled Casodex. 6. After dosing with R- or S-labelled Casodex, the urinary radioactivity consisted of the carboxylic acid metabolite formed by hydrolytic cleavage at the amide, whereas biliary radioactivity consisted of hydroxy-Casodex and Casodex, mainly conjugated with glucuronic acid. The clearance of R-Casodex by each of these pathways of metabolism was less than that of S-Casodex, with direct glucuronidation and hydroxylation showing greater enantioselectivity than hydrolysis.

Androgen Antagonists↗
PubMed1994

Inclusion of older adults with mental retardation in leisure opportunities.

Leisure satisfaction is associated with life satisfaction for older Americans. For those with mental retardation, obtaining inclusive leisure opportunities can be impeded by changes in health and social status, limited access to the community, underdeveloped leisure skills, and the need for support to participate in leisure opportunities. These challenges can be overcome through support for inclusion in the varied leisure opportunities generally available for older adults. Making such support possible may require conversion of traditional resources, such as adult day programs. We described the transition of one program towards providing support for inclusive leisure and made recommendations for future practice and research.

Aged↗
PubMed1993

The pharmacokinetics of Casodex enantiomers in subjects with impaired liver function.

1. Casodex is a novel non-steroidal antiandrogen being developed for the treatment of prostatic cancer. The antiandrogenic activity is predominantly in the R(-) enantiomer with little, if any, activity in the S(+) enantiomer. 2. The pharmacokinetics of the enantiomers of Casodex have been investigated over 28 days following a single oral dose of Casodex (50 mg) to 10 male subjects with histologically verified liver cirrhosis or fatty liver with fibrosis. Ten age matched male subjects with normal hepatic function served as a control group. 3. For both groups plasma concentrations of (S)-Casodex were lower than those for (R)-Casodex; this difference was about 10-fold at early time points and increased to about 25-fold by 24 h after dosage. 4. The kinetics of (R)-Casodex were similar in subjects with and without liver disease (Cmax: 750 vs 848 ng ml(-1); tmax: 24 - 30 h; t(1/2): 7.40 vs 7.22 days; AUC: 182 vs 225 microg ml(-1) h). 5. The kinetics of (S)-Casodex could not be described in the majority of subjects; in the remainder the mean terminal phase half-life for both groups was less than 1 day.

Androgen Antagonists↗
PubMed1991

The pharmacokinetics of Casodex in laboratory animals.

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs. 2. The binding of 14C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values greater than 95%; in dog there was evidence for decreased binding at concentrations greater than 12 micrograms/ml. 3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1 mg/kg to 10% and 12% at 250 mg/kg; in dog bioavailability decreased from 100% at 0.1 mg/kg to 31% at 100 mg/kg. 4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10 mg/kg but not at 250 mg/kg; in dog appreciable accumulation (9-12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10 mg/kg, but at 100 mg/kg the accumulation ratio was much lower (4-fold).

Administration, Oral↗
PubMed1990

The pharmacokinetics of Casodex in prostate cancer patients after single and during multiple dosing.

The pharmacokinetics of Casodex have been investigated in patients with prostatic carcinoma following single oral doses of 10 mg, 30 mg and 50 mg and during daily administration at these dose levels. Casodex displays prolonged absorption following a single dose, with peak plasma concentrations observed at up to 8 h for doses of 10 mg and 30 mg and up to 48 h for the 50 mg dose. The area under the plasma concentration-time curve increased linearly with dose, and Casodex was eliminated slowly from plasma (t1/2 about 6 days). During daily administration, Casodex accumulates about 10-fold in plasma at all dose levels; this is consistent with its long plasma elimination half-life, estimated by curve fitting of these multiple dose data to be 7-10 days. Trough plasma concentrations increased linearly with dose after both single and multiple dosing, achieving mean values of 1.80, 6.89 and 9.33 micrograms/ml for the 10 mg, 30 mg and 50 mg dose levels, respectively, after 12 weeks' dosing. Neither efficiency of renal function nor age had any apparent effect on the pharmacokinetics of Casodex. The pharmacokinetics of Casodex make it ideally suited to once-daily administration.

Absorption↗
PubMed1975

Augmentation of pituitary responsiveness to luteinizing hormone/follicle stimulating hormone-releasing factor (LH-RF) as a result of acute ovariectomy in the four-day cyclic rat.

Within 6 h of ovariectomy in adult rats with 4-day estrous cycles, plasma FSH titers were significantly elevated above those of sham-operated controls at all stages of the estrous cycle, whereas plasma LH concentrations were raised by ovariectomy only during diestrus day 2, proestrus or estrus. A single intravenous injection of a partially purified extract of ovine stalk-median eminence tissue (LH-RF) into sham-operated control rats or incubation of pituitaries from similar rats with the same releasing factor extract elevated LH and FSH output at all stages of the cycle. This response to LH-RF was related to the stage of the estrous cycle, maximal pituitary responsiveness occurring on proestrus. Ovariectomy 6 h before administration of LH-RF significantly augmented pituitary LH and FSH responsiveness both in vivo and in vitro. This elevation in hypophyseal responsiveness observed in vitro followed a cyclic pattern which could be superimposed on the normal cyclic changes in pituitary responsiveness, whereas the cyclic increase in pituitary LH responsiveness to LH-RF in vivo following acute ovariectomy was first detectable 16 to 18 h earlier than in intact controls, that is, on late diestrus day 2 rather than on the morning of proestrus. These results indicate that acute ovariectomy can augment pituitary responsiveness to LH-RF and can also advance the onset of the cyclic augmentation of pituitary responsiveness to LH-RF during the 24 h immediately preceding the ovulatory gonadotropin surge. Possible explanations for these effects are discussed.

Animals↗