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Biomedical subjects

A J Jackson

Publications and source records attributed to A J Jackson.

At least 19 recordsLinked to original sources
PubMed1995

The role of metabolites in bioequivalency assessment. II. Drugs with linear pharmacokinetics and first-pass effect.

Simulations were conducted to address the question of whether metabolite data are required for bioequivalence evaluation of immediate release formulations with drugs exhibiting linear pharmacokinetics and first-pass effect. Plasma level-time profiles were generated for parent drug and metabolite using relevant rate constants obtained from a bivariate normal distribution and designated random error. Simulation results showed that the need for metabolite data (Cmax) in the assessment of bioequivalence depends on the relative variability between the absorption process of the drug and first-pass route for metabolite(s). The importance of metabolite Cmax data in the evaluation of rate of availability is clearly demonstrated for drugs with a high degree of intra-subject variation in the first-pass metabolism compared to the absorption process of the drug. Under such conditions, a wider confidence interval was found for the metabolite rather than parent drug. Opposite results were obtained when the intra-subject variance was high for drug absorption relative to first-pass effect. Discrepancies were observed for the scenarios in which the elimination pathway of the metabolite is more variable than the absorption process of the drug. The simulation results were in agreement with real bioequivalence data. It is thus recommended that, in the absence of the information on the relative variability of absorption and first-pass process, both parent drug and metabolite data be included for documentation of bioequivalence, should the metabolite(s) play an important role in the determination of efficacy and safety of the drug.

Absorption↗
PubMed1995

The BN51 protein is a polymerase (Pol)-specific subunit of RNA Pol III which reveals a link between Pol III transcription and pre-rRNA processing.

The three eukaryotic nuclear RNA polymerase (Pol) contain common and unique subunits. Cloning of the unique Pol III subunit genes in yeast cells has revealed a potential homolog in the mammalian system, the BN51 gene. The human BN51 gene was originally isolated as a suppressor of a temperature-sensitive cell cycle mutant of BHK cells (tsBN51). Although tsBN51 cells have a marked decrease in RNA Pol III activity at the nonpermissive temperature, direct biochemical evidence for the BN51 protein being a human Pol III subunit was lacking. Using antibodies directed against the BN51 protein, we show the following: (i) the BN51 protein copurifies with Pol III activity, (ii) Pol III activity can be specifically immunoprecipitated from HeLa nuclear extracts, and (iii) the immunopurified BN51 complex is active in restoring both nonspecific and promoter-specific Pol III activity. Our findings provide direct biochemical evidence for BN51 being a Pol III-specific subunit. Despite the fact that BN51 is not a subunit of Pol I, the production of mature Pol I transcripts is inhibited in tsBN51 cells at the nonpermissive temperature. tsBN51 cells appear defective in processing the 32S precursor rRNA into mature 5.8S and 28S rRNA at the nonpermissive temperature. We surmise that ribosome assembly has halted because of the loss of Pol III transcripts. Thus, there is regulation of the synthesis of mature Pol I transcripts by a posttranscriptional mechanism based on the availability of Pol III transcripts.

HeLa Cells↗
PubMed1995

Morphometric analysis of corneal endothelial giant cells in normal and traumatized corneas.

Corneal endothelial cells from normal and traumatized human, primate, cat and rabbit eyes were studied by specular microscopy. Morphometric analysis was performed on micrographs of corneal endothelium using a semi-automated image analysis system. The results showed that under normal conditions the corneal endothelium of all four species exhibit major morphological similarities (mean cell areas: human 317 +/- 32 microns 2, primate 246 +/- 22 microns2, cat 357 +/- 25 microns 2, rabbit 308 +/- 35 microns 2). The normal corneal endothelium in man was found to be more polymegethous than that of the other species. Trauma to cat, primate and human corneas resulted in a long-term reduction in endothelial cell density and enhanced polymegethism. In contrast, the reparative response of the rabbit ensured the reformation of an essentially normal monolayer following injury. Endothelial giant cells were a normal inclusion in the rabbit corneal endothelium but were only significant in cat, primate and man following trauma. The presence of corneal endothelial giant cells in amitotic corneas may therefore represent a compensatory response in the absence of mitotic potential.

Adult↗
PubMed1994

Comparison of single and multiple dose pharmacokinetics using clinical bioequivalence data and Monte Carlo simulations.

The purpose of this study was to evaluate the relative performance and usefulness of single dose (SD) and multiple dose (MD) regimens for bioequivalence (BE) determination. Drugs such as indomethacin, procainamide, erythromycin, quinidine, nifedipine were tested for BE under SD and MD dose regimens. Drugs characterized by low accumulation indices (AI) showed virtually no change in the 90% confidence interval (CI) of AUC and CMAX upon multiple dosing. On the other hand, drugs with higher AI appeared to have smaller CI at steady-state. For example, the CI range of AUC and CMAX of quinidine (AI of 1.54) decreased from 26 to 12 and from 22 to 12, respectively, upon multiple dosing. A Monte Carlo simulation study of SD and MD bioequivalence trials was performed. The probability of failing the bioequivalence test was evaluated for several situations defined by different levels of variability and correlation in ka constants, presence or absence of inter- and/or intra-individual variability in clearance (CL) and volume of distribution (V), and different degrees of accumulation. All the possible combinations of these factors were tested with SD and MD study designs. All simulations used 1000 data sets with 30 subjects in each data set for a total of 144 unique designs (total of 144,000 simulations of bioequivalence trials). Upon multiple dosing, narrowing of CI ranges was observed for drugs simulated to have high AI high variability and a large difference in absorption constants (ka) between test and reference formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Paradoxical inhibition by aspirin of naloxone-induced adrenocorticotropin secretion in myotonic dystrophy.

The ACTH response to endogenous or exogenous CRH is increased in patients with myotonic dystrophy (DM), possibly because of abnormal function of cAMP-dependent protein kinases in this condition. Arachidonic acid (AA) metabolites are believed to interact with the cAMP-dependent second messenger system activated by CRH; therefore, drugs that interfere with AA metabolism may alter ACTH secretion in DM. In this study, seven DM patients were given naloxone, which stimulates endogenous CRH release, and aspirin, which inhibits the synthesis of prostaglandins from AA via the cyclooxygenase metabolic pathway. Pretreatment with aspirin reduced the mean integrated ACTH response to naloxone by 33% (P < 0.05). However, the corresponding 18% reduction in cortisol levels was not statistically significant (P > 0.10). These findings are in contrast to those of a previous study using an identical protocol, in which aspirin increased the ACTH response to naloxone in six normal volunteers. This difference between DM and control subjects is consistent with the hypothesis that the interaction between AA metabolites and the cAMP-dependent protein kinase-A second messenger system is abnormal in the corticotrophs of persons with DM.

Adrenocorticotropic Hormone↗
PubMed1994

Ophthalmic, health and social profile of guide dog owners in Northern Ireland.

Only 96 out of an estimated 28,000 registerable visually impaired persons, resident in Northern Ireland, currently make use of guide dogs for the blind. Results from this study indicate that guide dog owners represent a young, healthy and highly motivated subgroup of blind persons who have been profoundly visually impaired for prolonged periods of time. The implications of future ophthalmological developments, and of the educational and employment requirements of the visually impaired, are discussed.

Adolescent↗
PubMed1993

Aspirin increases the human hypothalamic-pituitary-adrenal axis response to naloxone stimulation.

Prostaglandins are believed to influence hypothalamic-pituitary-adrenal (HPA) axis function, but their specific effects on ACTH and cortisol secretion in humans are unclear. Acetylsalicylic acid (aspirin) blocks the synthesis of prostaglandins from arachidonic acid. We studied the effects of oral aspirin on the plasma ACTH and cortisol responses to iv naloxone, which increases endogenous CRH release, in six normal volunteers and on the adrenocortical response to synthetic ACTH boluses in seven other healthy subjects, using placebo-controlled, single blinded protocols. Aspirin pretreatment significantly increased the ACTH response to naloxone [mean peak increase from basal, 8.3 +/- 1.2 vs. 5.9 +/- 0.8 pmol/L (P < 0.05); mean integrated response, 431.9 +/- 51.5 vs. 295.1 +/- 26.6 pmol/L.min (P < 0.005); for aspirin/naloxone and placebo aspirin/naloxone, respectively]. However, the corresponding cortisol results did not show statistically significant differences (P < 0.20). The mean integrated ACTH and cortisol responses were 46% and 26% greater with aspirin, respectively. Aspirin did not influence the cortisol responses to synthetic ACTH administration given according to a dose-response protocol. We conclude that aspirin augments the HPA axis response to naloxone stimulation in normal humans without having a direct effect at the adrenal level. The action of aspirin on the human HPA axis is probably mediated via inhibition of cyclooxygenase, resulting in changes in arachidonic acid metabolites, which influence ACTH release from corticotrophs.

Adrenocorticotropic Hormone↗
PubMed1992

CRH-mediated pituitary-adrenal responses are inhibited by nifedipine in humans.

Sustained CRH-stimulated ACTH release in vitro depends on Ca2+ influx and is inhibited 30-40%, but not delayed, by dihydropyridine Ca2+ channel blockers. In five normal humans, we found that nifedipine pretreatment reduced integrated ACTH responses to the CRH-mediated stimulus of fenfluramine by 28% and cortisol responses by 34%, results comparable with those from in vitro reports. Nifedipine did not alter the timing of peak hormonal responses. We conclude that (1) in humans, nifedipine inhibits ACTH release by fenfluramine by blocking Ca2+ influx via L-type channels in corticotrophs; (2) the magnitude of fenfluramine-stimulated CRH release is probably unaltered by nifedipine and (3) because the timing is unaltered, nifedipine does not affect the rate of CRH delivery to the corticotroph.

Adrenocorticotropic Hormone↗
PubMed1991

Easy and practical utilization of CONSAM for simulation, analysis, and optimization of complex dosing regimens.

Complex dosing regimens simulated in the literature using a universal dosing regimen were calculated with a general dosing program developed using the program CONSAM. The program provides a rapid method of calculating nonuniform dosing regimens for up to n = 3 compartments for any linear model. Subject data can also be curve fitted with the program to obtain individual subject estimates to allow for dosage optimization, which is important in a clinical setting. Examples are presented to show the use of the program in optimizing a theophylline regimen, as well as estimation of a new parameter, Cuneq(T), which is defined as the average non-steady-state drug concentration at time t for a drug with an irregular dosing interval.

Computer Simulation↗
PubMed1991

Suitability of various noninfinity area under the plasma concentration-time curve (AUC) estimates for use in bioequivalence determinations: relationship to AUC from zero to time infinity (AUC0-INF).

The influence of random error and elimination rate on estimates of the area under the curve from zero to time infinity (AUCO-INF) was determined in a simulation study using noninfinity measured AUC values (i.e. AUCTM, area to a measured common sampling time, and AUCO-LAST, area to the last measured sampling time). Further, the extent of absorption of generic danazol, baclofen, and oxazepam was determined using measured methods of estimating area under the curve in bioequivalence studies. The noninfinity AUC estimates and their 90% confidence intervals for the difference in product means were compared for each individual drug. Products chosen fulfilled one of the following three criteria: (1) a high "apparent intrasubject variability" and a half-life greater than 8 hr (danazol); (2) a low apparent intrasubject variability and a half-life less than 4 hr (baclofen); and (3) products exhibiting a low apparent intrasubject variability and a half-life greater than 8 hr (oxazepam). For the simulated data, AUCTM performed best when subjects had similar half-lives (i.e., low variability), which results in AUCTM = AUCO-LAST. On the other hand, AUCO-LAST worked best with a high fractional standard deviation (fsd) and a short elimination half-life (i.e., less than 4 hr). The noninfinity 90% confidence intervals for danazol and oxazepam were inconsistent with those observed at AUCO-INF.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

The role of metabolites in bioequivalency assessment. I. Linear pharmacokinetics without first-pass effect.

The estimation of bioequivalency using metabolite data was investigated for immediate release formulations with drugs exhibiting linear pharmacokinetics and no first-pass effect. This was accomplished by generating parent drug and metabolite plasma level profiles assuming formation and excretion rate-limited pharmacokinetic models with absorption rate constants obtained from bivariate normal distributions and designated random errors. Simulation results indicated that bioequivalence determination using Cmax of parent drug and metabolite was independent of the metabolite models as evaluated by confidence interval approach. However, a clear difference with respect to the outcome of bioequivalence evaluation arises depending upon the utilization of Cmax values for the parent drug and metabolite. The major reason for this disparity was attributed to the minimal effect of the absorption process for the parent drug on the formation of the metabolite. This phenomenon results in an apparent lower intrasubject variability for Cmax of the metabolite and, in turn, a tighter confidence interval for Cmax of the metabolite in comparison with the parent drug. The simulated results have been found to be in agreement with the bioequivalency data for acetohexamide, allopurinol, procainamide, and sulindac. In all cases, the interval of the 90% confidence limit for Cmax of the metabolite is always smaller than that of the parent drug, regardless of the drug pharmacokinetics and the level of error contained in the data.

Acetohexamide↗
PubMed1991

The provision of ophthalmic services for a rehabilitation day care centre population with multiple physical handicaps.

The provision of the wide variety of support services necessary for patients with multiple handicaps is often poorly coordinated. In this study a group of 108 adults, aged from 19 to 90 years, who suffered from multiple physical handicaps and attended a rehabilitation day care centre, had their visual functions and requirements assessed by a multidisciplinary team. The programme consisted of five stages. Each patient was initially screened and subsequently referred for more detailed optometric, ophthalmological, low vision or rehabilitation assessments, where appropriate. Results indicated that many of the patients had not been receiving regular ocular assessments and would benefit from the provision of an optical appliance or ophthalmological treatment. The survey provided staff at the rehabilitation centre with information on the visual status of individual patients and enhanced general eye-care awareness.

Adult↗
PubMed1990

Naloxone-induced ACTH release in man is inhibited by clonidine.

1. Adrenergic mechanisms play an important role in regulation of ACTH release. We used the alpha 2-adrenergic agonist, clonidine, as a central nervous system inhibitor of ACTH release to see if it would alter naloxone-induced ACTH secretion in normal human volunteers. 2. There was a significant blunting of the mean peak level of ACTH and the mean peak change of ACTH from basal as well as the area under the ACTH-time curve when clonidine was given prior to naloxone. 3. We conclude that clonidine, by blocking central noradrenergic pathways, which stimulate corticotropin-releasing hormone secretion, inhibits naloxone-induced ACTH secretion. This suggests that naloxone causes ACTH release through these same central noradrenergic pathways.

Administration, Oral↗