Closure of the Thurso veterinary investigation centre.
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Animal Welfare↗
Biomedical subjects
B Holt
Publications and source records attributed to B Holt.
Estimating missing data: an iterative regression approach.
The problem of missing data is common in all fields of science. Various methods of estimating missing values in a dataset exist, such as deletion of cases, insertion of sample mean, and linear regression. Each approach presents problems inherent in the method itself or in the nature of the pattern of missing data. We report a method that (1) is more general in application and (2) provides better estimates than traditional approaches, such as one-step regression. The model is general in that it may be applied to singular matrices, such as small datasets or those that contain dummy or index variables. The strength of the model is that it builds a regression equation iteratively, using a bootstrap method. The precision of the regressed estimates of a variable increases as regressed estimates of the predictor variables improve. We illustrate this method with a set of measurements of European Upper Paleolithic and Mesolithic human postcranial remains, as well as a set of primate anthropometric data. First, simulation tests using the primate data set involved randomly turning 20% of the values to "missing". In each case, the first iteration produced significantly better estimates than other estimating techniques. Second, we applied our method to the incomplete set of human postcranial measurements. MISDAT estimates always perform better than replacement of missing data by means and better than classical multiple regression. As with classical multiple regression, MISDAT performs when squared multiple correlation values approach the reliability of the measurement to be estimated, e.g., above about 0. 8.
Animals↗
Optimizing the absorption of valspodar, a P-glycoprotein modulator, Part I: Selecting an oral formulation and exploring its clinical pharmacokinetics/dynamics.
Valspodar is a cyclosporine D analog used as a chemotherapy adjunct for modifying multidrug resistance. Two studies were sequentially performed to select an optimal oral formulation and to characterize selected aspects of its clinical pharmacokinetics/dynamics. An initial four-way crossover study with 20 volunteers compared the pharmacokinetics of single fasting administrations of 200 mg by intravenous infusion and 600 mg orally as a conventional oral solution, a microemulsion oral solution, and a microemulsion soft gelatin capsule. The two microemulsion dosage forms demonstrated significantly faster and less variable rates of absorption compared with the conventional oral solution. The microemulsion dosage forms were bioequivalent with absolute bioavailability nearly double that of the conventional oral solution. Based on these results, the microemulsion capsule was further investigated in a four-way randomized crossover study with 24 volunteers who received single fasting administrations of 200, 400, and 600 mg and a 400-mg administration after a fat-rich meal. Dose proportionality in area under the curve (AUC) was demonstrated over this dose range. Administration after a fat-rich meal caused a slight time lag until absorption began, a delay in time to reach the peak concentration, and a moderate increase of 24% in AUC. Serial determinations of total bilirubin were explored as a potential pharmacodynamic marker for P-glycoprotein inhibition. A similar magnitude of reversible hyperbilirubinemia was seen at all dose levels suggesting that P-glycoprotein inhibition in the biliary canaliculi was maximal even at the lowest dose tested. The microemulsion formulation (oral solution or soft gelatin capsule) represents an improved and less variable oral delivery form providing dose-proportional drug exposure over a clinically relevant dose range.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The effect of food on cabergoline pharmacokinetics and tolerability in healthy volunteers.
The effect of food on the pharmacokinetics and tolerability of cabergoline in man was investigated. For this purpose an open, randomized, single-dose study was conducted in 12 healthy male volunteers who received 1 mg cabergoline as tablets both under fasting conditions and after a breakfast containing a substantial amount of carbohydrates, fat, and proteins, in a crossover fashion. The two treatments were separated by a 4 week washout period. Plasma and urine were collected up to 336 and 168 h respectively after administration and cabergoline concentration was measured in both fluids using a validated radioimmunoassay. Tolerability assessment included haematology, blood chemistry, and urinalysis, blood pressure and heart rate measurements, and ECG. Under both fasting and fed conditions low but persistent cabergoline plasma levels were observed in the present study up to 2 weeks after drug intake, in agreement with the long-lasting prolactin-lowering activity of the drug. In subjects receiving cabergoline under fed or fasting conditions, Cmax values averaged 44 and 54 pg mL(-1), AUC(0-336 h) averaged 6392 and 5331 pg h mL(-1), Ae(0-168 h) averaged 12.7 and 11.9 micrograms, and t1/2 averaged 109.7 and 101.3 h, respectively. No statistically significant difference was found when Cmax, AUC(0-336 h), t1/2, and Ae(0-168 h) from subjects treated under fasting and fed conditions were compared. Median tmax values in subjects treated under fasting or fed conditions were identical (2.5 h). The statistical analysis applied to the parameters chosen to evaluate the variations in the blood pressure profiles observed either supine or standing did not show any significant difference between the fed and fasting conditions. Heart rate values were not significantly modified after cabergoline under either fed or fasting conditions. Laboratory evaluation showed some minor deviations from normal, which were not clinically relevant (only one subject showed an occasional and transient elevation in alkaline phosphatase which disappeared in the subsequent laboratory evaluations) and were considered for the most part not to be drug related. Eleven subjects reported adverse events (one after both treatments, five only after drug intake under fasting conditions, and five only after drug intake with food.
Adult↗
Effect of felbamate on the pharmacokinetics of lamotrigine.
To assess the possible interaction between lamotrigine and felbamate, a double-blind, randomized, placebo-controlled, two-way crossover study was conducted in 21 healthy male volunteers. Volunteers were given lamotrigine (100 mg every 12 hours) and felbamate (1,200 mg every 12 hours) or matching placebo for 10 days during each period of the crossover. After morning administration on day 10, blood samples were obtained over 12 hours for measurement of lamotrigine. Felbamate increased the maximum concentration (Cmax) and and area under the concentration-time curve from time 0 to 12 hours (AUC0-12) of lamotrigine by 13% and 14%, respectively, compared with placebo. The 90% confidence intervals of the log-transformed pharmacokinetic parameters were within the 80-125% bioequivalance limits, however. Felbamate had no significant effect on the urinary excretion of lamotrigine (total), unconjugated lamotrigine, or the N-glucuronide. One volunteer discontinued the study after developing a rash while taking lamotrigine and placebo. All other adverse events were primarily related to the central nervous system and gastrointestinal tract, with a higher incidence reported during coadministration of lamotrigine and felbamate than with placebo. Overall, felbamate appears to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
Adult↗
Male infertility after surgery for imperforate anus.
Congenital abnormalities of the genitourinary tract often coexist, and cryptorchidism is common in patients who have had imperforate anus. Twenty men who had pull-through procedures for imperforate anus in infancy have been evaluated for infertility. Seven had coexisting renal abnormalities, 4 had had recurrent epididymitis, 3 had had bilateral orchidopexies (at age 7 to 12), 2 had spina bifida, and 1 had a pituitary adenoma. Seven had no ejaculate (aspermia), 11 were azoospermic, 1 was severely oligozoospermic, and 1 had a normal sperm concentration in a small volume of ejaculate. Both vasa were blocked in 5 men, and this appeared to be a result of the original operative procedure. One vas was blocked in another 7 patients who had abnormalities on the contralateral side; three had epididymal blocks after epididymitis, and four had congenital malformations associated with an absent or ectopic kidney. After reconstruction (4), insertion of sperm reservoirs (4), microscopic epididymal sperm aspiration (2), or artificial insemination (1), sperm were retrieved from 9 men (ejaculated by 4) 2 pregnancies occurred. Male infertility after treatment of imperforate anus in infancy can be related to a wide variety of cause, some of which are amenable to treatment.
Abnormalities, Multiple↗
Human transbuccal absorption of diclofenac sodium from a prototype hydrogel delivery device.
The buccal delivery of the nonsteroidal antiinflammatory drug, diclofenac sodium (Voltaren), from a prototype hydrogel was studied in man in a randomized crossover design of buccal delivery and i.v. infusion. After a 30-min delay, plasma levels of diclofenac increased to near steady-state levels of 100 ng/ml by 3 hr. With each subject serving as his own control, the i.v. infusion data facilitated the calculation of a mean steady-state flux of diclofenac sodium of 2.1 +/- 0.6 mg/cm2-hr across human buccal mucosa and a time lag of 1.0 +/- 0.5 hr. The large flux of this ionized species indicates that the traditional lipoidal model of buccal permeation based on the partition coefficient is inadequate.
Absorption↗
A comparison of the relative sensitivities of factor VII and prothrombin time measurements in detecting drug interactions with warfarin.
We have studied the comparative abilities of the prothrombin time and factor VII clotting activity, measured using a chromogenic assay, to detect drug interactions with warfarin. Pharmacokinetic and pharmacodynamic data were collected from studies involving the single administration of 25 mg of warfarin in the absence and presence of fengabin, cimetidine, ranitidine, and enoxacin. Fengabin caused changes in both the pharmacokinetics and pharmacodynamics of warfarin, whereas cimetidine and enoxacin only caused changes in its pharmacokinetics. Ranitidine had no effect on either the pharmacokinetics or pharmacodynamics of warfarin. In general, factor VII clotting activity showed greater sensitivity but also greater variability than the prothrombin time to changes in clotting activity. Consequently, factor VII clotting activity did not have greater discriminatory power than the prothrombin time in detecting drug interactions involving warfarin.
Adult↗
Assessing stimulus control in natural settings: an analysis of stimuli that acquire control during training.
When a learner is taught a new response, the stimuli that influence its display are often unknown. The presence or absence of these stimuli alters the probability of occurrence of the response. By identifying the stimuli influencing the probability of newly acquired responses, interventionists may program for their generalization more effectively and efficiently. This investigation describes the application of an operant methodology to assess functional relationships between responses and specific stimulus variables. Four young adults with moderate mental retardation were taught to include "please" as part of requests they made in school. Four environmental stimuli, present during training, were assessed for the controlling properties they acquired. Each of the four was assessed prior to and after training by presenting it in isolation (i.e., the other three were varied). If the presence of a single stimulus associated with training did not occasion "please," then pairs of stimuli were probed. The results revealed that single-stimulus probing occasioned responding by only 1 learner; paired-stimulus probing set the occasion for including "please" by 2 others. Control of the 4th learner's responding was lost before training was introduced, because he began including "please" in his requests during baseline. The implications of these results are discussed in terms of analyzing stimulus control and promoting stimulus generalization.
Adolescent↗
Differential evaluation of the fetoplacental unit in patients with diabetes.
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Estradiol↗
The effect of E.E.C. directives on meat. (b) Abattoir design in relation to the E.E.C.
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Abattoirs↗
Dopamine and senescence in Drosophila melanogaster.
Five-day-old Drosophila melanogaster males, when exposed to 2-h-old males, will perform courtship rituals; the intensity and duration of this behavior rapidly diminishes with time. The ability of the older males to habituate to the attractive signals given off by the younger males is a dopaminergic-modulated experience-dependent modification of behavior that is abolished with increasing age. Dopamine-depleted females show increased resistance to copulation; 20-day-old females demonstrated an increase in copulation avoidance compared with younger (5-15-day-old) females. These changes in dopaminergic-modulated behaviors observed during aging parallel declines in whole body levels of dopamine. Immunocytochemical analysis of adult brains using an antibody raised against Drosophila tyrosine hydroxylase to visualize catecholaminergic cell bodies revealed increased degeneration of the cell bodies with aging. These results suggest that the deficits seen in dopaminergic-modulated behaviors may arise as a consequence of degenerative changes within the aging brain.
Aging↗