Search PubMed⌕ Search

Biomedical subjects

A J Jackson

Publications and source records attributed to A J Jackson.

72 records · Page 4Linked to original sources
PubMed1984

Novel device for quantitatively collecting small volumes of urine from laboratory rats.

A reusable urinary collection device suitable for quantitative collection of uncontaminated urinary samples from rats without using a metabolism cage has been designed. The device can be attached to the pelvic skin within 5 min with minimum handling and discomfort to the unanesthetized rat using an adhesive. The suitability of this device was investigated by collecting and analyzing urine over a 48-h period following the intraperitoneal injection of [14C]inulin. A two-way crossover study was done with samples from one of the two experiments being collected while the animal was housed in a commercially available metabolism cage equipped to separate urine and feces. The percent of the dose excreted, food and water consumption, and the urinary output were not statistically different for rats housed in the metabolism cages or with the collection device attached. Histopathological examination of the rats revealed no pathology after a 24-h period except minor skin inflammation which occurred both in controls and animals to which the device was attached. These studies demonstrate the comparability of the new urine collection device to a commercially available metabolism cage in the quantitative collection of small (0-7 mL) urine samples with less contamination of the samples from the environment.

Animals↗
PubMed1984

Liposome-entrapped diethylstilbestrol effect on prostate gland and plasma testosterone levels in rats.

The effects of liposome-encapsulated diethylstilbestrol (DES) on the size of the ventral prostate gland and total testosterone levels in rats were studied. DES was encapsulated in phosphatidycholine-cholesterol-stearylamine-alpha-tocopherol containing multilamellar liposomes in a molar ratio of 4:5:1:0.01. The liposome suspension or free DES plus blank liposomes were administered sc on days 1, 3, and 5 at a dose of 400, 87, or 12 micrograms/kg. Plasma testosterone values showed a decrease with dose for animals treated with either entrapped DES or free DES. Prostate gland weight per g animal and prostatic protein mg per g animal on day 7 were significantly decreased in the treated animals compared to those in controls dosed with DES plus buffer containing liposomes. In addition, there was a body weight loss for the high dose DES-encapsulated animals and for high and medium dose DES plus blank liposome-treated and blank liposome-treated animals over the treatment period, although only the DES-encapsulated group value was statistically significant (P less than 0.05). Animals at the other doses did not lose weight, but exhibited weight gains which were less than those observed for sham-injected animals. Rats that received 7 micrograms/kg liposome-entrapped DES for 4 weeks had significantly lower prostate gland weights, prostatic protein levels, and testosterone levels than control animals receiving the same regimen of free DES plus blank liposomes. Results from the studies indicate that liposome-entrapped DES was more effective in decreasing the size of the prostate gland and that the desired therapeutic end point (prostate ablation) may be attained with a lower dose of DES, which would decrease the risk of weight loss in the experimental animals.

Animals↗
PubMed1984

Pharmacokinetics of intravenously administered desmosine in sheep.

The pharmacokinetics of desmosine following a 5 mg intravenous dose was determined in five sheep. The biological half-life (t 1/2 beta) of desmosine varied between 81-489 min. Urinary recovery of unchanged desmosine indicated that the compound is not extensively metabolized and that the primary route of elimination is via the kidney.

Amino Acids↗
PubMed1984

Pharmacokinetics of 5-fluorouracil following different routes of intrahepatic administration in the canine model.

In an effort to achieve high concentrations of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure, several routes of intrahepatic administration were compared in the canine model. To ascertain these data, 5-FUra (30 mg/kg) was given as a bolus into either a systemic vein (femoral vein), hepatic artery, hepatic artery distal to its ligation after hepatic dearterialization, or through the portal vein. Three dogs were studied for each route with concomitant blood samples taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, and 60 min after injection. 5-FUra levels were determined in plasma by high-pressure liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data were best described by a multicompartmental model including the measured flows. Hepatic components of the model were separate arterial and portal compartments, with elimination from each described by linear kinetics. Analysis of the results indicated that the highest hepatic levels with the least systemic exposure, as indicated by drug levels in hepatic and peripheral vein, were realized following hepatic artery administration distal to its ligation after hepatic dearterialization.

Animals↗
PubMed1982

Plasma pharmacokinetics of intravenously administered atropine in normal human subjects.

The pharmacokinetics of atropine (dl-hyoscyamine) was studied in six normal volunteers following a single 1-mg intravenous dose of atropine. Atropine plasma levels were collected for 24 hours and analyzed by radioimmunoassay. Pulse rates were monitored and compared with predose values in each subject. Atropine plasma concentrations were fitted by least-squares regression analysis. The observed maximal increase in pulse rate, at 12 to 16 minutes after the dose, correlated with the maximum predicted tissue levels of atropine based on the computer fit of the plasma atropine concentration-time data. No correlation between the time of maximum response and atropine plasma concentrations was observed. The average half-life of atropine was 4.125 hours. This data may be used to design a multiple-dosing regimen for intravenous atropine in patients.

Adult↗
PubMed1982

The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man.

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.

Administration, Oral↗
PubMed1981

Human blood preservation: effect on in vitro protein binding.

In vitro plasma protein binding for phenytoin, meperidine, and bretylium tosylate was affected by the type of preserved human blood used for its estimation. Fresh heparinized plasma and serum gave equivalent fractions bound at the concentrations studied for all three drugs. However, the in vitro plasma binding of phenytoin and meperidine decreased 9-50% when estimated in fresh citrated plasma or commercially available lyophylized human serum at the concentration levels investigated. The fraction of bretylium tosylate bound to plasma protein decreased 30-40% when estimated in fresh citrated plasma but was unchanged when estimated in the lyophylized human serum.

Blood Preservation↗
PubMed1980

The effect of route of administration on the disposition of inulin encapsulated in multilamellar vesicles of defined particle size.

Studies were undertaken to evaluate the effect of multilamellar vesicle (MLV) size and route of administration on the tissue distribution of inulin encapsulated in phosphatidyl choline, cholesterol, phosphatidyl serine and alph tocopherol liposomes. Large (MLV (2.7--4.9 micrometers) administered intravenously delivered a large fraction of the dose to the liver, lungs and spleen. However, when large MLV were given intramuscularly (left thigh muscle), a smaller fraction of the absorbed dose was distributed to these organs. Small MLV (0.3--0.8 micrometers) administered by either route resulted in a smaller fraction of the dose distributing to the liver, lungs and spleen compared to large MLV. In addition, release from the injection site was found to be size-dependent with a larger fraction of the intramuscular dose remaining at 24 hours for the large MLV.

Animals↗
PubMed1979

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.

Animals↗
PubMed1979

The teratogenic activity of a thalidomide analogus EM12 in rats on a low-zinc diet.

The relationship between the teratogenicity of EM12, 2-(2,6-dioxopiperiden-3'-yl) phthalimidine, a stable analogue of thalidomide, and zinc status in the maternal animal was investigated using pregnant rats on a low-zinc diet (1 ppm zinc, days 0--14 gestation) as the experimental model. Previous studies with this compound in rats fed a commercial diet at oral doses up to 250 mg/kg per day for three days and intravenous doses up to 10 mg/kg per day for three days failed to produce "typical" thalidomide malformations. However, when a dose of 150 mg/kg was given intraperitoneally to rats on a low-zinc diet, typical thalidomide malformations occurred with an incidence of 57.5%.

Abnormalities, Drug-Induced↗
PubMed1978

The spiral constrictor of the gastroesophageal junction.

The gastroesophageal region was reconstructed from the histological analyses of five human newborn infants. In addition, the nusculature of eight (3 newborn and 5 adult) human stomachs obtained from autopsies, with the lower one-third of the esophagus attached, was dissected with the aid of a binocular dissecting microscope. The muscularis mucosae, in the region of the gastroesophageal junction, exhibited no increase in thickness, nor was there any indication of special mucosal folds. In addition, the gastroesophageal junction contained no morphologic evidence that would support the existence of an anatomic sphincter (a localized thickening of circular muscle fibers). However, the obliquely arranged inner circular muscle fibers of the esophagus separated into fascicular bundles below the esophageal opening. Some of the fasciculi, as they descended, again became circular in shape and continued into the stomach, forming the middle circular muscle layer, while other fasciculi maintained their oblique course toward the left surface of the esophagus. These fasciculi, coursing on the anterior and posterior surfaces of the esophagus, crossed and interdigitated along the left surface of the esophagus in the region of the incisura cardiaca. After crossing, the oblique fasciculi descended into the stomach forming the inner oblique muscle layer. Based upon this description of crossing and interdigitating fasciculi, it is suggested that closure of the gastroesophageal junction may be due to contraction of spirally arranged muscle. Since the term "sphincter" generally implies a circular structure, it is proposed that the term "spiral constrictor" be considered in naming this anatomical arrangement.

Adult↗
PubMed1976

Delayed initiation of SS1 pulses in the sea anemone Calliactis parasitica: evidence for a fourth conducting system.

1. Single electrical shocks to the column sometimes elicit a series of 1-6 pulses in the SS1 (ectodermal slow system) but the first pulse does not appear until 5-28 s after stimulation. These pulses occur in addition to the early SS1 pulse which follows every shock and which has a conduction delay of less than 1 s. 2. The threshold of the delayed SS1 response is different from the thresholds of the three known conducting systems (through-conducting nerve net, SS1, and SS2). 3. In the case of stimulation of the column, the delayed SS1 pulses do not arise at the point of stimulation but probably originate in the tentacles or upper column. The pulse origin can shift during a single burst. 4. The pathway from the point of stimulation to the site of origin of delayed SS1 pulses is endodermal. We propose that this pathway represents a fourth conducting system (Delayed Initiation System--DIS). The DIS must connect, across the mesogloea, with the ectodermal SS1. The long pulse delay and repetitive firing may derive from pacemaker activity in the DIS. The DIS pacemakers closely resemble the pacemakers connected to the through-conducting nerve net. The DIS may be neuronal. 5. Delayed SS1 pulse bursts from unattached anemones showed an earlier onset, and more pulses/burst, than those from attached anemones. 6. Delayed SS1 pulses can also be evoked by electrical, and in some cases mechanical, stimulation of the pedal disc, tentacles, and pharynx, but there are regional differences in the number of pulses evoked, in their delay, and in their site of origin.

Action Potentials↗
PubMedDate not supplied

Prediction of steady-state bioequivalence relationships using single dose data I-linear kinetics.

Simulated data using a linear one- and two-compartment body model with different absorption characteristics were used to evaluate the ability of single dose bioavailability data to predict the relationships that exist at steady state. This was done by comparing the confidence intervals obtained from single and multiple dose data sets for the parameters of Tmax, Cmax, and area under the curve from time zero to infinity (AUC0-infinity). As a consequence of Tmax and Cmax decreasing and increasing from single to multiple dosing regimens, the confidence intervals for these parameters reflected these changes. The 90 per cent confidence interval expressed as a percentage of the reference mean increased or decreased for Tmax dependent upon the ratio of Ka test/Ka reference, and decreased for Cmax while the interval for AUC0-infinity exhibited no predictable pattern and appeared to be influenced by the amount of error in the data set. Alteration of either the dosing interval or the fraction absorbed did not affect the pattern of change in the confidence intervals for Tmax and Cmax, but the latter did result in a decrease in the interval for AUC0-infinity. Analysis of the confidence intervals for Tmax, Cmax and AUC0-infinity in bioequivalency studies for quinidine gluconate and procainamide hydrochloride following administration of single and multiple doses to different subjects appeared to be consistent with the patterns observed for the simulated data sets.

Adolescent↗
PubMedDate not supplied

Prediction of steady state bioequivalence relationships using single dose data II-nonlinear kinetics.

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.

Adolescent↗
PubMedDate not supplied

Intramuscular absorption and regional lymphatic uptake of liposome-entrapped inulin.

An investigation of the effects of the liposome variables (size, surface area, and amount of injected lipid) on the intramuscular absorption and subsequent lymphatic uptake of drug from the injection site (left muscle) and in the opposite (right) muscle and lymph node was done in mice. Two size ranges were studied (0.3-2.0 mu and 0.15-0.7 mu). Large multilamellar vesicles were studied at lipid doses of 20.7 and 9.0 mg/kg, whereas small multilamellar vesicles were investigated at a dose of 9.5 mg/kg. Liposomes were composed of phosphatidylcholine/cholesterol/phosphatidylserine/alpha-tocopherol/14C-dipalmitoylphosphatidylcholine (as a marker for the lipid phase), 4:5:1:0.01:0.01 (molar ratio). 3H-inulin was used to monitor the aqueous phase. At 24 hr after administration, large liposomes tended to result in the largest fraction of drug at the injection site, with the 3H/14C ratio indicating stability of the remaining vesicles. Small liposomes showed a greater uptake of inulin via the lymphatics. Decreasing the total amount of injected lipid resulted in a slower absorption of large liposomes and a greater uptake via the lymphatics.

Absorption↗