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Biomedical subjects

J R Robinson

Publications and source records attributed to J R Robinson.

At least 91 records · Page 5Linked to original sources
PubMed1984

Relationship of chemical structure to corneal penetration and influence of low-viscosity solution on ocular bioavailability.

Current understanding of the mechanism of corneal penetration by organic molecules proposes the epithelial layer as the rate-limiting membrane for water-soluble compounds and the stromal layer as rate limiting for lipid-soluble compounds. This suggests that the relationship between corneal permeability and the logarithm of oil/water partition coefficients, for a series of drugs, should not be the typical, single, continuous, parabolic-shaped curve. Corneal penetration studies have been conducted in unanesthetized albino rabbits using various organic compounds, representing five orders of magnitude in partition coefficient, at a constant concentration of 4 X 10(-5) M dispensed in either a 1- or 90-centipoise (cps) solution. It has been shown that for non-ionizable compounds, a pair of bell-shaped curves were generated, one for lipid-soluble and one for water-soluble compounds. Small water-soluble species demonstrate very high apparent permeabilities, which may relate to the presence of aqueous pores or other paracellular drug movement. Penetration of ionizable compounds does not appear to correlate well with the structural relationships invoked for un-ionized compounds. Consistent with the proposed mechanisms of corneal penetration, oil-soluble drug substances show no improvement in drug bioavailability when dosed from a 90-cps solution, and water-soluble drugs show a modest improvement in ocular drug bioavailability. Small water-soluble substances demonstrate no improvement due to their already high bioavailability. The importance of nonproductive absorption and precorneal drainage on bioavailability is addressed.

Animals↗
PubMed1984

Radiologic evaluation before gastric bypass for morbid obesity.

During a 4 year period, 69 patients received gastric bypass with stapling and Roux-Y gastrojejunostomy for morbid obesity. The results of 67 preoperative radiologic evaluations of the gastrointestinal tract were analyzed. Of these patients, 17.9 percent (12 of 67) had previous cholecystectomy for cholelithiasis; 14.6 percent (10 of 67) had cholelithiasis found on preoperative evaluation. This gave an overall incidence of gallbladder disease of 32.8 percent. The upper gastrointestinal examination revealed four patients with hiatal hernia, three with reflux, and one with evidence of reflux esophagitis. Two patients had one duodenal diverticulum each. Ten small bowel follow-through examinations were performed, six of which revealed no abnormalities and four of which were consistent with previous jejunoileal bypass. Results of air-contrast barium enema showed 1 patient with a cecal mass which was subsequently found to be a fatty iliocecal valve and 16 patients had diverticulosis without evidence of diverticulitis. The remainder of the findings of all studies were unremarkable. When all is considered, including radiation dose, difficulty in performing examinations, and cost, we conclude that because of the low incidence of significant abnormalities, routine preoperative evaluation of these patients should only include radiographic or sonographic evaluation of the gallbladder. Other examinations should be obtained if the patients have current symptoms or previous gastrointestinal disease or gastric surgery.

Adult↗
PubMed1984

Ocular disposition of topically applied histamine, cimetidine, and pyrilamine in the albino rabbit.

Aqueous solutions of pyrilamine, cimetidine, and histamine were instilled into the eyes of albino rabbits and drug levels determined as a function of time in the cornea, conjunctiva, aqueous humor, and iris-ciliary body. For all three drugs, less than 1% of the applied dose penetrates to the aqueous humor. Moreover, cimetidine and histamine are significantly less bioavailable than pyrilamine. Both cimetidine and histamine appear to bind to precorneal mucin and thus exhibit binding to conjunctival tissue with subsequent low penetration into the cornea and prolonged peak times in the aqueous humor. In addition, both drugs show binding to the iris-ciliary body as well. The influence of solution pH on the penetration of these compounds was also investigated, and a factor of two increase in aqueous levels was noted for the pH range 5-8, which encompasses the pKa's for these compounds.

Administration, Topical↗
PubMed1982

Synthesis and bioevaluation of a series of fatty acid esters of p-[N,N-bis(2-chloroethyl)amino]phenol.

A series of even numbered fatty acid esters (C2-C18) of p-[N,N-bis(2-chloroethyl)amino]phenol were synthesized and evaluated as to acute toxicity as well as effectiveness against L-1210 mouse leukemia. The acetate through the decanoate derivatives demonstrated toxicity between 2 and 3 times that of phenol mustard in HA/ICR mice. The less soluble laurate, myristate, palmitate, and stearate derivatives were less toxic. Significant survival times in the leukemia studies (T/C% greater than or equal to 125) were observed for all compounds except the acetate and hexanoate derivatives. The myristate derivative produced the greatest significant increase in survival time, 162%. The palmitate and stearate derivatives produced significant survival at five and four dosage levels, respectively. The butyrate and laurate derivatives produced significant survival at three dosage levels and the octanoate, decanoate, and myristate at two dosage levels.

Aniline Mustard↗
PubMed1981

Mechanistic studies on transcorneal permeation of fluorometholone.

The mechanism of corneal fluorometholone penetration was studied using albino rabbits, and the apparent rate and extent of steroid accumulation in the various cell layers of the cornea and aqueous humor were determined for normal and abraded eyes. The results are compared and contrasted to the mechanism previously reported for pilocarpine. Fluorometholone readily penetrates the intact corneal epithelium and accumulates in the hydrophilic stromal layers of the cornea. The kinetic profile is similar to that of pilocarpine and is largely a result of the pre-corneal dynamic processes. Pharmacokinetic parameters for each tissue were determined to establish an overall mechanism for corneal permeation of the steroid.

Absorption↗
PubMed1980

Prelminary examination of rabbit conjunctival mucins.

Conjunctival mucins from albino rabbits were fractionated using gel filtration and anion-exchange chromatography. Charge homogeneity of the various conjunctival mucin fractions was confirmed by polyacrylamide gel electrophoresis. The molecular weight characteristics of the isolated fractions varied with the analytical scheme employed. Two schemes yielded mucins with molecular weights of 10(4), 10(5), and 10(6). However, when anion-exchange chromatography was the first step in the fractionation scheme, the dominant mucin had a molecular weight of 1.7 x 10(5). In contrast, when gel filtration chromatography was the first step, the dominant mucin had a molecular weight of 5.7 x 10(4). It was postulated that during migration through the anion-exchange matrix, the low molecular weight conjunctival mucin underwent trimer formation. Comparison with the mucin fractions isolated from tear mucoid threads revealed that the scheme beginning with anion-exchange chromatography preserved the fractionation pattern seen in tear mucoid threads. This result implies that conjunctival mucins undergo an association prior to or after their entry into the tear film. The molecular event of interest in this process is self-association of the species with a molecular weight of 5.7 x 10(4), resulting in a trimer with a molecular weight of 1.7 x 10(5). This trimer appears to resist deaggregation on exposure to a medium of lesser ionic strength. Several explanations are offered for its formation as well as for its stability. The implication of multiple conjunctival (tear) mucins for tear film stability also is discussed.

Animals↗
PubMed1980

Referrals to a psychiatric service from old people's homes.

One hundred consecutive referrals have been surveyed, the diagnostic and behavioural problems leading to referral considered and follow-up information obtained one year later. For most admission to hospital as in- or day-patients was unnecessary. Old people's homes do not make excessive demands on the psychiatric services, but deserve support, including help in developing a more tolerant and flexible approach to less confirming residents. This is becoming imperative now that old people's homes are dealing with increased numbers of disturbed residents.

Aged↗
PubMed1980

Corneal metabolism of pilocarpine in pigmented rabbits.

Cornea, aqueous humor, and iris-ciliary body levels of pilocarpine and its metabolite pilocarpic acid were determined in mixed-breed rabbits following topical dosing with 25 microliters of 1 X 10(-2) M pilocarpine. From the time-drug concentration profile it is clear that extensive metabolism of pilocarpine occurs in the cornea of pigmented rabbits. This finding contrasts sharply with similar studies in albino rabbits where relatively low levels of pilocarpine acid were observed. It is estimated that the first-order metabolism rate constant in albino rabbits is approximately two orders of magnitude smaller than in pigmented animals. A significant observation from this finding is the possibility that the reported greater dose requirement for heavily pigmented individuals may not be due to drug-pigment binding alone but also to extensive corneal drug metabolism.

Animals↗
PubMed1979

Pharmacokinetics of topically applied pilocarpine in the albino rabbit eye.

The temporal and spatial pattern of [3H]-pilocarpine nitrate distribution in the albino rabbit eye following topical administration was determined. A four-compartment caternary chain model describing this disposition corresponds to the precorneal area, the cornea, the aqueous humor, and the lens and vitreous. Simultaneous computer fitting of data from tissue corresponding to some compartments in the model supported the proposed model. Additional support was provided by the excellent correlation between predicted and observed values in multiple-dosing studies. Several important aspects of ocular drug disposition are evident from the model. The extensive parallel elimination at the absorption site gives rise to an apparent absorption rate constant that is one to two orders of magnitude larger than the true absorption rate constant. In addition, aqueous flow accounts for most of the drug removal. Thus, major effects on absorption and elimination, independent of the drug structure, suggest the possibility of similar pharmacokinetics for vastly different drugs.

Animals↗
PubMed1979

Mechanistic and quantitative evaluation of precorneal pilocarpine disposition in albino rabbits.

The low ocular bioavailability of topically applied pilocarpine is attributed to extensive precorneal drug loss in conjection with the resistance to corneal penetration. Several elements of precorneal loss were reported earlier, but a complete mechanistic understanding has not been available. The present study was designed to gain a better understanding of the mechanisms governing pilocarpine disposition in the precorneal areas as well as the relative influence of these parameters on ocular drug bioavailability. Radioactive pilocarpine and glycerin solutions were instilled into the precorneal area of the albino rabbit eye under various experimental conditions, and the drug concentration in the lacrimal lake was monitored as a function of time. The results demonstrated that nonconjunctival loss of pilocarpine, vasodilation due to the drug, and lacrimation due to vehicle formulation are additional aspects of precorneal drug disposition. The individual influence of all precorneal loss parameters on drug bioavailability was then assessed using a mathematical model formulated from experimental findings on both precorneal and intraocular drug disposition. Drainage and vasodilation, as well as nonconjunctival pilocarpine loss, exerted major influences on drug loss at the absorption site.

Administration, Topical↗
PubMed1979

Vehicle effects on ocular drug bioavailability III: Shear-facilitated pilocarpine release from ointments.

Pilocarpine release from water-in-oil emulsion ointments was studied in vitro and in vivo, using albino rabbits. Pilocarpine release from the vehicle to the ocular fluids was dependent on shear, i.e.,blinking, and the dosing system emulsifying efficiency. A mechanical shearing component was vital for correlating corneal drug penetration and the in vitro pilocarpine release pattern. Simple diffusion studies with the vehicles did not predict drug in vivo release, but the ointment systems were all superior to an aqueous pilocarpine solution. Incorporation of a mechanical shearing component to mimic blinking gave good correlation of in vitro and in vivo results. Also, increasing the vehicle emulsifying efficiency by surfactant addition decreased shear-facilitated drug release and in vivo performance. Finally, increasing the internal aqueous phase volume fraction decreased in vivo performance and was linked to the influence of effective drug concentration in the vehicle.

Animals↗
PubMed1978

Control of water content of respiring kidney slices by sodium chloride and polyethylene glycol.

1. Cortical slices from kidneys of adult rats were incubated for 1 and 2 hr at 25 degrees C in oxygenated solutions containing 5 mM-K, 2.5 mM-Ca and Mg, 0.007 M-phosphate buffer (pH 7.4) and 5 mM-glucose, together with 1, 2, 4 and 6% polyethylene glycol (PEG 6000) and 46, 92, 123, 154 and 231 mM-NaCl.2. There were no significant differences in water content between slices incubated for 1 and for 2 hr.3. The slices contained more water when the concentration either of NaCl or of PEG 6000 was lower.4. Larger increases in the contribution of NaCl to total osmolarity were required to prevent increases in water content accompanying relatively small reductions in the contribution of PEG 6000. At a physiological salt concentration around 300 m-osmole/l., it took 10 m-osmole/l. of additional NaCl to compensate for the loss of 1 m-osmole/l. PEG 6000 and keep the volume of cell water normal.5. The much greater contribution, osmole for osmole, which PEG 6000 made to tonicity suggests that metabolic activity failed to make the cell membranes effectively semipermeable; they were still substantially permeable to NaCl.6. Comparison with earlier results suggested that ionic strength affected colloid osmolarity similarly in respiring and in non-metabolizing cells; and that respiration at 25 degrees C somehow kept the concentration of diffusible solutes in the cells sufficiently lower than outside to compensate for a swelling effect of intracellular colloid osmolarity which, in the absence of metabolism, could be balanced by 20 m-osmole/l. PEG 6000 added to the medium.

Animals↗
PubMed1977

Simplified method for the determination of residues of carbofuran and its metabolites in crops using gas-liquid chromatography-mass fragmentography.

The gas-liquid chromatographic behaviour of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (carbofuran), its 3-keto-, and 3-hydroxy-derivatives, their respective phenolic hydrolysis products and the heptafluorobutyryl (HFB) derivatives of the carbamates and phenols were studied by examining the column effluent using chemical ionization mass spectrometry. In contrast to the behaviour of the carbamates, their HFB derivatives consistently produced ions having intensities proportional to the quantities injected. The common base-peak ion at 228 a.m.u. was used to quantitate these materials at the 0.02-1 ppm level in field-treated carrots, celery, tomatoes and corn with minimal sample preparation.

Carbofuran↗
PubMed1977

Quantitative effects of unsaturated fatty acids in microbial mutants. VII. Influence of the acetylenic bond location on the effectiveness of acyl chains.

The ability of a series of 18 carbon acetylenic fatty acids to fulfill the unsaturated fatty acid requirements of Escherichia coli and Saccharomyces cerevisiae was investigated. Despite their high melting points (greater than 40 degrees C), several isomers of the acetylenic fatty acids were as efficient or more efficient in supporting growth than the analogous fatty acid having a cis-double bond. The efficiencies of the different positional isomers in supporting cell proliferation varied from essentially 0 cells per fmol for the 2-5 and 13-17 isomers to high values when the acetylenic bond was near the center of the chain: e.g. 45 E. coli and 5.5 S. cerevisiae cells/fmol for the 10 isomer. A striking ineffectiveness of the 9 isomer was observed with E. coli. The 7, 8 and 10 isomers were at least 10-fold more efficient than any of the other positional isomers in supporting the growth of E. coli. In contrast, the 9 isomer was among the most effective acetylenic fatty acids tested with the yeast mutant. Chromatographic analysis of the extracted lipids indicated that each of the acetylenic isomers tested (except delta2 and delta3) could be esterified by the prokaryotic and eukaryotic microorganisms. The content of unsaturated plus cyclopropane acids observed when growth ceased in E. coli cultures supplemented with growth-limiting concentrations of the acetylenic fatty acids ranged from approx. 15 mol% for the 8 isomer to approx. 35 mol% for the 14 and 17 isomers. The 8-11 isomers were observed to be esterified predominantly at the two position in phosphatidylethanolamine of E. coli and in phosphatidylcholine of S. cerevisiae.

Cell Division↗
PubMed1977

Aqueous chamber drug distribution volume measurement in rabbits.

A method was developed for aqueous chamber drug distribution volume measurement in the albino rabbit, and the apparent volume of distribution was determined for inulin, pilocarpine alkaloid, and 1-hexanoic acid. The method consists of injecting a suitable concentration of drug, in an appropriate volume of fluid, into the anterior chamber of the eye and monitoring the decline in drug concentration as a function of time by periodic sampling of the aqueous humor. Graphical analysis of the resulting data yields both the apparent volume of distribution and the turnover rate constant of the aqueous humor. The technique does traumatize the eye, causing formation of plasmoid aqueous, which does not interfere with the apparent drug distribution volume measurement or the determination of aqueous humor turnover. Inulin was used to determine the physiological aqueous volume, 287 mul, in good agreement with literature values. The turnover rate constant was 0.016 min-1, also in good agreement with literature values. The apparent volume of distribution for pilocarpine alkaloid was 575 mul in albino eyes and 760 mul in pigmented irides; for 1-hexanoic acid in albino eyes, it was 760 mul. For pilocarpine alkaloid, literature citations on the fraction of dose absorbed have been based on an assumed apparent volume of distribution of 250-300 mul. Therefore, a factor of two error has been introduced when using albino eyes and a factor of almost three has been introduced when using pigmented eyes. The implication of the apparent volume of distribution for pilocarpine in its ocular disposition is discussed, as is the unexpected observation that pilocarpine alkaloid apparently inhibits formation of plasmoid aqueous and follows one-compartment kinetics during these studies. Is is shown that the one-compartment kinetics for pilocarpine are due to its biological activity in the aqueous chamber.

Animals↗