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Biomedical subjects

J R Robinson

Publications and source records attributed to J R Robinson.

At least 109 records · Page 6Linked to original sources
PubMed1977

Vehicle effects on ocular drug bioavailability II: Evaluation of pilocarpine.

The influence of vehicle composition on ocular penetration of pilocarpine was studied in the albino rabbit. Increasing the pH of a vehicle promoted increased corneal penetration for pilocarpine, in accordance with the pH-partition hypothesis, but a similar series of experiments with a nonionizable drug, glycerin, gave similar results. The extent of pH-induced lacrimation by the vehicle and its effect on precorneal drug concentration also was determined. Increased pilocarpine absorption at neutral to slightly alkaline pH was due primarily to its peculiar solubility characteristics coupled with less irritation and lacrimation rather than a direct pH effect on the molecule. Incorporation of pilocarpine into a petrolatum-based ointment vehicle resulted in increased aqueous humor pilocarpine levels above those provided by an equivalent dose of aqueous solution. The mechanism of this increase was determined to be a higher effective concentration of pilocarpine in the ointment vehicle coupled with an increase in contact time of the dose. The ointment system also exerted an unusual form of vehicle control in that it promoted the corneal penetration of pilocarpine while impeding uniform mixing of the dose with tears and thereby imposed a restriction on the amount of pilocarpine available to the ocular tissues.

Animals↗
PubMed1976

Metastatic carcinoma of the ureter.

Three patients had carcinoma of the stomach, rectum, and lung, respectively, metastatic to the ureter in the absence of other known metastasis. Two of the three patients had abdominal pain, while the other patient had no upper urinary tract symptoms. All patients had excretory urograms that showed delayed or no excretion of contrast medium on the side of obstruction. Obstruction was confirmed with retrograde pyelography in each case. Two of three patients were treated with nephrectomy. Metastatic carcinoma of the ureter should be considered in patients with malignant disease with initial symptoms consistent with ureteral obstruction. The diagnosis may be suggested by pyelographic demonstration of an obstructed ureter. Symptomatic patients may require nephrectomy.

Adenocarcinoma↗
PubMed1976

Binding of sulfisoxazole to protein fractions of tears.

By using equilibrium dialysis experiments, it is shown that sulfisoxazole binds extensively with albumin and alpha-globulin and to a lesser extent with gamma-globulin and lysozyme, all of which are normal components of tears. The binding of sulfisoxazole to the various protein fractions quantitatively accounts for the over-all binding of this drug to human tears. It is suggested that to predict the binding of drugs to proteins in lacrimal fluid, both in normal and pathological conditions, it is necessary to conduct binding studies of the drug with the major protein fractions of tears. More-over, it is essential to know the composition of the major protein fractions of tears in both normal and various pathological conditions to conduct the necessary in vitro binding studies.

Albumins↗
PubMed1976

Quantitative precorneal disposition of topically applied pilocarpine nitrate in rabbit eyes.

The present study was designed to quantitate the influence of several precorneal factors on the disposition of topically applied ophthalmic drugs. With tritiated pilocarpine nitrate methodology was developed for in vivo assessment of the relative contribution of tear turnover, instilled solution drainage, and nonproductive absorption to the loss of drug from the precorneal area. Studies were conducted in both awake and anesthetized rabbits whose drainage ducts were either unobstructed or plugged, and the loss of drug was monitored directly from the precorneal area or as appearance in the aqueous humor. By selective variation in experimental conditions, the influence of tear turnover, instilled solution drainage, and nonproductive absorption on ocular drug bioavailability was separately studied and quantitated. Instilled solution drainage was by far the largest contributing factor in the loss of drug from the precorneal area of the eye and, in the range of instilled volumes normally employed, tear turnover played a relatively minor role in drug loss. Compared to the cornea, precorneal tissue other than the cornea has a considerably greater surface area and thus is a potentially signifanct route for drug loss. However, under normal circumstances, loss by this route was minimal as compared to loss via instilled solution drainage.

Administration, Topical↗
PubMed1976

Mechanistic studies on transcorneal permeation of pilocarpine.

The mechanism of corneal pilocarpine penetration was studied in the albino rabbit using radiochemical techniques. The apparent rate and extent of pilocarpine accumulation in the aqueous humor and the various cell layers of the cornea were determined for both intact and abraded eyes. For the first time, drug levels were monitored in the epithelium and stroma-endothelium of the intact cornea using a tissue-scraping technique. In addition, a new postinstillation rinsing method was devised to evaluate the rate of corneal uptake. The results demonstrate a dual role for the corneal epithelium, both as a barrier to drug penetration and as a reservoir for drug in the intact cornea. The transcorneal pilocarpine flux is slower than the data appear to indicate, and previous overestimates of the apparent absorption rate constant are due to parallel elimination processes occurring at the absorption site. Pharmacokinetic parameters were determined for each tissue to generate an overall mechanism for corneal permeation.

Animals↗
PubMed1976

Exercise capacity of black sickle cell trait males.

Aerobic capacity data were collected on matched groups of 16 black sickle cell trait males and 16 non-trait males. The subjects were matched on race, age, weight, sex, physical activity profile, skinfolds, and smoking habits. Total treadmill times, predicted and actual Vo2 max, max HR, and recovery HR were compared. The Bruce Multi-Stage Treadmill Test was administered with continuous ECG and OCC (Oxygen Consumption Computer) monitoring. The results indicated no significant difference (P greater than .05) between the trait and non-trait subjects on any of the performance variables.

Adolescent↗
PubMed1976

Pediatric dosing considerations in ophthalmology.

In almost all cases concerned with topically applied ophthalmic drugs, no distinction is made between adults and infants or children with regard to the concentration and amount of drug used. Even though maximal therapeutic effects are usually observed, there can be significant short- and long-term toxicity problems. Based on some modest assumptions it should be possible to reduce doses without sacrificing therapeutic effectiveness in infants and children up to three years of age. The overriding concern should be, however, potential toxicity problems which may exist in infants and children, in particular the neonate, due to their low body weight and the fact that in most cases, more than 90 percent of an instilled dose in potentially available to act systemically. Total body surface area can be used as a measure for determining potentially toxic doses in children. Especially for potent drugs, with both short- and long-term manifestations, toxicity considerations may necessitate some sacrifice in therapeutic effectiveness of a given drug or switching to an alternate drug in order to insure a reduction in toxic side effects.

Absorption↗
PubMed1976

Attaching community psychiatric nurses to general practice.

A scheme for attachment of psychiatric nurses from hospital to group practice in Oxford is described. One community psychiatric nurse can work satisfactorily with eight general practitioners covering a population of about 18,000. From analysis of a working year, it is concluded that this arrangement improves the care of patients in the community by providing psychiatric help at times when it was previously unavailable or unacceptable.The implications of such a scheme for the workings of the primary health care team and the hospital psychiatric service are considered, and a case is made for a further study involving a comparison between practices with and without the attachment of a community psychiatric nurse.

Community Mental Health Services↗
PubMed1975

Genetic expression of aryl hydrocarbon hydroxylase activity in the mouse.

Monooxygenases require NADPH and molecular oxygen during the metabolism of numerous endogenous hydrophobic substrates and carcinogenic and toxic exogenous chemicals. The complexity of these membrane-bound multicomponent drug-metabolizing enzyme systems is reviewed. What "aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity" actually represents is reviewed and discussed. At least two forms of the hydroxylase activity exist and we suggest that they are associated with different molecular species of membrane-bound CO-binding hemoprotein (i.e., they are associated with different enzyme active-sties). At least two, and probably more than two, nonlinked loci are responsible for the genetic expression of new cytochrome P1450 formation and aryl hydrocarbon hydroxylase induction--and the stimulation of 10 other monooxygenase "activities"--in the mouse treated with certain aromatic hydrocarbons. The individual variability of hydroxylase activity in an inbred and in a random-bred strain of micr is illustrated. The basal hydroxylase activity appears to be inherited differently from the aromatic hydrocarbon-inducible hydroxylase activity. The potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin can stimulate increases in these hepatic monooxygenase activities and p1450 formation in so-called "nonresponsive" mice, whereas inducers such as beta-naphthoflavone and 3-methylcholanthrene cannot. Thus, the genetically "nonresponsive" micr apparently possess the structural and regulatory genes necessary for expression of these inducible monooxygenase activities and associated new formation of cytochrome P1450. We suggest that a mutation has occurred in the "nonresponsive" inbred strains that results in production of an inducer-binding receptor having a diminished affinity for aromatic hydrocarbons.

Animals↗
PubMed1975

Influence of topical anesthesia on tear dynamics and ocular drug bioavailability in albino rabbits.

The bioavailability of topically applied ocular drugs is very poor, due largely to drug loss through drainage and tear turnover. The use of high viscosity solutions or solid matrixes to delay or eliminate drainage is the usual approach for decreasing drug loss but the alternative approach of chemically reducing tear turnover and/or solution drainage has not been investigated. By means of a simple isotopic dilution technique, using radioactive technetium sulfur colloid, the quantitative influence of topical anesthetics on tear production and instilled solution drainage was determined. The reduction in the rate of tear turnover and solution drainage varies for different anesthetics and is dose dependent. The implication of these results for some long accepted clinical procedures is discussed, and questions are raised regarding the present understanding of the mechanisms of tear production. Quantitation of precorneal drug loss through instilled solution drainage and tear turnover permits the establishment of a baseline for ocular drug bioavailability. Aqueous humor drug concentration versus time profiles of radioactive pilocarpine nitrate were obtained, both in the presence and absence of topical anesthesia. The results verify the importance of tear turnover and instilled solution drainage as a major route of drug loss in the eye. Moreover, the success of the present study in improving ocular drug bioavailability by the chemical approach of repressing solution drainage and tear turnover suggests that this approach is viable for improving drug bioavailability.

Anesthesia, Local↗
PubMed1975

Vehicle effects on ocular drug bioavailability i: evaluation of fluorometholone.

The influences of drug concentration and vehicle composition on the corneal penetration of the steroid fluorometholone were studied in the albino rabbit. Aqueous dosing systems included a saturated solution and 0.1, 0.05, and 0.1% suspensions of micronized fluorometholone. Two different doses of a 0.1% oleaginous ointment were also studied. The results from the 0.1 and 0.5% suspensions show a peak aqueous humor steroid concentration at 30 min and a substantial sustaining effect with these two concentrations. The results also support the belief that moderate dilution of a suspension of a slowly soluble drug may not substantially lower the aqueous humor drug levels or, conversely, that use of a higher concentration suspension may not improve the aqueous humor drug concentration-time profile. The 0.1% suspension and the saturated solution did not produce a sustaining effect. The results demonstrate for the first time that the particles present in a dose of suspension are retained within the cul-de-sac of the eye and contribute significantly to the amount of steroid penetrating the cornea. This finding was confirmed by a study in which the eye was rinsed with saline solution 30 min after instillation of a dose of a 0.05% suspension. The rinsing procedure prematurely terminated the sustaining effect of the suspension. The results of the ointment studies show that partitioning of the lipophilic steroid from the oleaginous vehicle has a greater rate-limiting influence on corneal penetration than the dissolution rate parameter associated with the aqueous suspensions. Peak aqueous humor concentration was not achieved until 3 hr after dosing and was comparable to the 0.1 and 0.05% suspensions. Predosing of the eye with a saturated solution or the 0.1% suspension prior to dosing with ointment overcomes the inability of the ointment to provide adequate drug at short times following dosing. In this case, peak levels were achieved within 60 min and then maintained. The duration of aqueous humor levels and the amount penetrating from the ointment were greater than the suspensions, and these effects are discussed relative to the mechanism. Differences in aqueous humor levels produced by 25- and 50-mg doses of ointment were minimal. A discussion of the results from all studies is presented in the context of present theories regarding the role of the lipophilic epithelial layer of the cornea as a barrier to drug penetration.

Administration, Oral↗
PubMed1975

Ocular evaluation of polyvinyl alcohol vehicle in rabbits.

The flow properties and viscosity of the vehicle into which drugs are incorporated can be determining factors in the bioavailability of topically applied ophthalmic drugs. It is shown, in rabbits, that when polyvinyl alcohol and methylcellulose are compared on a viscosity basis, there is essentially no difference in the two vehicles with regard to their influence on ocular drug bioavailability. Moreover, the rate of drainage loss for polyvinyl alcohol solutions, as determined by the radioactive technetium technique, compares favorably to methylcellulose solutions of similar viscosity. The relationship between viscosity and contact time or drainage loss of a drug is not a direct one, but an optimum viscosity range exists for polyvinyl alcohol solutions. This optimum range of 12-15 cps in rabbits is identical to that found for methylcellulose and differs considerably from the commonly employed viscosity in commercial preparations. Based on the methylcellulose-polyvinyl alcohol comparison, it appears that vehicles exhibiting or approximating Newtonian flow properties show comparable effects as ophthalmic vehicles. Finally, a discussion of non-Newtonian vehicles and their expected behavior in the eye is presented.

Animals↗