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Biomedical subjects

T F Patton

Publications and source records attributed to T F Patton.

30 records · Page 2Linked to original sources
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

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↗
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

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↗
PubMedDate not supplied

Platinum levels in human erythrocytes following intravenous administration of cisplatin: importance of erythrocytes as a distribution site for platinum species.

Recent reports of the extent of uptake of cisplatin and possible biotransformation products of cisplatin by red blood cells of humans receiving this drug have been conflicting. In vitro and in vivo studies of the platinum content of washed red blood cells following exposure to cisplatin have been conducted. Low levels of platinum were found in the red cell lysate of the erythrocytes of humans receiving cisplatin. The platinum was primarily associated with red cell lysate and little, if any, platinum appeared to be associated with the cell membrane. The in vivo studies indicated that the intracellular platinum levels are rapidly achieved following cisplatin administration and the platinum concentration appears to be linearly related to the administered dose. However, the fraction of platinum found within the erythrocytes is slight, representing only about 1 per cent of the administered dose. In light of the reactivity of cisplatin with compounds containing divalent sulphur and the millimolar glutathione levels present within erythrocytes, it is unlikely that the platinum released from the red blood cell is in the form of cisplatin. Therefore, it is doubtful that the red blood cell is a major site for cisplatin distribution and the anticancer activity of the platinum released from red blood cells is questionable.

Biotransformation↗
PubMedDate not supplied

Age-related differences in ophthalmic drug disposition I. Effect of size on the intraocular tissue distribution of pilocarpine in albino rabbits.

It has previously been documented that substantially different aqueous humour drug levels are observed in rabbits of different ages when the same dose of pilocarpine is instilled into the eye. Also, it has been shown that the aqueous humour volume ratio for rabbits of different ages can be used to predict aqueous humour levels of pilocarpine attained after topical dosing. In the present study, concentrations of pilocarpine in the cornea, aqueous humour, iris-ciliary body, lens, and vitreous humour were determined in both 20-day old and 60-day old rabbits following the topical administration of identical doses of drug. For tissues other than the aqueous humour and iris-ciliary body, consideration of only tissue size differences between rabbits of different ages will not suffice to explain the observed differences in pilocarpine concentration. Any attempt to develop rational age-related dosage modifications for ophthalmic drugs must include a consideration of functional and developmental differences as well as size effects.

Aging↗
PubMedDate not supplied

Age-related differences in ophthalmic drug disposition II: drug-protein interactions of pilocarpine and chloramphenicol.

Although drug-protein interactions have been shown to be important in the transport of drugs into and through the eye, age-related differences in ocular drug-protein binding have not been explored. This study was designed to investigate protein binding characteristics of pilocarpine and chloramphenicol in aqueous humour and plasma from rabbits of different ages. The method of equilibrium dialysis was used to quantitate drug-protein interactions. Younger animals showed decreased binding of chloramphenicol in plasma when compared to older rabbits. On the other hand, the interactions of both drugs with aqueous humour proteins were more extensive in younger rabbits. Age-related differences in drug-protein binding were not directly related to the total protein contents of the respective biological fluids. These findings suggest possible age-related differences in the relative protein fractions contained in aqueous humour and plasma, or qualitative differences in the binding capacity of the proteins involved.

Aging↗
PubMedDate not supplied

Pharmacokinetics of non-protein-bound platinum species following administration of cis-dichlorodiammineplatinum(II).

The pharmacokinetics of non-protein-bound platinum species derived from cis-dichlorodiammineplatinum(II) (cis-platinum) was studied under a variety of dosing conditions. Following rapid infusions (15-minute) of cis-platinum at 100 mg/m2, the unbound drug declined in a biphasic mode with a mean terminal half-life of 48 minutes. The mean beta-phase half-life after a 6-hour infusion of the same dose of cis-platinum was 26 minutes. Urinary excretion of filterable platinum was substantially greater after a 6-hour infusion than after a 15-minute injection. Concomitant administration of mannitol appeared to result in higher peak plasma concentrations and decreased urinary excretion of unbound platinum species but did not alter the terminal half-life. Renal impairment was associated with extremely high plasma levels of filterable platinum but did not affect other pharmacokinetic parameters. Preliminary data on the distribution of cis-platinum to ascitic fluid are also presented.

Ascitic Fluid↗
PubMedDate not supplied

Plasma levels and urinary excretion of methyl-GAG following iv infusion in man.

The pharmacokinetics of methyl-GAG was studied after nephrectomy in five patients with renal cell carcinoma and in one patient with breast cancer. Following rapid infusion (30 minutes) of 700 mg/m2 of methyl-GAG, terminal half-life of 136-224 hours. Drug levels declined to 6%-20% of the initial plasma concentration in the first 24 hours. Approximately 40% of the dose was recovered in the urine after 2 weeks. Extensive extravascular distribution of methyl-GAG is suggested.

Antineoplastic Agents↗
PubMedDate not supplied

Pediatric dosing considerations in ophthalmology--dosage adjustments based on aqueous humor volume ratio.

By simplifying a pharmacokinetic treatment, an equation can be derived which predicts that equal areas under aqueous humor concentration-time profiles can be obtained by administering a dose to infants which is some fraction of the normal adult dose. This fraction is obtained by dividing the aqueous humor volume of the child by that of the adult. This theory has been tested using rabbits as an experimental model. Using literature values for aqueous humor volumes, it was possible to calculate what fraction of a dose of pilocarpine administered to 20-day-old rabbits would result in the same ocular concentrations of drug as in 60-day-old rabbits. When the experiment was performed, agreement between predicted and experimental values was excellent. Although admittedly an oversimplified treatment, these results are the first step in a comprehensive pharmacokinetic model which should result in a more rational approach to ophthalmic drug delivery in infants and children.

Animals↗