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Biomedical subjects

T F Patton

Publications and source records attributed to T F Patton.

At least 19 recordsLinked to original sources
PubMed1989

The kinetics of timolol in the rabbit lens: implications for ocular drug delivery.

This study examines the uptake and distribution of timolol in the rabbit lens following topical instillation using a heuristic approach. The implications of anisotropic drug diffusion through the lens are presented here and discussed in the context of actual in vivo data. The dynamics of timolol in the lens involve an initial, rapid uptake of the drug by the capsule and epithelium followed by slower, anisotropic diffusion through the cortex body. Kinetically, the capsule and epithelium can be treated as a separate compartment which is distinct from the cortex and which serves to provide a concentration gradient for subsequent diffusion of timolol into the dense interior structures of the lens. Model simulations support the hypothesis that the preferred route of penetration of timolol into the vitreous humor via the lens is the diffusion of drug around the capsule/epithelium and peripheral cortical layers. It is also shown that due to the high and increasing diffusional resistance toward the center of the lens, as well as the diminishing drug concentrations in the capsule and epithelium, steady-state levels in the lens may be extremely difficult to achieve in some therapeutic situations. This phenomenon could have a significant impact on the success or failure of a drug treatment involving the lens and ocular tissues.

Administration, Topical↗
PubMed1987

Physicochemical determinants of drug diffusion across the conjunctiva, sclera, and cornea.

This investigation examined some of the barrier properties of the conjunctival, scleral, and corneal membranes. The diffusion of nadolol, timolol, propranolol, penbutolol, sucrose, and inulin was measured across the isolated corneal and scleral membranes of the rabbit using a two-chamber glass diffusion cell. Drug absorption across the cornea and the conjunctiva was studied in vivo by measuring precorneal drug clearance. The drug samples were analyzed either by HPLC or liquid scintillation counting (LSC). For all the compounds tested, the scleral permeability was significantly higher than the respective corneal permeability. The permeability coefficients of the beta-blockers varied in the following manner: propranolol > penbutolol > timolol > nadolol for the cornea, and penbutolol > propranolol > timolol > nadolol for the sclera. The cornea offered substantially more resistance to inulin, a polar, macromolecular substance, than did the conjunctiva. However, the cornea and conjunctiva offered comparable resistance to the smaller and less polar drug timolol. This information may serve as a basis for optimizing the intraocular delivery of drugs that are poorly absorbed across the cornea due to their physicochemical properties.

Animals↗
PubMed1985

Importance of the noncorneal absorption route in topical ophthalmic drug delivery.

Transcorneal permeation has traditionally been the mechanism by which topically applied ophthalmic drugs are believed to gain access to the internal ocular structures. Relatively little attention has been given to alternate routes by which drugs may enter the eye. A system has been developed which allowed the investigation in vivo of the contribution of noncorneal absorption to intraocular drug levels after topical dosing. Using timolol and inulin as probe drugs, it was shown that the noncorneal absorption route may contribute significantly to drug penetration into intraocular tissues. Furthermore, results demonstrated that drugs absorbed by the noncorneal route appeared to enter certain intraocular tissues by a mechanism which bypasses the anterior chamber. These studies suggested that intraocular penetration via noncorneal routes involves penetration of drug across the conjunctiva/sclera. Neither reentry from the general circulation after drug absorption into the blood or drug delivery by the local vasculature accounted for the observed results. In terms of topical ophthalmic drug delivery, the noncorneal absorption route may be important for drugs that are poorly absorbed across the cornea due to their physical-chemical properties. We have demonstrated this using inulin as a model for a poorly absorbed, high molecular weight substance.

Absorption↗
PubMed1985

Phase I evaluation and pharmacokinetics of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193).

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-nucleoside with antitumor activity against several murine tumor models, including Lewis lung carcinoma. The mechanism whereby this compound exerts its antineoplastic effects is most likely related to a state of guanine nucleotide depletion whereby the anabolite, thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of Tiazofurin administered on a 5-day, every-28-day schedule. Tiazofurin levels were measured using a high-pressure liquid chromatography assay, and pharmacokinetic studies were performed in patients treated at each dose level. Nineteen patients received a total of 24 courses of the drug in doses ranging from 550 to 2200 mg/sq m. The dose-limiting toxicities were pleuropericarditis and a general illness best described as a "viral-like" syndrome (manifested by severe malaise, headaches, myalgias, fever, nausea, vomiting, and diarrhea). Other toxicity included myelosuppression, hyperuricemia, elevated serum creatine phosphokinase and serum glutamic oxaloacetic transaminase, conjunctivitis, mucositis, and desquamation of the palms of the hands. Plasma clearance of Tiazofurin followed a biexponential pattern with a harmonic mean terminal half-life of 7.6 h. The mean volume of distribution at steady state was 30 liters/sq m, and the mean plasma clearance was 3 liters/h/sq m. The total cumulative urinary excretion ranged from 15 to 49%. The maximally tolerated dose of Tiazofurin on a 5-day schedule was 1650 mg/sq m. The recommended dose for Phase II evaluations is 1100 mg/sq m for 5 days. However, exploration of other schedules which might allow administration of more Tiazofurin combined with biochemical studies including thiazole-4-carboxamide adenine dinucleotide measurements would be desirable.

Adult↗
PubMed1983

Effect of probenecid on the pharmacokinetics of aminophylline.

The authors investigated the effect of probenecid on the pharmacokinetics of aminophylline. Seven normal volunteers served as their own controls in a crossover study. In the first phase, subjects received an oral dose of aminophylline after an overnight fast. In the second phase, probenecid was given orally 30 minutes prior to the administration of aminophylline. Serum and urine theophylline levels were determined by high performance liquid chromatography. Statistical analysis showed that probenecid had no significant effect on any of the pharmacokinetic parameters measured. Probenecid appears to have little or no influence on the liver metabolism of theophylline.

Aminophylline↗
PubMed1981

Effect of various vehicles and vehicle volumes on oral absorption of triamterene in rats.

The oral bioavailability of triamterene in rats was investigated after its administration as a suspension in lipid and aqueous vehicles in addition to lactic acid solution. Triamterene is poorly soluble in both aqueous and lipid vehicles. A 1-ml oral dose volume showed that lipid vehicles may provide some enhancement of oral availability compared with aqueous suspensions. However, when the vehicle volume was reduced to a realistic dosage form volume for the rat, peanut oil and aqueous suspensions were indistinguishable from each other with respect to peak height, peak time, and overall bioavailability. For a given vehicle small vehicle volumes resulted in a better relative oral availability than did large vehicle volumes.

Animals↗
PubMed1981

A physiologically based pharmacokinetic model for the intraocular distribution of pilocarpine in rabbits.

This report presents a mathematical model which has been developed to describe the intraocular disposition of pilocarpine following topical dosing in rabbits. The model uses experimentally determined parameters such as rates of tissue uptake of drug and equilibrium distribution coefficients. Differential mass balance equations for pilocarpine in the cornea, aqueous humor, iris-ciliary body, and lens were written and solved numerically. Measured tear concentrations, following topical dosing wih pilocarpine, were fit by a monoexponential curve and used as the forcing function of the model. By using a combination of known physiological and experimentally determined parameters, predictions of intraocular tissue levels of pilocarpine were made. These predictions were then compared to experimentally determined concentration-time profiles.

Animals↗
PubMed1981

Clinical kinetics on intact cisplatin and some related species.

Plasma concentrations of cisplatin, total platinum, and total filterable platinum were monitored in 24 patients after either 50 or 100 mg/m2 of cisplatin by rapid intravenous injection. Half the patients at each dose were pretreated with mannitol. Total platinum levels declined in a triphasic fashion with a terminal half-life (t1/2)greater than or equal to 24 hr. Both total filterable platinum and cisplatin levels declined in a monophasic manner and exhibited t1/2 of 0.3 to 0.5 hr. The ratio of cisplatin to total filterable platinum in plasma remained constant (0.6 to 0.8) over the time period (2 hr) during which they could be detected, while the ratio of the plasma levels of cisplatin to total platinum decreased continuously from approximately 0.5 at 5 min to approximately 0.10 at 2 hr. Larger doses of cisplatin resulted in higher plasma levels of all three species monitored, and although the increases appeared somewhat less than proportional to dose, terminal plasma slopes were not dose dependent. Neither mannitol nor dose had an effect on the various species ratios, nor did mannitol appear to affect either plasma levels or terminal plasma decline.

Cisplatin↗
PubMed1980

Topically applied pilocarpine. Human pupillary response as a function of drop size.

Previous studies with use of animal models have shown that, for topically applied ophthalmic drugs, the fraction of dose absorbed into the eye is increased as the volume in which the drug is instilled is decreased. Such findings have not previously been confirmed in humans. In the present study, the miotic response to instilled doses of 20 and 50 microL of 0.5% pilocarpine hydrochloride was compared in ten adult human volunteers. Although the 20-microL drop represents a substantial dosage reduction, the miotic response was essentially equivalent to that obtained with the 50-microL drop. These findings imply that, due to the large drainage loss of topically applied ophthalmic drugs, volumes delivered by commerical ophthalmic droppers may in some cases be larger than required to achieve the desired response.

Administration, Topical↗
PubMed1978

Preliminary pharmacokinetic model of pilocarpine uptake and distribution in the eye.

A pharmacokinetic model that permits prediction of aqueous humor pilocarpine levels following topical application to rabbit eyes was developed. The model is able to account for changes in both instilled solution volume and drug concentration. The model, although simplified, relies mainly on experimentally verifiable and independently measured parameters. Its utility lies in its ability to account quantitatively for the large drainage loss of instilled drug solutions and its predictive ability regardless of the instilled volume or concentration. The framework established by this model will allow further sophistication as more experimental data become available and should be adaptable to other ophthalmic drugs.

Animals↗
PubMed1978

Ocular bioavailability and systemic loss of topically applied ophthalmic drugs.

We used 20-day-old rabbits as a model to show that the ocular bioavailability of topically applied pilocarpine nitrate increased as the instilled volume of the drug was decreased. Decreasing the instilled volume from 25 to 5 microliter permitted a dosage reduction of greater than 2.5 times without sacrificing overall drug concentrations in the eye. Since only a small fraction of topically applied doses to the eye actually reached the interior of the eye, the remainder of the dose was lost and available for systemic absorption. The reduction in dosage permitted by this approach resulted in less drug appearing in the general circulation, as shown by comparative plasma level-time profiles. The advantages of reducing drop size are improved ocular bioavailability permitting the use of smaller doses; and less systemic drug loss, thus reducing the potential for systemic side effects. These advantages could be especially significant in the pediatric and geriatric age groups.

Administration, Topical↗
PubMed1978

Studies on the distribution of dianhydrogalactitol into the central nervous system of the rat.

The distribution of dianhydrogalactitol-C14 (DAG-C14) which had been administered to rats as an iv bolus injection was studied in plasma and brain tissue. Analysis of samples was carried out by a high-pressure liquid chromatography method which specifically responds to the parent drug. Samples were monitored by both ultraviolet and liquid scintillation spectrometry. Plasma level measurements indicate that intact DAG has a relatively short half-life in plasma (t1/2= 43.7 minutes) and brain (t1/2 = 50.3 minutes). These findings differ significantly from those studies which have measured total radioactivity when monitoring DAG levels; and should be considered in the design of DAG dose regiments. Data from both brain and plasma were consistent with a classic two-compartment open model.

Animals↗
PubMed1977

Pharmacokinetic evidence for improved ophthalmic drug delivery by reduction of instilled volume.

The bioavailability of topically applied pilocarpine nitrate was studied as a function of instilled volume. As the instilled volume decreased, the fraction of dose absorbed increased. The relationship between fraction absorbed and instilled volume was not direct, but appropriate adjustment of instilled volume and concentration should permit substantial dosage reductions without sacrifice of drug concentration in the eye. The implications of these findings from both a therapeutic and toxicity standpoint are discussed.

Animals↗