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Biomedical subjects

K D Rittenhouse

Publications and source records attributed to K D Rittenhouse.

7 recordsLinked to original sources
PubMed2000

Microdialysis and drug delivery to the eye.

The eye presents unique challenges in both the development of tools for elucidating drug disposition as well as for the development of modes of drug delivery for treatment of ocular diseases. In this paper, we present a discussion of the anatomical and physiological characteristics and limitations present in the eye for microdialysis sampling of endogenous substrates and xenobiotics. To date, over twenty papers describing microdialysis approaches for assessment of ocular drug delivery and endogenous substrate characterization have been published. Although the majority of papers describe sampling of vitreous humor, recent efforts have been directed towards ocular anterior segment sampling using microdialysis. With this approach, an appreciable reduction in animal use has been realized. In addition, simultaneous examination of administered drug and endogenous substrates modulated by the drug is possible with this approach, facilitating construction of ocular pharmacokinetic/pharmacodynamic relationships through use of relevant surrogate markers.

Animals↗
PubMed2000

Pharmacodynamics of beta-blocker modulation of aqueous humor production.

A conscious rabbit model with microdialysis sampling of endogenous aqueous humor ascorbate was developed in order to assess the pharmacodynamics of beta-blocker modulation of aqueous humor production. CMA/20 microdialysis probes were implanted in the anterior chamber of each eye of rabbits (n = 6). After a 2 week recovery period, an i.v. bolus of 14C-ascorbate (20 microCi) was administered. Blood samples and aqueous humor microdialysis probe effluent were collected and analysed for endogenous and 14C-ascorbate to estimate the basal rate of ascorbate blood to aqueous humor secretion (Ro). After a 1 hr washout, each rabbit received a series of three doses of 3H-propranolol (750-3000 microg, 16.5 microCi mg(-1)) every 60 min into the lower cul-de-sac of each eye. Probe effluent was analysed for endogenous ascorbate and 3H-propranolol; ascorbate and propranolol in the iris/ciliary body, vitreous and aqueous was determined at the end of the experiment. Nonlinear least-squares regression analysis of the concentration-time profiles for aqueous humor ascorbate was performed to estimate the change in aqueous humor flow. The average basal aqueous humor ascorbate secretion rate was approximately 48/microg hr(-1). Propranolol (1500 microg) produced significant increases in aqueous humor ascorbate, this observation is consistent with a reduction in aqueous humor production (approximately 47%). Analysis of intraocular tissue ascorbate indicated that propranolol inhibited ascorbate secretion at the 3000 microg dose, the highest dose examined in this study; this inhibition was not observed at the 750 microg or 1500 microg doses. Changes in aqueous humor production precipitated by the administration of beta-adrenergic antagonists can be estimated by measuring changes in aqueous humor ascorbate concentrations in the conscious rabbit. Microdialysis sampling of aqueous humor for endogenous ascorbate provides a relevant analytic tool to estimate modulatory effects of anti-glaucoma drugs on aqueous humor production.

Acetazolamide↗
PubMed2000

Assessment of ascorbate ocular disposition in the conscious rabbit: an approach using the microdialysis technique.

PURPOSE: This study was performed to evaluate the transport kinetics of ascorbate in aqueous humor of conscious rabbits. METHODS: Following the development of a spectrophotometric assay for ascorbate in serum, aqueous humor and microdialysate, and preliminary studies of ascorbate systemic disposition in the rabbit, microdialysis probes were placed into the anterior chamber of one eye, and the posterior chamber of the contralateral eye, of four New Zealand white rabbits. After a one-month recovery period, conscious rabbits were placed in restraining devices, and marginal ear veins were cannulated for repeat blood sampling and ascorbate administration. A tracer i.v. bolus of (14)C-ascorbate, followed by stepwise increasing i.v. infusions of unlabelled ascorbate, was administered. Estimates of basal ascorbate transport into aqueous were determined by analysis of tracer ( 14)C-ascorbate in microdialysis probe effluent and serum. Kinetic modeling was employed to assess ascorbate disposition during infusion. RESULTS: Systemic disposition of exogenously administered ascorbate was well characterized by a two-compartment model. Kinetic modeling returned physiologically realistic volumes for the posterior chamber, and reliable estimates governing ascorbate flux into, between, and from the posterior and anterior chambers. CONCLUSIONS: In vivo assessment of ascorbate kinetics in aqueous humor and blood of the rabbit was facilitated by the microdialysis technique. Contrary to reports in the literature, ascorbate saturable uptake from blood to aqueous was not observed at physiologic blood concentrations ( approximately 11 to 30 mg/L).

Animals↗
PubMed1999

Microdialysis evaluation of the ocular pharmacokinetics of propranolol in the conscious rabbit.

PURPOSE: This study was conducted to assess the effects of anesthesia and aqueous humor protein concentrations on ocular disposition of propranolol. METHODS: Rabbits were anesthetized and a microdialysis probe was inserted into the anterior chamber of one eye; the contralateral eye served as a control. At timed intervals after probe placement, a 100-microl sample of aqueous humor was aspirated from each eye to determine protein concentration. In vitro protein binding parameters were used to simulate the impact of protein concentration on propranolol disposition. To assess the influence of anesthesia, probes were implanted in the anterior chamber of each eye. After >5-day stabilization, conscious and anesthetized rabbits (n = 3/group) received a 200-microg topical dose of [3H]DL-propranolol in each eye; propranolol was assayed in probe effluent. RESULTS: Changes in aqueous humor protein concentrations were observed following probe insertion. Simulations demonstrated that the unbound propranolol AUC (approximately 2.4-fold) in aqueous humor should be reduced due to protein influx. Intraocular propranolol exposure in anesthetized rabbits was approximately 8-fold higher than in conscious rabbits, and approximately 1.9-fold higher than in rabbits without a post-surgical recovery period. CONCLUSIONS: Anesthesia and time-dependent aqueous humor protein concentrations may alter ocular pharmacokinetics, and must be taken into account in the design of microdialysis experiments.

Adrenergic beta-Agonists↗
PubMed1998

Evaluation of microdialysis sampling of aqueous humor for in vivo models of ocular absorption and disposition.

The dynamics of beta-adrenergic-associated reductions in aqueous humor production for treatment of elevated intraocular pressure are not well understood. In particular, the relationship between ocular pharmacokinetics and pharmacodynamics has yet to be established. This study was undertaken to develop a procedure for examining the ocular absorption and disposition of topically administered ophthalmic beta-adrenergic antagonists in individual animals. Dogs were anesthetized with isoflurane and a microdialysis probe was implanted in the anterior chamber of one eye and perfused with 0.9% saline at a rate of 2 microliters min-1. 3H-propranolol was administered by intracameral injection or topically. Each dog received intracameral and topical propranolol, in alternate eyes on separate days, in a randomized cross-over fashion. Microdialysis probe effluent was collected every 5 min for > or = 2.5 h; concentrations of propranolol were determined by liquid scintillation spectroscopy and were corrected for probe recovery of the substrate as determined by in vivo retrodialysis (approximately 46%) to estimate aqueous humor concentrations. In separate experiments in rabbits, microdialysis probes were implanted in each eye. 3H-propranolol was administered topically to one eye; the contralateral eye received intracameral 3H-propranolol. Model-independent pharmacokinetic parameters for each treatment phase were calculated. The mean +/- S.D. times to peak concentration of propranolol in aqueous humor were 86.6 +/- 47.6 min in the dog and 54.1 +/- 20.4 min in the rabbit. The terminal rate constant was 0.0189 +/- 0.00429 min-1 in the dog vs. 0.00983 +/- 0.00546 min-1 in the rabbit. Intraocular tissue availability of propranolol differed markedly between the dog (n = 3) and rabbit (n = 3) (approximately 0.056 in the dog vs. approximately 0.55 in the rabbit). These results demonstrate the utility of microdialysis sampling for examination of ocular pharmacokinetics.

Absorption↗
PubMed1993

Artifactual variation in randomly amplified polymorphic DNA banding patterns.

Randomly amplified polymorphic DNA (RAPD) and arbitrarily primed PCR (AP-PCR) represent novel DNA polymorphism assays that involve the amplification of random DNA segments using PCR and oligonucleotide primers of arbitrary sequence. Products defining the polymorphisms exhibit Mendelian inheritance and thus possess tremendous potential utility as genetic markers in a diverse array of scientific disciplines. Amplification profiles for specific oligonucleotide primers are highly dependent on the specific conditions of the reaction; banding patterns may thus vary extensively because of inconsistencies in a number of reaction parameters. Artifactual variation represents a potential problem in surveys of genetic variation in natural populations and must be discriminated from true polymorphism for the applications of RAPD to be both accurate and reliable.

Base Sequence↗