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Biomedical subjects

Y W Chien

Publications and source records attributed to Y W Chien.

At least 55 records · Page 3Linked to original sources
PubMed1990

Bioavailability of propranolol following oral and transdermal administration in rabbits.

The systemic bioavailability of propranolol was evaluated following oral and transdermal administration in rabbits. Using a four-way crossover study, the bioavailability of propranolol following oral administration was determined to be 12.3 +/- 5.9%, indicating that propranolol is subject to extensive hepatic first-pass metabolism in rabbits. Transdermal delivery of propranolol, via an adhesive delivery device, resulted in a bioavailability of 74.8 +/- 10.1%, indicating that the transdermal delivery of propranolol can significantly increase systemic bioavailability over oral administration. Skin irritation studies indicated that neither propranolol nor the adhesive used in the device caused any appreciable skin irritation.

Administration, Cutaneous↗
PubMed1990

A numerical approach to study the effect of binding on the iontophoretic transport of a series of amino acids.

The objective of this investigation was to quantitate the effect of binding on the iontophoretic transport of a series of amino acids. The diffusivity and concentration in the stratum corneum and viable skin were estimated from the passive permeation profiles through whole and stripped skin. Using these parameters and the Langmuir binding parameters from equilibrium binding studies, the passive permeation and desorption profiles were simulated using a bilayer skin permeation model. The parameters were adjusted until convergence with experimental data was achieved. Then the iontophoretic profiles were simulated, using the parameters from the simulated passive permeation studies, an estimate of convective flow from the flux of tritiated water, and measurement of the potential across the skin. The overall effect of binding on the iontophoretic profiles was found to dampen the effect of the iontophoresis treatment; the profiles appear flatter, and the transition to passive diffusion less distinct compared to profiles which do not include the binding parameters. It also appear that the degree of skin hydration has a substantial effect on the shape of the iontophoretic profile, such that approximately 50% of the enhancement in the iontophoretic profile of freshly excised skin continues after treatment.

Amino Acids↗
PubMed1990

Enhancement of the in vitro skin permeability of azidothymidine (AZT) via iontophoresis and chemical enhancer.

Azidothymidine (AZT) was used as a model drug to study the effect of iontophoresis on the skin permeation of a neutral compound. The rate of in vitro permeation across hairless rat skin was low and highly variable. With iontophoresis treatment the permeation rate was two- to threefold greater than by passive diffusion. The addition of varying amounts of sodium chloride to the donor enhanced the iontophoretic permeation rate an additional two- to threefold possibly due to convective forces. The addition of N-decylmethyl sulfoxide (C10MSO) to the donor increased the permeation rate by several hundred-fold over passive diffusion for hairless rat skin and approximately 75-fold for human skin. No additional enhancement was observed with the combination of C10MSO and iontophoresis treatment at constant current or constant voltage. It may be that the presence of C10MSO lowers the zeta potential of the skin, thus enhancement due to convective flow is minimized.

Animals↗
PubMed1989

Effect of propranolol on the myocardial contractility of normotensive and spontaneously hypertensive rabbits: relationship of pharmacokinetics and pharmacodynamics.

Myocardial contractility of normotensive and spontaneously hypertensive rabbits was determined following an iv bolus injection of propranolol HCl. Left ventricular pressure and dimension were used to calculate the contractility parameters of (dP/dt)max, maximum fiber shortening velocity (Vcf), and the slope of the end systolic pressure-end systolic volume line (ESP-ESV line). Hypertension was induced by a methoxamine HCl iv infusion which mimicked the cardiac effects seen in essential hypertension. Propranolol caused a significant decrease in all contractility parameters (p less than 0.05) within 15 min after administration, with a peak effect occurring after 30-35 mins. The pharmacokinetics and pharmacodynamics of propranolol were fit using Hill's equation in conjunction with the concentration of drug in the theoretical effect compartment. The normotensive group of rabbits had a calculated EC(50) of 12.7 ng/ml, while the hypertensive group had an EC(50) of 6.9 ng/ml, indicating that the hypertensive rabbits were much more sensitive to the propranolol than the normotensive group. In addition, the normotensive group of rabbits demonstrated a much different pharmacokinetic-pharmacodynamic relationship than that of the hypertensive group, indicating that the hypertensive state of the animal has a significant effect upon the concentration-effect relationship.

Animals↗
PubMed1989

Drug absorption through mucosal membranes: effect of mucosal route and penetrant hydrophilicity.

The influence of mucosal route and penetrant hydrophilicity on the in vivo absorption of a model lipophilic compound, progesterone, was investigated in ovariectomized rabbits. The absorption rate and systemic bioavailability of progesterone and its monohydroxy, dihydroxy, and trihydroxy derivatives were evaluated and compared following oral, nasal, rectal, and vaginal administrations. Nasal delivery resulted in a significantly higher rate and extent of progesterone absorption than oral, rectal, or vaginal administration. The rate and extent of mucosal absorption decreased as penetrant hydrophilicity increased for the nasal, rectal, and vaginal routes. The results of this investigation indicate that the absorption characteristics of a lipophilic compound, such as progesterone, are influenced by the properties of both the mucosa and the drug.

Absorption↗
PubMed1989

Transdermal dual-controlled delivery of contraceptive drugs: formulation development, in vitro and in vivo evaluations, and clinical performance.

Several transdermal contraceptive device (TCD) formulations were developed to provide a dual-controlled transdermal delivery of levonorgestrel (LN), a potent progestin, and 17 beta-estradiol (E2), a natural estrogen. Using a sensitive HPLC method, the in vitro release and skin permeation profiles of LN and E2 from various TCD formulations were simultaneously characterized in the hydrodynamically well-calibrated Valia-Chien skin permeation cells and both were found to follow zero-order kinetics. The rates of drug release and skin permeation were observed to vary significantly depending upon some formulation parameters. Six-month stability studies were performed on seven formulations at room and elevated temperatures (37 and 45 degrees C), and two (Formulations 4 and 5) were found to be acceptable, based on drug recovery, release rate, and skin permeation rate data. Judging from the 6-month accelerated stability studies, it is projected these two formulations will have shelf-life of at least 2 years. As a result of development of an efficient manufacturing process, Formulation 4 was selected for further evaluation. One-week primary skin irritation evaluation in 6 rabbits indicated that Formulation 4 is nonirritating, and it was thus selected for Phase I clinical bioavailability/dose proportionality studies in 12 healthy female volunteers of child-bearing age. Results of pharmacokinetic and pharmacodynamic analyses demonstrated that it is capable of achieving and maintaining a steady-state serum level of LN throughout the 3-week treatment period by weekly applications of one or two TCD patches (10 or 20 cm2). A dose proportionality was obtained in the serum drug levels, daily dose delivered, and contraception efficacy. An excellent correlation was obtained for the rates of transdermal delivery determined by the in vitro studies using human cadaver skin, the in vivo studies in rabbits, and the clinical studies in living subjects.

Adhesives↗
PubMed1989

Transdermal controlled delivery of propranolol from a multilaminate adhesive device.

The feasibility of transdermal controlled delivery of propranolol was investigated by conducting in vitro skin permeation studies using rabbit pinna (ear) skin. A new multilaminate adhesive device which is capable of releasing propranolol in a controlled fashion over a 24-hr period had been developed and was evaluated transdermally using rabbit pinna skin. Skin permeation of propranolol from the device was found to be controlled by the stratum corneum during the early phase of permeation and then by the adhesive device during steady-state permeation. The rabbit pinna skin was shown to be a good animal model for studying the transdermal permeation of propranolol from the device, when compared to human cadaver skin.

Adhesives↗
PubMed1989

Different hemodynamic effects of atrial natriuretic factor and nitroglycerin in rats with congestive heart failure.

Atrial natriuretic factor (ANF) decreases cardiac filling pressure, suggesting that diminished venous return is an important mechanism for the associated reduction in cardiac output. To determine whether ANF reduces cardiac preload through venodilation in congestive heart failure (CHF), we compared the hemodynamic effects of ANF-(99-126) with those of the venodilator nitroglycerin in conscious rats with CHF induced by coronary artery ligation previously. Depending on the extent of myocardial infarction, rats were subdivided into two groups: 1) mild or 2) severe CHF. Incremental intravenous infusions of ANF (0.1, 0.25, 0.5 micrograms.kg-1.min-1) or nitroglycerin (2, 5, 10 micrograms.kg-1.min-1) were administered for 20 min at each dose. Both agents reduced cardiac filling pressures. There was no change in cardiac output or arterial pressure at any dose of ANF in rats with severe CHF, but cardiac output decreased at higher ANF doses in rats with mild CHF. In contrast, nitroglycerin produced no change in cardiac output at any dose in either CHF group, although it decreased arterial pressure at the higher doses in rats with severe CHF. ANF increased whereas nitroglycerin decreased hematocrit in both CHF groups. The ANF-induced hematocrit increase also occurred in those rats with vesicovenous shunts designed to prevent volume contraction induced by diuresis. These data suggest that ANF and nitroglycerin decreased cardiac filling pressure through different hemodynamic mechanisms. The known venodilator action of nitroglycerin was associated with decreased hematocrit, suggesting enhanced transcapillary fluid migration. However, ANF produced an opposite effect on fluid migration as demonstrated by an increased hematocrit, suggesting a mechanism other than venodilation must be operative in reducing cardiac filling pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Rate-control drug delivery systems: controlled release vs. sustained release.

Recently, several technical advancements have been made in the development of new generation of drug delivery systems. These systems are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic efficacy, and/or targeting the delivery of drug to a tissue. Depending upon the technical sophistication, these rate-control drug delivery systems can be classified into three major categories: (i) pre-programmed drug delivery, (ii) activation-controlled drug delivery, and (iii) feedback-regulated drug delivery. Various types of drug delivery devices which have been recently marketed or under active development are grouped, on technology basis, under each category. The fundamentals behind the development of each type of the rate-control drug delivery systems with the successful examples of biomedical application are analyzed, aiming to gain a better understanding of the science and technology involved as well as to pave a solid foundation for future development of innovative new drug delivery systems.

Animals↗
PubMed1988

Transdermal controlled administration of indomethacin. I. Enhancement of skin permeability.

It was observed experimentally that indomethacin delivered in an aqueous suspension has a greater skin permeation rate in an ionized form than in a nonionized form. In this investigation, a matrix-type transdermal drug delivery system was developed to deliver indomethacin molecules in nonionized form. The skin permeation rate of nonionized indomethacin molecules from this system could be substantially improved by incorporating skin permeation enhancers, such as straight-chained alkanols, alkanoic acids, and esters. These enhancers form microreservoirs with indomethacin in the lipophilic silicone polymer matrix. By varying the alkyl chain length of alkanol, alkanoic acid, and its ester, the concentration of permeation enhancer, or the loading dose of indomethacin in the polymer matrix, the skin permeation rate of nonionized indomethacin molecules can be enhanced by as much as 30 times, which is almost sevenfold greater than the rate for ionized indomethacin molecules.

Administration, Cutaneous↗
PubMed1988

Pharmacokinetics and bioavailability of hydromorphone: effect of various routes of administration.

The pharmacokinetics and bioavailability of hydromorphone following various routes of administration, i.e., intravenous, oral, intranasal, and transdermal, were investigated in rabbits. Hydromorphone plasma concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC). Comparison of area under the concentration versus time curve (AUC) between intravenous and oral administrations showed a low bioavailability of hydromorphone after oral administration. The nasal absorption of hydromorphone was studied by the in situ nasal recirculation technique, and the results showed that hydromorphone is well absorbed from the nasal mucosa. The transdermal permeation of hydromorphone was also evaluated for 24 hr and a steady-state plasma concentration (0.135 micrograms/ml) was achieved during the 6- to 24-hr periods following the application of a transdermal patch on the inner pinna of the rabbit's ear.

Administration, Cutaneous↗
PubMed1988

Increased ANF secretion after volume expansion is preserved in rats with heart failure.

To examine whether the failing heart has reached a maximal capacity to increase plasma atrial natriuretic factor (ANF) concentration, the change in plasma immunoreactive ANF level due to acute blood volume expansion was determined in conscious rats with chronic heart failure. Varying degrees of myocardial infarction and thus heart failure were induced by coronary artery ligation 3 wk before study. Compared with controls, infarcted rats had decreases in mean arterial pressure (-10 mmHg, P less than 0.01), cardiac index (-27%, P less than 0.001), renal blood flow (-35%, P less than 0.01), and peak left ventricle-developed pressure after aortic occlusion (an index of pressure generating ability; -15%, P less than 0.01), and increases in central venous pressure (+1.7 mmHg, P less than 0.01), left ventricular end-diastolic pressure (+10 mmHg, P less than 0.001), total peripheral resistance (+28%, P less than 0.01), and plasma ANF level (752 +/- 109 vs. 244 +/- 33 pg/ml, P less than 0.001). Plasma ANF was correlated with infarct size, cardiac filling pressures, and left ventricle pressure-generating ability. At 5 min after 25% blood volume expansion, plasma ANF in rats with heart failure increased by 2,281 +/- 345 pg/ml; the magnitude of the changes in circulating ANF and hemodynamic measurements was similar in controls. The results suggest that plasma ANF level can be used as a reliable index of the severity of heart failure, and that the capacity to increase plasma ANF concentration after acute volume expansion is preserved in rats with heart failure. There was no evidence of a relative deficiency of circulating ANF in this model of heart failure.

Animals↗
PubMed1988

Transdermal drug delivery: a review of pharmaceutics, pharmacokinetics, and pharmacodynamics.

This article provides a critical literature review on the recent advances in the research and development of rate-controlled transdermal therapeutical systems for systemic medication. The article focuses its discussion on the recent development in the fundamentals, developmental concepts, and biomedical assessment of the transdermal controlled drug administration. The scope of the review consists of the following areas: mechanism of percutaneous absorption; enhancement of skin permeability; in vitro and in vivo evaluations of transdermal permeation kinetics and assessment of in vitro-in vivo relationship; pharmacokinetics and pharmacodynamics of transdermal controlled drug administration and establishment of pharmacokinetic/pharmacodynamic relationship; clinical performance of rate-controlled transdermal therapeutic systems; and potential development in rate-controlled transdermal drug delivery.

Administration, Cutaneous↗
PubMed1988

Development of the rabbit model for studying the effects of propranolol on cardiac contractility: relationship of intravenous pharmacodynamics and pharmacokinetics.

The New Zealand white rabbit (3-4 kg) was chosen as an experimental model to determine the effects of propranolol, by intravenous bolus administration, on cardiac contractility. The cardiovascular effects were measured by systolic time interval recordings for up to 8 h. The study was performed on two groups of animals with 5 rabbits receiving active drug and another 5 rabbits receiving saline placebo. All animals were anesthetized by parenteral administration of urethane/acepromazine. The results indicated that at 15 min after intravenous administration, propranolol caused a maximum decrease in heart rate (p less than 0.01), as well as a maximum increase in QS2 (p less than 0.01), LVET (p less than 0.01), PEP (p less than 0.01) and PEP/LVET (p less than 0.05). Approximately 90 min after drug administration, a significant (p less than 0.01) "rebound phenomenon" was observed in the active group which continued throughout the 8-h observation period. This preliminary study suggests that the rabbit is a useful animal model to study the effects of propranolol on cardiac contractility.

Animals↗
PubMed1987

Drug permeation across the skin: effect of penetrant hydrophilicity.

The hydrophilicity of progesterone, a lipophilic steroid itself, was progressively increased by incorporating one or more hydroxy substituents at different positions on the steroidal skeleton. Effects of these hydrophilic substituents on the permeation of progesterone across the intact skin and stripped skin of the hairless mouse were studied using a hydrodynamically well-calibrated in vitro skin permeation system. The steady-state rate of permeation across the intact skin and stripped skin was found to be approximately proportional to the solubility of drugs in the stratum corneum or in the viable skin, respectively. Furthermore, the solubility of progesterone and its hydroxyl derivatives in the stratum corneum was noted to decrease gradually as the hydrophilicity of the penetrant increased. This finding was similar to that of a previously reported study of drug permeation across the lipophilic silicone membrane. However, the solubility of these progestins in the viable skin was observed to be dependent not only on the penetrant hydrophilicity but also on the position of the OH group on the penetrant molecule. The diffusivity of progesterone and its hydroxyl derivatives across the stratum corneum and viable skin was almost independent of the hydrophilicity of the drugs.

Animals↗