Oliver Yoa Pu Hu

Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a common lethal disease in Asia and there is no effective chemotherapy. Identification of new effective drugs in the treatment of inoperable HCC is urgently need. This is a phase II clinical study to investigate the efficacy, toxicity and pharmacokinetics of paclitaxel in HCC patients. Twenty patients with measurable, unresectable HCC, normal serum bilirubin, normal bone marrow and renal functions were studied. Paclitaxel 175 mg m(-2) was given intravenously over 3 h every 3 weeks. No complete or partial responses were observed. Five patients had stable disease. Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paclitaxel is metabolized by the liver and the pharmacokinetics of paclitaxel in cancer patients with liver involvement or impairment may be important clinically. Pharmacokinetic study was completed in 13 HCC patients. The paclitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.

Mucoadhesive buccal disks for novel nalbuphine prodrug controlled delivery: effect of formulation variables on drug release and mucoadhesive performance

The objective of this work was to assess the effects of drug solubility and loading percent, as well as Carbopol 934/hydroxypropylcellulose (CP/HPC) ratio, on drug release and mucoadhesive performance of the nalbuphine prodrug loaded buccal disks. Drug release rates for the disks were found to be a function of drug solubility, with higher drug release rates for disks loaded with more hydrophilic prodrugs and an increased amount of beta-cyclodextrin. The drug release rates increased with loading percents for nalbuphine hydrochloride, whereas an opposite drug release trend was observed for disks loaded with nalbuphine enanthate, which can be explained by the diffusional drug release mechanism. The CP/HPC ratio affected release rates of nalbuphine enanthate, whereas the ratio had no impact on the release of nalbuphine hydrochloride. Within the 2 days of experiment time, all formulations attached well to the porcine buccal tissues, indicating those formulation variables had no influence on the mucoadhesive performance of CP/HPC-based buccal disks.

ASSESSING SENSITIVITY AND SIMILARITY IN BRIDGING STUDIES

In pharmaceutical industry, the sponsors are interested in bringing their drug products from one region (e.g., the United States of America) to another region (e.g., Asian Pacific) to increase the exclusivity of the drug products in the marketplace. However, it is a concern whether the clinical results can be extrapolated from the target patient population in one region to a similar but different patient population in a new region due to a possible difference in ethnic factors. The International Conference on Harmonization (ICH) recommends that a bridging study may be necessarily conducted to extrapolate the clinical results between regions. However, little or no information regarding the criterion for determining whether a bridging study is necessary based on the evaluation of the complete clinical data package is provided by the ICH. Furthermore, no criterion on the assessment of similarity of clinical results between regions is given. In this paper, we propose the use of a sensitivity index as a possible criterion for regulatory authorities in the new region to evaluate whether a bridging clinical study should be conducted and the sample size of such a bridging clinical study. A criterion and a statistical method for assessment of similarity of clinical results between regions are also proposed, using the concept of population bioequivalence [FDA. Guidance for Industry—Statistical Approaches to Establishing Bioequivalence, Center for Drug Evaluation and Research, Food and Drug Administration: Rockville, MD, 2001] assuming that study site is random.

Controlled release of nalbuphine prodrugs from biodegradable polymeric matrices: influence of prodrug hydrophilicity and polymer composition

Abstract The objective of this work was to assess the effects of nalbuphine prodrug hydrophilicity and lactide/glycolide copolymer ratio on drug release from lactide/glycolide based polymeric matrices. A panel of four nalbuphine prodrugs with various ester chains were incorporated into poly ( d,l -lactide) based matrices by using the solvent evaporation method. Drug release rates for the matrices were found to be a function of prodrug hydrophilicity, with higher drug release rates for matrices with more hydrophilic prodrugs. Data analysis using the Higuchi expression indicated that the release of various prodrug from poly ( d,l -lactide) based matrices was consistent with a diffusion mechanism. The prodrug release rate constants derived from the Higuchi expression correlated well with prodrug solubilities. In the second part of the study, the effect of lactide/glycolide copolymer ratio on nalbuphine propionate release was studied. The drug release rate and matrix hydration rate were found to be a function of copolymer ratio, with faster drug release and matrix hydration for matrices with lower lactide/glycolide ratio copolymers. The nalbuphine propionate release profiles fit well to the Higuchi expression, indicating that drug release from the Poly ( d,l -lactide-co-glycolide) based matrices was consistent with a diffusion mechanism. The drug release rates correlated well with matrix hydration rates, suggesting that different polymer compositions may attribute to various matrix hydration and therefore affect drug release from the PLGA matrices.

Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis.

The in vitro transport of nalbuphine (NA) and its prodrugs across various skins was investigated in order to assess the effects of prodrug lipophilicity on passive as well as iontophoretic permeation. The passive diffusion of NA and its prodrugs increased with the drug lipophilicity. Iontophoresis significantly increased the transport of NA and its prodrugs; the enhancement ratio was highest for NA and decreased as the drug lipophilicity increased. Measurements using intact and stratum corneum (SC)-stripped skins showed that the SC was the major skin diffusion barrier for the passive permeation of NA and nalbuphine pivalate (NAP). The iontophoretic permeation of NA and NAP across intact and SC-stripped skins indicated that the SC layer was not rate-limiting for the permeation of NA, but remained the rate-limiting barrier for transdermal permeation of NAP. Permeation studies using SC-stripped and delipidized skins suggested that the intercellular pathway was the predominant route for the passive permeation of NA and NAP as well as the iontophoretic permeation of NAP across the SC. The relative rates of passive and iontophoretic permeation across Wistar rat skins demonstrated that a significant amount of NA may permeate skin via the appendageal routes, whereas NAP permeated predominantly through the lipid matrix.

Evaluation of gastric emptying in severe, burn-injured patients.

ObjectiveThe aim of this study was to evaluate the possible effect of a severe burn on gastric emptying by determining the absorption kinetics of orally administered acetaminophen. DesignA prospective, controlled study. SettingA ten-bed burn center in a 1,300-bed university hospital. PatientsTen adult patients suffering from second-degree burn involving > 20% of total body surface area and 20 normal, healthy volunteers who acted as controls. InterventionsPatients received routine treatment such as nutritional support and cimetidine. However, opiates were stopped for at least 12 hrs before the start of the study, and nonsteroidal anti-inflammatory drugs as alternatives were used. After an 8-hr fast, the subjects in gested 0.5 g acetaminophen with 200 mL of water. The plasma concentrations of acetaminophen were determined by high-performance liquid chromatography, and the absorption kinetics was estimated from determination of time to reach the maximum plasma concentration, the maximum plasma concentration, and the area under the plasma concentration, time curve. Measurements and Main ResultsThe mean time for reaching the maximum plasma concentration was 33 ± 24 (SD) mins in patients and 39 ± 24 mins in the healthy volunteers. The mean area under the plasma concentration-time curve from time 0 to 120 mins and the mean maximum plasma concentration were 556 ± 190 μg/mL/min and 9.5 ± 3.5 μg/mL in patients, and 539 ± 131 μg/mL/min and 7.8 ± 2.8 μg/mL in volunteers, respectively. There was no statistical difference between groups in the time to reach the maximum plasma concentration, the area under the plasma concentration-time curve from time 0 to 120 mins, and the maximum plasma concentration. The time for reaching the maximum plasma concentration was not correlated with the severity of the burn (% area of burn) and the duration of healing (days) after burn. ConclusionsWe conclude that severe burn injury does not affect the kinetics of gastric emptying, and that 200 mL of water ingested 2 hrs before anesthesia is quite safe in severely burned patients. Also, the absorption kinetics of acetaminophen was not altered by burn injury. (Crit Care Med 1993; 21:527–531)

Transdermal delivery of nalbuphine and its prodrugs by electroporation.

The aim of this study was to assess the effects of electroporation on transdermal permeation of nalbuphine (NA) and its prodrugs. The permeation characteristics were investigated under various electrical factors and skin barriers to elucidate the mechanisms involved in transdermal delivery of NA and its prodrugs by skin electroporation. The in vitro permeation studies were performed using side-by-side diffusion cells. The various electrical factors investigated were pulse voltage, pulse duration and pulse number; the different skin barriers studied were intact hairless mouse skin, stratum corneum (SC)-stripped skin, delipid skin as well as furry Wistar rat skin. The prodrugs were fully converted to parent drug after skin permeation. Application of electroporation significantly enhanced transdermal permeation of NA and its prodrugs. The enhancement ratios were highest for NA and the four prodrugs showed the similar permeability after electroporation. The permeation amounts of NA and its prodrugs may be increased by application of higher pulse voltage, pulse duration as well as pulse number. Various kinetics and mechanisms were observed for the permeation of the hydrophilic NA and lipophilic nalbuphine enanthate through different skin barriers by applying electroporation. This study demonstrated that electroporation may enhance and control transdermal permeation of NA and its prodrugs. The results also indicated that the physicochemical properties of prodrug had significant effects on kinetics as well as mechanisms of transdermal permeation by electroporation.

Controlled release of nalbuphine propionate from biodegradable microspheres : In vitro and in vivo studies

The objective of this work was to assess the in vitro characteristics, in vivo pharmacokinetics and in vivo pharmacodynamics of nalbuphine propionate (NAP)-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate NAP into poly (d,l-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of the microspheres were evaluated using scanning electron microscopy which showed a spherical shape with smooth surface. A prolonged in vitro drug release profile was observed, with approximately 71.1% of incorporated drug released in 96 h. The release profile fit well to the Baker and Lonsdales spherical matrix model, suggesting the release of NAP from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after subcutaneous injection of NAP-loaded microsphere showed a sustained plasma nalbuphine (NA)-time profile, with 100% relative bioavailability comparing to the AUC obtained after intravenous injection. The in vitro release pattern correlated well with the in vivo pharmacokinetic profile. The pharmacodynamic studies evaluated using paw pressure model also showed a prolonged pharmacological response after injection of microspheres. A linear correlation between the percent analgesic effect and the logarithm of plasma NA concentration was obtained, suggesting the pharmacological response can be reflected by plasma drug concentration. This correlation may be utilized for evaluating the pharmacological responses of various NA and its prodrug-based formulations with known plasma NA concentrations.

Determination of buprenorphine by high-performance liquid chromatography with fluorescence detection: application to human and rabbit pharmacokinetic studies

A rapid, sensitive, precise and accurate high-performance liquid chromatographic assay with fluorescence detection was developed for the determination of buprenorphine in human, rabbit, pig and dog plasma. It is comprised of only a one-step extraction procedure with hexane-isoamyl alcohol at pH 9.25 and reversed-phase chromatography on a muPorasil column. The recoveries of buprenorphine and nalbuphine (internal standard) were greater than 90%. Calibration graphs were linear over the concentration range 3-300 ng/ml with a coefficient of variation, both within-day and between-day, of less than 9% at any level. The limit of detection was 1.0 ng/ml of plasma based on a signal-to-noise ratio of 3. Eight other clinically used narcotics were investigated to check for potential interferences and their analytical conditions. The possible decomposed compounds of buprenorphine were also checked for the specificity of this assay. The method has been successfully applied to the stability and pharmacokinetic studies of buprenorphine. Buprenorphine in plasma did not decompose significantly at -20 degrees C for four weeks. Pharmacokinetic application in six rabbits and a surgical patient revealed that buprenorphine followed a linear three-compartment model with two distribution phases. The two distribution and elimination half-lives and the clearance of buprenorphine were 1.32, 24.8 and 230 min and 224 ml/min in human plasma, and 0.94, 12.5 and 232 min and 30 ml/min in rabbit plasma.

A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide

ABSTRACT Relatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identified and cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were collected from 153 tuberculosis (TB) patients, and the results were evaluated to confirm whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that coadministration of amidase inhibitor (bis-p-nitrophenyl phosphate [BNPP]) decreases or prevents PZA- and PZA metabolite-induced hepatotoxicity in rats. PA and 5-OH-PA are more toxic than PZA. Electron microscopy showed that PZA and PA treatment of rats significantly increases aspartate transaminase (AST) and alanine aminotransferase (ALT) activity and galactose single-point (GSP) levels (P < 0.005). PA and 5-OH-PA levels are also significantly correlated with hepatotoxicity in the urine of TB patients (P < 0.005). Amidase inhibitor, BNPP, decreases PZA-induced, but not PA-induced, hepatotoxicity. This is the first report of a cell line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA-induced hepatotoxicity.