Safety and Efficacy of Oral Nalbuphine on Postoperative Pain in Hemorrhoidectomy Patients: A Randomized, Double-blind, Placebo-controlled, Pivotal Trial.

OBJECTIVES: Severe postoperative pain requiring opioid treatment has been reported in 20% to 40% of hemorrhoidectomy patients. Compared with morphine, nalbuphine offers better hemodynamic stability, a lower risk of respiratory depression, and a lower potential for addiction. Nalbuphine was developed from the intravenous form into an oral form (PHN131) to alleviate moderate-to-severe pain. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, multiple-dose, parallel-design trial was conducted to evaluate the safety and efficacy of PHN131 in patients undergoing hemorrhoidectomy. Eligible patients were randomly assigned to receive either PHN131 soft capsules containing nalbuphine hydrochloride 60 mg or placebo capsules. Intramuscular diclofenac was the rescue analgesic. Pain was measured by the area under the curve of mean Visual Analog Scale pain intensity scores. RESULTS: Visual Analog Scale results in patients receiving PHN131 were significantly lower than placebo group scores through 48 hours postoperatively (149.2±75.52 vs. 179.6±65.97; P =0.0301). According to Brief Pain Inventory Short-Form scores, the impact of pain on quality of life was significantly smaller for the PHN131 group than for the placebo group. Time to the first use of diclofenac postoperatively was significantly longer in the PHN131 group than in the placebo group. The cumulative dosage of diclofenac in the PHN131 group was only around half of that in the placebo group ( P <0.0001). Drug-related adverse events were mild-to-moderate and resolved by the treatment end. No drug-related severe adverse events were observed. DISCUSSION: Our findings demonstrate that PHN131 is effective and well-tolerated in the treatment of moderate-to-severe post hemorrhoidectomy pain and may provide another option for patients to control their pain.

A novel galactose electrochemical biosensor intended for point-of-care measurement of quantitative liver function using galactose single-point test.

Liver disease has emerged as a healthcare burden because of high hospitalization rates attributed both to steatohepatitis and to severe hepatic toxicity associated with changes of drug exposure. Early detection of hepatic insufficiency is critical to preventing long-term liver damage. The galactose single-point test is recommended by the US FDA as a sensitive means to quantify liver function, yet the conventional method used for quantitation of circulating galactose still relies on the standard colorimetric method, requiring time-consuming and labor-intensive processes, and is confined to the medical laboratory, thus limiting prevalence. To facilitate time- and cost-effective disease management particularly during a pandemic, a pocket-sized rapid quantitative device consisting of a biosensor and electrochemical detection has been developed. An in vitro validation study demonstrated that the coefficient of variation was less than 15% and deviations were between -4 and 14% in the range of 100-1500 µg/mL. The device presented good linear fit (correlation coefficient, r = 0.9750) over the range of 150-1150 µg/mL. Moreover, the device was found to be free from interference of common endogenous and exogenous substances, and deviated hematocrit, enabling a direct measurement of galactose in the whole blood without sample pre-treatment steps. The clinical validation comprising 118 subjects showed high concordance (r = 0.953) between the device and the conventional colorimetric assay. Thus, this novel miniaturized device is reliable and robust for routine assessment of quantitative liver function intended for follow-up of hepatectomy, drug dose adjustment, and screening for galactosemia, allowing timely and cost-effective clinical management of patients.

Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury.

Tubular cell apoptosis significantly contributes to cisplatin-induced acute kidney injury (AKI) pathogenesis. Although KCa3.1, a calcium-activated potassium channel, participates in apoptosis, its involvement in cisplatin-induced AKI is unknown. Here, we found that cisplatin treatment triggered an early induction of KCa3.1 expression associated with HK-2 cell apoptosis, the development of renal tubular damage, and apoptosis in mice. Treatment with the highly selective KCa3.1 blocker TRAM-34 suppressed cisplatin-induced HK-2 cell apoptosis. We further assessed whether KCa3.1 mediated cisplatin-induced AKI in genetic knockout and pharmacological blockade mouse models. KCa3.1 deficiency reduced renal function loss, renal tubular damage, and the induction of the apoptotic marker caspase-3 in the kidneys of cisplatin-treated KCa3.1 (-/-) mice. Pharmacological blockade of KCa3.1 by TRAM-34 similarly attenuated cisplatin-induced AKI in mice. Furthermore, we dissected the mechanisms underlying cisplatin-induced apoptosis reduction via KCa3.1 blockade. We found that KCa3.1 blockade attenuated cytochrome c release and the increase in the intrinsic apoptotic mediators Bax, Bak, and caspase-9 after cisplatin treatment. KCa3.1 blocking inhibited the cisplatin-induced activation of the endoplasmic reticulum (ER) stress mediator caspase-12, which is independent of calcium-dependent protease m-calpain activation. Taken together, KCa3.1 blockade protects against cisplatin-induced AKI through the attenuation of apoptosis by interference with intrinsic apoptotic and ER stress-related mediators, providing a potential target for the prevention of cisplatin-induced AKI.

Long-term and short-term effects of hemodialysis on liver function evaluated using the galactose single-point test.

AIM: The galactose single-point (GSP) test assesses functioning liver mass by measuring the galactose concentration in the blood 1 hour after its administration. The purpose of this study was to investigate the impact of hemodialysis (HD) on short-term and long-term liver function by use of GSP test. METHODS: Seventy-four patients on maintenance HD (46 males and 28 females, 60.38 ± 11.86 years) with a mean time on HD of 60.77 ± 48.31 months were studied. The GSP values were compared in two groups: (1) before and after single session HD, and (2) after one year of maintenance HD. RESULTS: Among the 74 HD patient, only the post-HD Cr levels and years on dialysis were significantly correlated with GSP values (r = 0.280, P < 0.05 and r = -0.240, P < 0.05, resp.). 14 of 74 patients were selected for GSP evaluation before and after a single HD session, and the hepatic clearance of galactose was similar (pre-HD 410 ± 254 g/mL, post-HD 439 ± 298 g/mL, P = 0.49). GSP values decreased from 420.20 ± 175.26 g/mL to 383.40 ± 153.97 g/mL after 1 year maintenance HD in other 15 patients (mean difference: 19.00 ± 37.66 g/mL, P < 0.05). CONCLUSIONS: Patients on maintenance HD for several years may experience improvement of their liver function. However, a single HD session does not affect liver function significantly as assessed by the GSP test. Since the metabolism of galactose is dependent on liver blood flow and hepatic functional mass, further studies are needed.

Commonly used excipients modulate UDP-glucuronosyltransferase 2b7 activity to improve nalbuphine oral bioavailability in humans.

PURPOSE: Nalbuphine (NAL) is a potent opioid analgesic, but can only be administered by injection. The major aim of this study was to develop an oral NAL formulation employing known excipients as UDP-glucuronosyltransferase 2B7 (UGT2B7) inhibitors to improve its oral bioavailability. METHODS: Twenty commonly used pharmaceutical excipients were screened in vitro by using liver microsomes to identify inhibitors of UGT2B7, the major NAL metabolic enzyme. Tween 20 and PEG 400 were potent UGT2B7 inhibitors and both were co-administered (Tween-PEG) with NAL to rats and humans for pharmacokinetic and/or pharmacodynamic analyses. RESULTS: In animal studies, oral Tween-PEG (4 mg/kg of each) significantly increased the area under the plasma NAL concentration-time curve (AUC) and the maximal plasma concentration (Cmax) by 4- and 5-fold, respectively. The results of the pharmacodynamic analysis were in agreement with those of the pharmacokinetic analysis, and showed that Tween-PEG significantly enhanced the analgesic effects of orally administered NAL. In humans, oral Tween-PEG (240 mg of each) also increased NAL Cmax 2.5-fold, and AUC by 1.6-fold. CONCLUSIONS: Tween-PEG successfully improved oral NAL bioavailability and could formulate a useful oral dosage form for patient's convenience.

Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship.

This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure-activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes. The percent inhibition and IC50 of each flavonoid were calculated and used to develop SAR and QSAR. The most effective flavonoid was orally co-administered in vivo with a cholesterol-reducing drug, fluvastatin, which is normally metabolized by CYP2C. The most potent CYP2C inhibitor identified in vitro was tamarixetin (IC50 = 1.4 µM). This flavonoid enhanced the oral bioavailability of fluvastatin in vivo, producing a >2-fold increase in the area under the concentration-time curve and in the peak plasma concentration. SAR analysis indicated that the presence of a 2,3-double bond in the C ring, hydroxylation at positions 5, 6, and 7, and glycosylation had important effects on flavonoid-CYP2C interactions. These findings should prove useful for predicting the inhibition of CYP2C activity by other untested flavonoid-like compounds. In the present study, tamarixetin significantly inhibited CYP2C activity in vitro and in vivo. Thus, the use of tamarixetin could improve the therapeutic efficacy of drugs with low bioavailability.

Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects.

To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25% ∼ 64%), increased area under the plasma level-time curves (30~76%), increased area under the time infinity (43% ∼ 80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.

Selected pharmaceutical excipient prevent isoniazid and rifampicin induced hepatotoxicity.

BACKGROUND & AIMS: The incidence of isoniazid (INH)- and rifampicin (RIF)-induced abnormal liver enzyme activity is 27% but only 19% with INH alone. Cytochrome P450 2E1 (CYP2E1) is thought to contribute to the synergistic effects of RIF and INH. Pharmaceutical excipients are inactive ingredients that are added to a pharmaceutical compound. The purpose of this study was to screen excipients for CYP2E1 inhibition and identify whether the screened excipients prevented INH/RIF-induced hepatotoxicity. METHODS: Fifty-five known pharmaceutical excipients were screened for CYP2E1 inhibition. The hepatotoxic doses of INH and RIF were 50 and 100 mg/kg/day, respectively. Hepatotoxicity was assessed by the galactose single point (GSP) method (a US Food and Drug Administration (FDA) recommended quantitative liver function test), liver histopathology, malondialdehyde (MDA) assay, and measurement of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. We chose the CYP2E1-specific substrate chlorzoxazone to assess CYP2E1 activity in animal and human. RESULTS: Mannitol inhibited CYP2E1 activity by 54% in mice with INH/RIF-induced hepatotoxicity (p < 0.005). Serum AST, ALT and GSP levels were significantly increased 3.8- to 7.8-fold in these mice (p < 0.005), and these levels could be lowered by mannitol. Mannitol significantly alleviated the depletion of hepatic glutathione (GSH) and partially reversed the increase in MDA formation in mice treated with INH/RIF (p < 0.005). Mannitol also decreased CYP2E1 activity by 58% in humans (p < 0.005). Furthermore, an antituberculosis (TB) efficacy assay revealed that mannitol did not affect the anti-TB effects of INH/RIF. CONCLUSIONS: Mannitol, an FDA-approved excipient, was found to be a CYP2E1 inhibitor. Mannitol may be a useful adjuvant for drugs that induce hepatotoxicity through CYP2E1, such as INH and RIF.

Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity.

Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg(-1) day(-1). Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31- to 0.48-fold (p < 0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p < 0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol's utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

Simultaneous determination of nalbuphine and its prodrug sebacoly dinalbuphine ester in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic study in humans.

A rapid, simple, sensitive and selective ultraperformance liquid chromatography-tandem spectrometry (UPLC-MS/MS) method for the determination of nalbuphine and its prodrug sebacoly dinalbuphine ester (SDE) was developed and validated in human plasma. The sample pretreatment involves basification and iterative liquid-liquid extraction with ethyl-ether-dichloromethane (7:3, v/v) solution, followed by LC separation and positive electrospray ionization (ESI) API-3000 mass spectrometry detection. The chromatography was on a Waters Acquity UPLC BEH HILIC column (2.1 × 100 mm, 1.7 µm). The mobile phase was composed of acetonitrile and water (83:17, v/v) that contained 0.2% formic acid and 4 mm ammonium formate at a flow rate of 0.25 mL/min. Ethylmorphine and naloxine were selected as the SDE and nalbuphine internal standard (IS), respectively. The calibration curve for both was linear over the range from 0.05 to 20 ng/mL, with correlation coefficients ≥0.995. The lower limit of quantification was set at 0.05 ng/mL. The intra- and inter-day precision values for nalbuphine and SDE were acceptable as per FDA guidelines. The method was applied successfully to determine nalbuphine concentration in human plasma samples obtained from four Taiwanese volunteers receiving intramuscularly administration of sebacoyl dinalbuphine ester. The method is sensitive, selective and directly applicable to human pharmacokinetic studies involving nalbuphine.

The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity.

BACKGROUND: Earlier studies have demonstrated an association between N-acetyltransferase 2 (NAT2) catalytic activity and the genotype of a recently published tag single nucleotide polymorphism (SNP), rs1495741. There have been no reports on the relationship between the rs1495741 genotype and antituberculosis drug-induced hepatotoxicity (ATDIH) to date. OBJECTIVE: The aim of the present study was to determine the frequency of the NAT2 tag SNP (rs1495741) in the Taiwanese and its relation to the incidence of ATDIH. MATERIALS AND METHODS: A total of 348 tuberculosis patients were enrolled to determine the frequency of NAT2 tag SNP rs1495741 and its relation to the incidence of ATDIH. The conventional NAT2 variants alleles have also been investigated. Furthermore, to evaluate the correlation of NAT2 activity and rs1495741 genotypes, a pharmacokinetic study of isoniazid was also conducted in healthy volunteers. RESULTS: Among the 348 tuberculosis patients, 20 (5.7%) were diagnosed with ATDIH. The frequencies of the three rs1495741 genotypes, viz., AA, AG, and GG, were 24.7, 52.3, and 23.0%, respectively. Significant differences among rs1495741 genotypes and susceptibility to hepatotoxicity were noted (odds ratio=14.068, P<0.05). Moreover, the rs1495741 genotypes showed an association with the isoniazid dosage required for induction of hepatotoxicity. In the pharmacokinetic study, NAT2 activity was strongly associated with genotype categories (P<0.001). CONCLUSION: The present study demonstrated that the three genotypes according to rs1495741 were in good accordance with conventional NAT2 alleles-inferred phenotypes and the tag SNP could be used as a proxy to determine the susceptibility to ATDIH.

A novel mechanism underlies the hepatotoxicity of pyrazinamide.

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.

A new approach to facilitate diagnosis of nonalcoholic fatty liver disease through a galactose single point method in rats with fatty liver.

BACKGROUND: Liver biopsy reliably diagnoses nonalcoholic fatty liver disease, but its invasiveness and inter- and intra-observer errors limit its usefulness in monitoring. AIMS: Use a galactose single point method or combined biochemical parameters to improve assessments of nonalcoholic fatty liver disease in a rat model. METHODS: Three nonalcoholic fatty liver disease severities were generated in 50 rats: a control group (n=18) on a standard diet, and 2 study groups on a choline-deficient diet (n=18), with and without treatment with silymarin (n=14). At weeks 4, 8, and 18, a galactose solution (0.5 g/kg/body weight) was rapidly injected intravenously. Sixty minutes later, internal artery blood was taken for biochemical analyses, including galactose. The livers were then removed for haematoxylin-eosin staining and to measure the hepatic lipid content. RESULTS: Alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin, and total protein were each significantly correlated with nonalcoholic fatty liver disease severity. Regarding logistic regression, galactose single point method and total protein were significantly predictive. The optimal alanine aminotransferase cutoff point for nonalcoholic fatty liver disease prediction from the receiver-operating characteristic curve had 72.4% sensitivity and 52.4% specificity; galactose single point method alone had 82.8% and 72.4%, whereas galactose single point method+total protein showed 82.8% and 81.0%. CONCLUSIONS: Both galactose single point method and galactose single point method+total protein had greater diagnostic sensitivity and specificity for nonalcoholic fatty liver disease than traditional biochemical tests.

Development of oseltamivir phosphonate congeners as anti-influenza agents.

Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.

Herb-drug interaction of 50 Chinese herbal medicines on CYP3A4 activity in vitro and in vivo.

The purpose of this study is to evaluate the effects of Chinese herbal medicines on the enzymatic activity of CYP3A4 and the possible metabolism-based herb-drug interactions in human liver microsomes and in rats. Fifty single-herbal preparations were screened for the activity of CYP3A4 using human liver microsomes for an in vitro probe reaction study. The enzymatic activity of CYP3A4 was estimated by determing the 6ß-hydroxytestosterone metabolized from testosterone performed on a liquid chromatography-tandem mass spectrometry (LC-MS/MS). Huang Qin (Scutellaria baicalensis Geprgi), Mu Dan Pi (Paeonia suffruticosa Andr.), Ji Shiee Terng (Spatholobus suberectus Dunn.) and Huang Qi (Astragalus membranaceus [Fisch] Bge) have been demonstrated to have remarkable inhibiting effects on the metabolism of CYP3A4, whereas Xi Yi Hua (Magnolia biondii Pamp.) exhibited a moderate inhibition. These five single herbs were further investigated in an animal study using midazolam. Mu Dan Pi, Ji Shiee Terng and Huang Qi were observed to have greatly increased in the C(max) and AUC of midazolam. This study provides evidence of possible herb-drug interactions involved with certain single herbs.

Association of galactose single-point test levels and phenytoin metabolic polymorphisms with gingival hyperplasia in patients receiving long-term phenytoin therapy.

STUDY OBJECTIVE: To evaluate whether the occurrence or severity of gingival hyperplasia is associated with liver function test results or phenytoin metabolism. DESIGN: Prospective analysis. SETTING: University-affiliated medical center in Taipei, Taiwan. PATIENTS: Sixty-six patients (mean age 37.9 yrs) with epilepsy who were receiving phenytoin for more than 1 year. Intervention. Four blood samples were drawn from each patient for liver function testing, concentrations of phenytoin and its metabolites R-5-(4'-hydroxyphenyl)-5-phenylhydantoin (R-HPPH) and S-HPPH, and genotyping of cytochrome P450 (CYP) 2C9 and 2C19. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of phenytoin and its metabolites were determined by a high-performance liquid chromatography method. The CYP2C9 and CYP2C19 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. Conventional liver function assays and a quantitative liver function test--galactose single-point (GSP) measurement--were performed. Statistical analyses were performed to evaluate the association between liver function test results as well as metabolic phenotype and the occurrence and severity of gingival hyperplasia. Among liver function tests, only GSP levels showed a significant difference between patients with and those without gingival hyperplasia. Patients with an elevated GSP level (> or = 280 microg/ml) had a significantly higher odds ratio (OR 4.51) for the occurrence of gingival hyperplasia. In addition, increased R-HPPH (OR 1.02) and phenytoin (OR 1.09) concentrations were associated with an increased occurrence of gingival hyperplasia. However, only increased GSP and R-HPPH concentrations had significantly higher ORs (2.84 and 1.02, respectively) associated with the severity of gingival hyperplasia. Although mean +/- SD plasma R-HPPH concentration was significantly lower in CYP2C19 poor metabolizers compared with CYP2C9 and CYP2C19 extensive metabolizers and CYP2C9 poor metabolizers (30.38 +/- 16.73 vs 68.22 +/- 44.75 and 78.95 +/- 51.67 microg/ml, respectively), no significant association between genotype and gingival hyperplasia was found. CONCLUSION: Increased GSP, phenytoin, and R-HPPH concentrations were associated with increased occurrence of phenytoin-induced gingival hyperplasia; only increased GSP and R-HPPH concentrations were associated with increased severity of this adverse effect.

Effects of hyperglycemia on quantitative liver functions by the galactose load test in diabetic rats.

Blood galactose clearance after an intravenous galactose load has been widely used as a quantitative liver function test. We have developed a novel quantitative rat liver function test, the galactose single point (GSP) method, to assess residual liver function with various injuries by measuring single time point galactose concentration in blood after an intravenous bolus injection of galactose. The goal of this study was to evaluate the influence of nonhepatic factors such as hyperglycemia on GSP and galactose elimination capacity (GEC) in rats. Four groups of animal studies were carried out, as follows: (1) normal control (NC), (2) streptozotocin-induced diabetes (DM), (3) carbon tetrachloride-induced hepatotoxicity (CCl(4)), and (4) streptozotocin-induced diabetes with CCl(4)-induced hepatotoxicity (DM + CCl(4)). The serum glucose levels in the diabetic groups (DM and DM + CCl(4)) were significantly increased compared with the NC and CCl(4) groups (P < .001). A significant increase in hepatic activities of aspartate aminotransferase and alanine aminotransferase was observed in the CCl(4)-treated groups (CCl(4) and DM + CCl(4)) compared with the NC and DM groups (P < .001). In comparison with the NC group, the values of GSP and GEC in the diabetic groups (DM and DM + CCl(4)) were significantly reduced (P < .001) and increased (P < .01), respectively. Galactose single point had highly significant correlations with GEC (P < .001). These results suggest that galactose metabolism tests-as quantitative parameters of liver function-should be interpreted with caution in the condition of a significant hyperglycemia.

Pharmacokinetics of oral rosiglitazone in Taiwanese and post hoc comparisons with Caucasian, Japanese, Korean, and mainland Chinese subjects.

PURPOSE: Rosiglitazone, an insulin-sensitizing thiazolidinedione, acts as a ligand for the y-subtype of the peroxisome proliferator-activated receptor in the regulation of glucose homeostasis and lipid metabolism. The aims of this study were to determine the pharmacokinetics of oral rosiglitazone in Taiwanese and to post hoc compare the ethnic differences among Caucasian, Japanese, Korean, and Mainland Chinese. METHODS: Twelve Taiwanese healthy male subjects received 4 and 8 mg of rosiglitazone. Similar protocols were used in the previously unpublished studies conducted in 25 Caucasian, 32 Japanese, 8 Korean, and 12 Mainland Chinese healthy male subjects. The 4 mg dose data were used for ethnicity comparisons. RESULTS: The respective pharmacokinetic properties of Taiwanese, Caucasian, Japanese, Korean and Mainland Chinese are: terminal half-life (hr): 4.18 +/- 0.43, 3.96 +/- 1.31, 3.83 +/- 0.78, 4.70 +/- 1.19 and 4.37 +/- 0.63; Cmax (ng/ml): 384.1 +/- 59.3, 260.2 +/- 75.7, 401.9 +/- 102.3, 345.3 +/- 60.6, and 406.2 +/- 52.0; AUC0-inf (h*ng/ml): 2078 +/- 433, 1249 +/- 566, 1901 +/- 397, 1938 +/- 534, and 2158 +/- 498. The Cmax and AUC0-inf of Caucasian were significantly (p = 0.002, 0.008) lower and CL/F and V/F were significantly (p = 0.000, 0.003) higher than those of other races. These differences of Cmax, AUC0-inf, CL/F and V/F between Caucasian and other races became insignificant after normalized by dose and weight. CONCLUSIONS: In a given dose by body weight, ethnicity had no significant impact on the pharmacokinetics of rosiglitazone in normal healthy volunteers.

Submicron lipid emulsion as a drug delivery system for nalbuphine and its prodrugs.

This study investigates the submicron lipid emulsion as a potential parenteral drug delivery system for nalbuphine and its ester prodrugs. Submicron emulsions were prepared using egg phospholipid as the main emulsifier, various co-emulsifiers were also incorporated, including Brij 30, Brij 98, and stearylamine. Squalene as the oil phase formed stable emulsions with small particles. Drug release was affected by incorporating various co-emulsifiers and drugs with various lipophilicity. The loading of nalbuphine into lipid emulsions resulted in the slower and sustained release of nalbuphine. Lipid emulsions containing Brij 98 could further enhance the release of prodrugs as compared to the aqueous solution (control) especially for nalbuphine enanthate (NAE). Hemolysis caused by the interaction between erythrocytes and lipid emulsions was investigated. Brij 30 and Brij 98 could shield the hemolytic activity of phospholipids in the oil/water interface, decreasing the acute toxicological potential of the emulsions. The in vivo analgesic activity of various emulsions was examined by a cold ethanol tail-flick test. The analgesic duration and potency were significantly increased by incorporating nalbuphine and NAE into Brij 98-containing emulsions. There was no need for nalbuphine benzoate (NAB) to show a controlled delivery manner by encapsulating into emulsions, since NAB itself could prolong the analgesic duration of nalbuphine due to the slow enzyme degradation. The in vivo analgesic activity correlated well to the profiles of in vivo pharmacokinetic profiles. The study demonstrates the feasibility of using submicron lipid emulsion as the parenteral drug delivery system for nalbuphine and its prodrugs.

The effects of electrically assisted methods on transdermal delivery of nalbuphine benzoate and sebacoyl dinalbuphine ester from solutions and hydrogels.

The aim of this study was to assess the effects of iontophoresis and electroporation on transdermal delivery of nalbuphine (NA) and its two novel prodrugs: nalbuphine benzoate (NAB) and sebacoyl dinalbuphine ester (SDN) from solutions as well as from hydrogels. Hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) were used in hydrogel formulations to evaluate their feasibility for delivery of NA and its prodrugs. Application of iontophoresis or electroporation significantly enhanced the in vitro permeation of NA and its prodrugs. The enhancement effect was more pronounced after applying iontophoresis. The combination of two electrically assisted methods enhanced the delivery of NA; however, no such enhancement was observed for the permeation of NAB and SDN. Hydrogels containing low concentration HPC did not affect the passive as well as electrically assisted permeation of NA and its prodrugs. The increase of hydrogel concentration as well as molecular weight significantly decreased the electrically assisted permeation of NA, whereas the permeation of NAB and SDN remained unchanged. For the electrically assisted permeation from CMC-based hydrogels, the reduced permeation from higher percentage of CMC hydrogels may be attributed the viscosity effect as well as the ion competition effect. The above results demonstrated that lipophilicity and molecular size, as well as hydrogel compositions had significant effects on skin permeation of NA, NAB and SDN via passive diffusion or under the electric field.