Quantitative rat liver function test by galactose single point method.

The purpose of this study was to investigate the galactose single point (GSP) method, a residual liver function test recently recommended by the US Food and Drug Administration, which can be a useful tool for rat liver function measurement. Rats were treated either with carbon tetrachloride (CCl(4)) alone (1 mL/kg, intraperitoneally [i.p.]) for one day or with isoniazid (INH) alone (150 mg/kg, i.p.) or (in order to ameliorate the effects of INH) with a combination of INH and bis-p-nitrophenyl phosphate (BNPP) (25 mg/kg, i.p.) for 21 days. Hepatotoxicity was assayed by plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and scores of histological activity index-necroinflammation (HAI-NI) of the respective liver specimens. The GSP method in rats was defined by the galactose blood level after 60 min. Significant differences in GSP values were observed between controls and the CCl(4)-treated rats. After 21 days of treatment, no significant changes in AST and ALT values were observed among the control, INH and INH-BNPP groups. There were significant differences in average GSP values for controls (P < 0.001) and INH-BNPP (P < 0.001) compared with INH alone. Highly significant correlations (P < 0.001) were obtained between GSP and scores of HAI-NI for all the groups. GSP was concluded to be a more sensitive biomarker of INH-induced hepatotoxicity than AST or ALT in the rats. The GSP method has been proved to be a simple and useful tool for the quantitative determination of liver function in rats, which can possibly be extended to other animals.

Pharmacokinetics and pharmacodynamics of enantiomers of pimobendan in patients with dilated cardiomyopathy and congestive heart failure after single and repeated oral dosing.

Pharmacokinetics and pharmacodynamics of pimobendan were studied in eight patients with dilated cardiomyopathy and chronic congestive heart failure after single dosing and after 2-week repeated dosing of 5 mg racemic pimobendan. Enantiomers of pimobendan and its demethylated metabolite in plasma and in red blood cells were measured. In the single-dose study, the peak plasma levels of 16.3 +/- 4.0 and 17.0 +/- 3.1 ng/ml of (+)- and (-)-pimobendan were observed at 0.9 hour after dosing. The concentration-time curves followed a two-compartment model, with terminal half-lives of 2.56 +/- 0.35 and 2.93 +/- 0.33 hours for (+)- and (-)-pimobendan (p > 0.05), respectively. The oral volumes of distribution after equilibrium were 3.26 +/- 0.74 and 3.13 +/- 0.75 L/kg, and oral clearances were 28.6 +/- 7.0 and 21.9 +/- 4.1 ml/min/kg for (+)- and (-)-pimobendan (p > 0.05), respectively. In red blood cells, the respective (+)- and (-)-pimobendan concentrations were 5.8 and 8.4 times higher than those in plasma, indicating a stereoselective partitioning of drugs between plasma and red blood cells. The pharmacodynamic effect of pimobendan was evaluated by echocardiography. The ejection fraction, mean velocity of circumferential fiber shortening, aortic flow peak velocity, cardiac index, and stroke volume index significantly increased 50% to 60%. The left ventricular end-systolic dimension, systolic blood pressure, and diastolic blood pressure significantly decreased 8% to 11%. These effects lasted for more than 8 hours. In a 2-week repeated-dose study, there was no significant dose accumulation in plasma and red blood cells. The pharmacokinetic parameters were similar to those in the single-dose study, except for significantly shorter absorption half-lives. The baseline levels of cardiac index and stroke volume index were significantly higher than the baseline levels in the single-dose study. This suggests an accumulation of pharmacodynamic effects despite a relatively short elimination half-life.

Novel galactose single point method as a measure of residual liver function: example of cefoperazone kinetics in patients with liver cirrhosis.

A novel, simple, clinically useful quantitative liver function test, called the galactose single point (GSP) method, was developed to assess residual liver function by measuring galactose blood concentration 1 hour after galactose was administered (0.5 g/kg). This method was applied to the study of cefoperazone kinetics in patients with hepatic cirrhosis. To study the influence of hepatic cirrhosis on the residual liver function and the correlation between the residual liver function and the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 healthy volunteers and 12 patients with liver cirrhosis. The GSP method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were done for each volunteer and patient to measure residual liver function. The galactose concentrations were determined enzymatically. Cefoperazone was administered intravenously, and blood and urine samples were collected at appropriate intervals after drug administration. All blood and urine samples were stored at -30 degrees C until high-performance liquid chromatography analysis. Cefoperazone plasma concentrations were much higher in cirrhosis patients than in normal subjects at all times. The elimination half-life, hepatic clearance, mean residence time, and renal clearance of cirrhosis patients differed significantly from those of healthy volunteers. The plasma protein binding was unaltered in both groups. Urinary excretion of cefoperazone was significantly increased in cirrhosis patients (23.95 +/- 5.06% for normal men and 51.09 +/- 11.50% in cirrhosis patients). Hepatic clearance, fraction excreted in urine, and total clearance significantly correlated with GSP, GEC, and MGEC (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of fosinoprilat in Chinese and whites after intravenous administration.

The pharmacokinetics of fosinoprilat was studied in 12 healthy Chinese men after a 7.5 mg intravenous dose of fosinoprilat. The data were compared with those from an earlier study using the same protocol in nine healthy white men. Blood and urine samples were obtained before and at various time intervals after fosinoprilat administration up to 24 hours and 48 hours, respectively. Pharmacokinetic parameters were calculated by fitting the plasma or serum concentrations to a three-compartment model. The total clearance (Clt), renal clearance (ClT), and nonrenal clearance (ClNR) were significantly lower in Chinese (16.29 +/- 6.92, 6.85 +/- 2.97, and 9.44 +/- 5.08 mL.hr-1.kg-1) than those obtained in whites (29.88 +/- 6.36, 13.55 +/- 3.45, and 16.33 +/- 5.07 mL.hr-1.kg-1). The Chinese subjects had a significantly lower volume of distribution (Vc [volume of distribution of central compartment] and Vdss [volume of distribution at steady state]) (29.38 +/- 21.12 and 73.67 +/- 40.20 mL/kg) than white men (58.14 +/- 15.01 and 152.49 +/- 24.89 mL/kg). The Chinese men also had a shorter elimination half-life than whites, although not statistically significant. The respective half-lives in Chinese and whites were 5.51 +/- 1.53 and 8.24 +/- 1.99 hours. The significant differences in ClNR and ClR may be related to lower liver elimination function and lower kidney excretory function, respectively. Plasma protein binding may contribute to part of the difference in the volume of distribution. Chinese men have smaller volume of distribution and clearances of fosinoprilat after intravenous administration compared with white men. The cumulative urine excretion of fosinoprilat was not different between Chinese and whites. Chinese may require a lower fosinoprilat dosage to obtain plasma concentrations similar to whites after intravenous administration. However, since a relatively high variation was found in fosinopril oral absorption, the oral dosage of fosinopril for Chinese and whites may not be different. Further study is obviously needed to elucidate whether the pharmacodynamic effect may be different between Chinese and whites.

Fosinopril: pharmacokinetics and pharmacodynamics in Chinese subjects.

This study examined thepharmacokinetics and pharmacodynamics of fosinopril (IVand oral) in Chinese subjects to determine whether they were different from a group of somewhat heavier and older Western control subjects previously published using the same methods. It was an open-label, randomized, balanced, two-way crossover study comparing oral and IV pharmacokinetics in 12 healthy Chinese subjects in a clinic in Taiwan. Each subject received 10 mg of oral fosinopril or 7.5 mg of IV fosinoprilatin a randomized sequence with sampling for fosinoprilat concentrations over 48 hours. Standard pharmacokinetics, including AUC, Cmax Tmax, T 1/2, Vss, bioavailability, total clearance, and renal and nonrenal clearance, were determined as well as pharmacodynamic effects on angiotensin-converting enzyme (ACE) activity. Following oral administration of 10 mg fosinopril, AUC0-T and AUCinf were 1,556 +/- 586 ng x hr/mL and 1,636 +/- 620 ng x hr/mL, respectively; T 1/2 was 17.4 +/- 11.4 hr; Cmax was 183.4 +/- 59.4 ng/mL; and median Tmax was 4.0 hr, with > 99% protein binding. Following IV administration of 7.5 mg fosinoprilat, AUC0-T and AUCinf were 7,727 +/- 2,638 ng x hr/mL and 7,816 +/- 2,693 ng x hr/mL, respectively; T 1/2 was 13.0 +/- 5.2 hr; and median Tmax was 4.0 hr, with 99.5% +/- 0.22% protein binding and a Vss of 5,850 +/- 2,780 mL. Bioavailability was 22.3% +/- 7.9%. Percent urinary excretion was 7.6% +/- 2.6% after oral dosing and 42.6% +/- 6.1% after IV dosing. After IV, dosing total clearance was 1,088 +/- 439 mL/hr, renal clearance was 472 +/- 213 mL/hr, and nonrenal clearance was 617 +/- 246 mL/hr. ACE inhibition was essentially complete through 12 hours and markedly reduced through 24 hours. Compared to a somewhat heavier and older previously reported control group, pharmacokinetic values were similar except for a slightly lower AUC and total clearance in Chinese and a statistically significantly lower nonrenal clearance. Pharmacodynamic effects on ACE activity were essentially identical. There is no reason to expect significant differences in fosinopril dosing or effect in a Chinese population compared to a Western population.

Pharmacokinetic and pharmacodynamic studies with 4'-epi-doxorubicin in nasopharyngeal carcinoma patients.

The plasma pharmacokinetic profile of 4'-epidoxorubicin (epirubicin) was investigated in 28 patients with nasopharyngeal carcinoma (NPC) after single i.v. rapid infusions. All patients had normal liver and renal functions. Plasma concentrations of the parent compound were specifically determined by a high-performance liquid chromatographic (HPLC) method, with UV detection at 254 nm. Plasma levels of the compound were fitted to a three-compartment open model; a triexponential decrease in plasma concentrations with a long terminal plasma half-life (44.8 +/- 21.2 h) was observed in 27 patients. The respective mean (+/- SD) serum concentration at 72 h and the AUC, plasma clearance, and terminal elimination rate constant in complete responders were 7.67 +/- 1.98 ng/ml, 4,002 +/- 3,080 ng.h/ml, 26.6 +/- 12.9 l/h.m2, and 0.009 +/- 0.007 l/h, whereas those in nonresponders were 4.96 +/- 1.8 ng/ml, 1.88 +/- 652.8 ng.h/ml, 44.4 +/- 15 l/h.m2, and 0.017 +/- 0.006 l/h, respectively; these differences were significant (P less than 0.05). Epirubicin produced a 52% response rate, including 6 patients with a complete response, 8 with a partial response, 11 with no change, and 2 with progressive disease. No relationship could be found between the various pharmacokinetic parameters and either leukopenia, age, or sex. These observations strongly suggest that plasma clearance may be one of the determining factors affecting the response or nonresponse of NPC patients to epirubicin, and a dose adjustment according to plasma clearance would probably increase the response rate.

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.

Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol.

1. The studies of relationships between blood levels of reduced haloperidol HL (RH) and clinical efficacy in haloperidol (HL)-treated patients have yielded variable results. On the other hand, the contribution of RH upon HL's extrapyramidal side effects (EPS) had been suggested in animal models as well as in preliminary clinical studies with limited subjects. 2. This study explored the relationships between blood drug levels and clinical effects and EPS of HL in 48 Chinese acutely exacerbated schizophrenic inpatients. After a single-blind placebo period of one week, the patients were treated with a fixed dose 10 mg of HL for two weeks. Steady-state levels of HL and RH in plasma (n = 48) and in red blood cells (RBC) (n = 37) were measured by high performance liquid chromatography. 3. The mean RH/HL ratio in RBC in the Chinese (0.55) is lower than that in non-Chinese patients as reported in the literature (> 2), so is the RH/HL ratios in plasma. 4. No significant relationship emerged between percent improvement in BPRS total score and any of drug indices (HL, RH, sum of two compounds (HL+RH), and RH/HL ratio) in plasma and in RBC. Furthermore, the responders did not differ significantly from the nonresponders in each drug index. 5. Plasma RH levels were significantly higher in 30 patients experiencing EPS compared with the other 18 patients (mean 2.14 +/- 1.71 (S.D.) ng/ml vs. 1.38 +/- 0.37 ng/ml, p < 0.05). No significant differences in other drug indices were noted between subjects with or without EPS.

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

Information from clinical and pharmacokinetic studies of angiotensin-converting enzyme inhibitors (ACEIs) has come from subjects who are mostly male and Caucasian, but the use of ACEIs extends to populations worldwide. Significant differences between Chinese in general and male Caucasians have been demonstrated in the pharmacokinetics/dynamics of other drug classes that could have implications for the use of ACEIs in the Chinese population. These include: significant Chinese/Caucasian genetic variation in the renin-angiotensin system based on an insertion/deletion (O/D) polymorphism of the ACE gene; the genetic determination of plasma ACE activity in the Chinese population; and genetic factors involving the disease substrate which may also influence the response to treatment. Oral and IV pharmacokinetic data from various studies of Chinese and Caucasian subjects are available for cilazapril, fosinopril, and perindopril, and pharmacodynamic data are available for eight different ACEIs. Based on these data, there are few differences among the pharmacokinetics of ACEIs between Chinese and Caucasians. Most ACEIs showed good blood pressure lowering efficacy in Chinese (benazepril, enalapril, fosinopril and spirapril), with perhaps less blood pressure lowering with cilazapril or a relatively shorter-term effect with cilazapril or perindopril compared to Caucasions. Chinese experience more cough from ACEIs (captopril and enalapril) than Caucasians. Data suggest that fosinopril may not induce cough in as many subjects as other ACEIs, and this seems to be true of Chinese as well. The mechanism, currently unknown, could involve fosinopril's dual elimination pathway (hepatic and renal). Pharmacokinetic data also support the use of fosinopril in congestive heart failure where elimination pathways may be impaired. In conclusion, ethnic differences between Chinese and Caucasians with respect to ACE and AGT gene polymorphism, which might be expected to differentially affect the action of ACEIs in these two ethnic groups, do not, in fact, have such an effect. Rather, differences among the ACEIs appear to be more important. Journal of Human Hypertension (2000) 14, 163-170.

Determination of galactose in human blood by high-performance liquid chromatography: comparison with an enzymatic method and application to the pharmacokinetic study of galactose in patients with liver dysfunction.

Galactose, the C-4 epimer of glucose, is an agent of choice for the quantitation of liver function. A simple, precise, and accurate high-performance liquid chromatographic (HPLC) assay with refractive index detection was developed for the determination of galactose in human whole blood. The method consists of organic solvent-heavy metal deproteinization procedures and reversed-phase chromatography on a cation-exchange column in the calcium form. Calibration graphs were linear over the concentration range 100-2500 microgram/mL, with correlation coefficients > 0.999. The within-day coefficient of variation (CV) ranged from 2.08 to 8.94%, and the between-day CV ranged from 1.61 to 10.9%. The limit of quantitation was 100 micrograms/mL in whole blood. However, the limit of detection was 75 micrograms/mL based on a signal-to-noise ratio of > or = 3. Eight structurally related sugars and polyols were investigated to check for potential interferences using the analytical condition of the assay. The possible metabolites of galactose present in the body were also checked to determine the specificity of this assay. The proposed HPLC assay was compared with an enzymatic assay and an excellent correlation was observed (HPLC = 1.0299Enz. - 12.907, r = 0.952, p < 0.001). This HPLC method has been successfully applied to the pharmacokinetic study of galactose in six patients with liver dysfunction. Following the intravenous administration of a dose of 0.5 g/kg body weight, galactose pharmacokinetics followed a nonlinear two-compartment model with Michaelis-Menten elimination from the central compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of promazine in patients with hepatic cirrhosis--correlation with a novel galactose single point method.

We examined promazine pharmacokinetics in nine patients with hepatic cirrhosis and in six healthy subjects. A specific and sensitive HPLC method was used to measure promazine concentrations in plasma, plasma water (free drug), red blood cells, and urine after oral administration of promazine (2 x 50 mg tablet). There were highly significant reductions in total plasma clearance (p < 0.01), free drug total plasma clearance (p < 0.01), metabolic clearance (p < 0.01), metabolic clearance of free drug (p < 0.01), and fraction bound (p < 0.01) in the cirrhotic patients. The elimination half-life and the area under the plasma concentration-time curve were significantly increased (p < 0.001 and p < 0.05, respectively) in the cirrhotic patients. However, the overall excreted promazine in urine, time to the promazine peak concentration, distribution half-life, renal clearance, apparent volume of distribution, and the promazine concentration ratio between plasma and red blood cells were not different. Thus caution is needed in using promazine for patients with hepatic cirrhosis. A newly developed galactose single point (GSP) method was applied to quantitatively measure the residual liver function in cirrhosis patients and successfully correlated it with promazine elimination half-life (r = 0.770, p < 0.01), total plasma clearance of free drug (r = 0.899, p < 0.005), metabolic clearance of free drug (r = 0.902, p < 0.005), and plasma protein binding (r = 0.822, p < 0.005). GSP may be a convenient index for promazine routine dosage adjustment in patients with liver cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients.

This study examined the relationship between the metabolic ratios of dextromethorphan/dextrorphan, haloperidol disposition, and the incidence of extrapyramidal side effects in schizophrenic patients. Eighteen schizophrenic patients were phenotyped with a test dose of dextromethorphan prior to the initiation of haloperidol treatment. The metabolic ratio of dextromethorphan/dextrorphan was determined in each patient. Patients were treated with oral haloperidol 10 mg/day for 2 weeks. Blood samples for haloperidol and reduced haloperidol were obtained at week 2 of haloperidol treatment. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC with electrochemical detection. Significant correlations of dextromethorphan/dextrorphan metabolic ratios vs. plasma haloperidol concentrations, reduced haloperidol concentrations, and reduced haloperidol/haloperidol ratios were found (r = 0.726, P = 0.0007; r = 0.782, P = 0.0001; and r = 0.619, P = 0.006, respectively). Ten patients who experienced extrapyramidal side effects had higher reduced haloperidol concentrations and reduced haloperidol/haloperidol ratios than the other patients (2.49 +/- 1.42 [S.D.] ng/ml vs. 1.10 +/- 0.46 ng/ml, P = 0.014 and 0.287 +/- 0.102 vs. 0.192 +/- 0.065, P = 0.030). The former also had a trend to have higher haloperidol concentrations and dextromethorphan/dextrorphan ratios than the latter (8.04 +/- 2.91 ng/ml vs. 5.83 +/- 1.79 ng/ml, P = 0.066 and 0.023 +/- 0.017 vs. 0.011 +/- 0.010, P = 0.077). Phenotyping patients has the potential to assist clinicians in predicting plasma drug concentrations during the subsequent neuroleptic drug treatment. Further research with phenotyping and psychotropic drug metabolism in psychiatric patients is needed.

Dose-dependent reduced haloperidol/haloperidol ratios: influence of patient-related variables.

Plasma reduced haloperidol (RH) concentrations or RH to haloperidol (HL) ratios have been suggested to be important in determining the clinical efficacy and extrapyramidal side effects of HL. In this study, we measured the steady-state plasma HL and RH levels by high performance liquid chromatography and analyzed the effects of various variables (dose, gender, age, and body weight) on RH/HL ratios in four dose groups of Chinese schizophrenic inpatients: 10 mg/day (n = 84), 20 (n = 111), 30 (n = 29), and 60 (n = 55). In addition, the polymorphic distribution of RH/HL ratios, suggested by previous investigators, was further tested in each dosage group (for controlling the potential dosage effect on RH/HL ratios). As a result, both age and body weight could influence RH/HL ratios. Each year increase in age (after adjusting the effects of gender, body weight, and dosage) would elevate the RH/HL ratio by 0.0067 (P < 0.0001). On the other hand, after adjusting gender, age, and dosage effects, each kg increment in body weight would decrease the RH/HL ratio by 0.0044 (P < 0.01). Gender did not influence the ratio. Furthermore, the high dosage groups had higher RH/HL ratios (even with other variables being controlled). In comparison with the 10 mg group, the 60 mg group exhibited a higher mean RH/HL ratio by 0.84 (P < 0.0001) and the 30 mg group did by 0.31 (P < 0.0001). The 20 mg group was almost equal to the 10 mg group in RH/HL ratios. Besides, at each dosage group, the frequency distribution of RH/HL ratios seemed to be predominantly unimodal with a small proportion of extreme outliers. The results of this study clearly indicate that aging or a high dose (> or = 30 mg/day) of HL could raise the plasma RH/HL ratio, while an increasing body weight would reduce that. In contrast, gender does not affect the ratios.

Determination of fenoverine, a modulator of smooth muscle motility, in capsules and in human plasma: application to dosage form stability and a pilot study in humans.

Fenoverine is a novel, potent, musculotropic, spasmolytic agent that affects primarily the gastrointestinal tract, bile duct, and female genital organs. A simple, specific, and accurate HPLC method was developed for the determination of fenoverine in capsules and plasma. This method has been successfully applied to stability studies of fenoverine capsules and to a pilot study in a normal, healthy volunteer following oral administration of fenoverine. For the determination of fenoverine in capsules, a Nucleosil 5-micron CN column, with acetonitrile:0.1 M ammonium acetate (60:40) as mobile phase and detection at 254 nm, was employed. The mean correlation coefficient of the calibration curve (n = 6) for the assay was 0.9999 over a concentration range of 24.6 to 147.6 micrograms/mL of fenoverine standard solutions. Fenoverine did not decompose significantly at 4, 45, 55, and 65 degrees C for 3 months. The mean correlation coefficients of within-day and between-day calibration curves were 0.9995 and 0.9999, respectively, over a range of 10 to 1000 ng/mL of fenoverine in plasma. The limit of detection was 10 ng in plasma.

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.

Relative bioavailability of trimeprazine tablets investigated in man using HPLC with electrochemical detection.

The stability, partition coefficient, plasma protein binding, red blood cell distribution, and whole blood concentrations of trimeprazine were investigated. Trimeprazine solution was stable for 6 months at -20 degrees C and 3.5 months at 40 degrees C. In whole blood trimeprazine was stable for 5 weeks at -20 degrees C, 24 h at 4 degrees C, 4 h at 25 degrees C and 1 h at 37 degrees C. The apparent hexane-water partition coefficient varied from 1.50 (at pH 4.83) to over 100 (at pH 10.54). The fraction bound to plasma protein exceeded 0.9 as estimated by equilibrium dialysis with correction for volume shift. The mean plasma/red blood cell concentration ratio was 1.17 and the mean red blood cell/plasma distribution coefficient was 8.65. Six healthy adult males received single 5 mg doses of trimeprazine in a syrup (5 mg in 10 ml) and tablets with at least two weeks between doses. Blood was collected for 48 h. The mean (+/- s.e.m.) times for peak blood concentrations were 3.5 +/- 0.22 h for the syrup and 4.5 +/- 0.43 h for the tablets. There were no significant differences in Cmax values. The overall mean (+/- s.e.m.) terminal phase half-life was 4.78 +/- 0.59 h. Mean (+/- s.e.m.) areas under the concentration time curves from 0 to infinity (AUC infinity) were 11.0 +/- 1.99 ng h-1 ml-1 and 7.67 +/- 1.05 ng h-1 ml-1 for syrup and tablets, respectively. The mean relative bioavailability for the tablets was approximately 70% with respect to the syrup.

Antibiotic use in public hospitals in Taiwan after the implementation of National Health Insurance.

BACKGROUND AND PURPOSE: Only limited data is available on the patterns of antibiotic use in hospitals in Taiwan before and after the implementation of national health insurance. This study aimed to determine the patterns of use of antibiotics in public hospitals in Taiwan after the implementation of the National Health Insurance program and to compare these with patterns prior to the implementation. METHODS: Data on the annual use of all antibiotics in public hospitals in Taiwan during the period from fiscal year (FY) 1994-1995 to 1997-1998 were collected and analyzed. Hospitals included seven medical centers, 19 regional hospitals, 53 district hospitals, and eight specialty service hospitals. RESULTS: The annual cost of antibiotics made up 17.4% of the annual cost of all medication used in these hospitals in FY 1994-1995, and decreased year by year to 12.6% in FY 1997-1998. During the study period, 57.4% of the total cost of antibiotics were incurred by medical centers, 24.6% by regional hospitals, 16.2% by district hospitals, and 1.8% by specialty service hospitals. The most commonly used class of antibiotic was cephalosporins, accounting for 48.0% to 54.3% of total antibiotic costs. The second most commonly used class of antibiotic was penicillins, accounting for 15.9% to 17.4% of total antibiotic costs. In FY 1994-1995, the next most commonly used classes of antibiotics were aminoglycosides, fluoroquinolones, and other beta-lactams, respectively, but by FY 1997-1998 these had changed to fluoroquinolones, glycopeptides, and aminoglycosides, respectively. Among the various cephalosporins used, first-generation cephalosporins accounted for 76.1% of all cephalosporins used in FY 1994-1995, which increased year by year to 84.0% in FY 1997-1998. Second-generation cephalosporins accounted for 20.7% of all cephalosporins used in FY 1994-1995, decreasing to 13.2% in FY 1997-1998. CONCLUSION: The introduction of the National Health Insurance program in Taiwan brought about a major change in antibiotic use patterns in public hospitals.

Paw pressure test in the rabbit: a new animal model for the study of pain.

BACKGROUND: In order to develop an animal model which is suitable for the pharmacokinetic (PK) and pharmacodynamic (PD) studies of analgesics in the field of pain assessment, we examined a new animal model, the paw pressure test (PPT), in rabbits for the study of pain. METHODS: The sensitivity of the model was tested with a broad range of drugs, including mu-opioid agonist (morphine), kappa-opioid agonist (nalbuphine), three non-opioid analgesics (acetaminophen, ketorprofen and indomethacin) and two non-analgesics (droperidol and diazepam). Furthermore, PK and PD studies of nalbuphine (chosen as an example of analgesics) were performed. RESULTS: The authors found that the PPT in rabbits recognized the antinociceptive activities of both opioid and non-opioid analgesics with no positive response to non-analgesics. AD50s determined by the PPT in rabbits for morphine and nalbuphine were 3.1 and 8.4 mg/kg, respectively. In the PK and PD studies, the plasma concentration time profiles of nalbuphine were well fitted to a linear two-compartment open model, and the correlation between pharmacokinetics and pharmacodynamics was significant (p < 0.05). CONCLUSIONS: These results suggest that the PPT in rabbits can be used extensively to explore the analgesic effects (PD) of a broad range of analgesics. Also, with this model, PK and PD studies of analgesics can be easily performed.

Comparison of PCA nalbuphine and morphine in Chinese gynecologic patients.

BACKGROUND: The aim of this study was to evaluate the efficacy and side effects of PCA nalbuphine (intravenous) versus morphine on postoperative pain in Chinese gynecologic patients. METHODS: Sixty women undergoing abdominal hysterectomy or myomectomy under spinal anesthesia were enrolled into the investigation. Patients were randomly divided into 2 groups (n = 30 each). Group 1 received intravenous nalbuphine using PCA device for the management of postoperative pain, whereas group 2 received PCA morphine for the same purpose. During the first 48 hours postoperatively, we collected the following data: analgesic doses, pain scores, vital signs, nausea, vomiting, pruritus and dizziness. RESULTS: The results showed that despite different treatments, pain scores on day 1 and day 2 postoperatively were low and were not significantly different between groups. Meanwhile, the cumulative consumption of PCA nalbuphine (32 +/- 10 mg) and PCA morphine (30 +/- 9 mg) was similar. Both treatments showed only minor side effects and the incidence of each side effect was not significant between groups. CONCLUSIONS: Both PCA nalbuphine and morphine are effective in the treatment of postoperative pain in Chinese gynecologic patients undergoing hysterectomy or myomectomy after spinal anesthesia and the potency of nalbuphine is similar to that of morphine.