bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficiency of different criteria for selecting pharmacokinetic multiexponential equations
Authors: Imbimbo Bruno P. , Martinelli Paolo , Rocchetti Maurizio , Ferrari Gianni , Bassotti Gabrio , Imbimbo Ennio 
Published: October 2006

AbstractSeveral statistical and empirical approaches have been proposed to select the multiexponential equation that best describes the time course of the plasma concentration of a drug. Recently, a new criterion (Ip) has been proposed according to which the model that best interprets a set of experimental data points is the one with the smallest area between the approximate confidence limits of estimated plasma concentration. We used large Montecarlo simulations to compare the ability of different selection criteria to select the correct model from data generated with an independent, normally distributed random error. The new criterion (Ip), Akaike's information criterion, the Schwartz test, and the F ratio test were studied. In this situation, the correct model was known and the performances of different selecting methods were assessed by examining their sensitivity to the number of exponential terms, the number of data points, and the size of the exponents in the true model. Mono‐, bi‐, and triexponential equations were studied. Overall mean percentages of right identification were 98·1 per cent for the new index, 82.8 per cent for Akaike's information criterion, 89.5 per cent for the Schwartz test, and 97.7 per cent for the F ratio test. The Akaike and Schwartz tests were not as efficient as the other tests with few (8–10) data points. The Ip and the F test raise the percentages of right identification of the model when the hybrid elimination rate macroconstants differ by at least a factor of four. These large simulations show that the new selection criterion for pharmacokinetic multiexponential equations compares well with the F test and is superior to the Akaike and Schwartz tests.
Plasma concentrations of disulfiram after injection of suspended micropellets into alcoholic subjects
Authors: Cid Edison , Cid Edison , Feuerhake Oscar , Boisier Iris , Chandía Rolando 
Published: October 2006

AbstractThe disposition of disulfiram after administration in a new formulation was studied in rats and alcoholic patients. The suspension consisted of microcrystals suspended in a mixture of propylene glycol and water and injected subcutaneously into rats and humans; the course of the plasma concentration of diethyldithiocarbamate with time was followed by gas–liquid chromatography. Systemic delivery of disulfiram was observed to occur for a month. The data demonstrate that this form has the properties of a sustained‐release formulation when implanted subcutaneously. There was no evidence of local or systemic adverse reactions.
HI‐6 and 2‐pam in sheep: Pharmacokinetics and effects on muscle tissue following intramuscular injection
Authors: Moore David H. , Hayward Isaac J. , Steve Tucker F. , Lukey Brian 
Published: October 2006

AbstractThe pharmacokinetics of 2‐PAM, a component of the current nerve agent antidote therapy for U.S. military forces was compared to the pharmacokinetics of another acetylcholinesterase reactivator HI‐6. Additionally, the effects of these compounds on muscle tissue following intramuscular injection was examined. Plasma concentrations of the oximes were determined by HPLC. Plasma concentration—time profiles for both oximes fit a one‐compartment open model with first‐order absorption and elimination. The results demonstrate that the half‐time of absorption of the two oximes are nearly the same while the maximum plasma concentration of HI‐6 was significantly higher than that for 2‐PAM. Musculoirritancy was assessed on the basis of quantitative histological examinations of the injection sites and by the measurement of serum creatinine phosphokinase. Comparison of the scores from the histological sections demonstrate no difference between the two oximes. Serum creatinine phosphokinase values were elevated following injections of HI‐6, but were not consistently elevated following the 2‐PAM injections.
A method for calculating the mean residence times of catenary metabolites
Authors: Cheng Haiyung 
Published: October 2006

AbstractA method for calculating the mean residence times of metabolites in the body, systemic circulation, and peripheral tissue is described. The calculations require the AUC, AUMC, and derivatives of the plasma concentration versus time curves of the metabolite and its precursor. The method is applicable to metabolites with any precursor order and does not require separate administration of the metabolite. The approach is applied to published data for the primary and secondary metabolites of ketamine.
Pharmacokinetics and oral bioavailability of carbimide in man
Authors: Obach R. , Torrent J. , Colom H. , Pruñonosa J. , Peraire C. , Domenech J. 
Published: October 2006

AbstractA pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0·1, 0·3, 0·6, and 1 mg kg−1 and linear pharmacokinetics were observed for this dose range. Elimination half‐life and total plasma clearance values ranged from 42 to 52 min and from 14·4 to 20·5 ml kg−1 min−1, respectively. After oral administration of 1 and 1·5 mg kg−1 of carbimide, elimination half‐life values were 75 and 61 min, respectively, being higher than the corresponding value obtained after 0·3 mg kg−1 doses, i.e. 39 min. In all cases, rapid absorption was indicated by tmax values ranging from 10·5 to 15·5 min. Absorption was not complete, the oral bioavailability being 53 per cent and 70 per cent for the 0·3 and 1 mg kg−1 carbimide dose, respectively. The data indicate that there is a first‐pass effect for carbimide.
Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects
Authors: Baldock G. A. , Brodie R. R. , Chasseaud L. F. , Taylor T. , Walmsley L. M. , Catanese B. 
Published: October 2006

AbstractThe pharmacokinetics of the anti‐inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min−1) but high volume of distribution (ca. 1101); the apparent terminal half‐life in plasma was ca. 8h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (<10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non‐specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.
The pharmacokinetics of atropine and diazepam in sheep: Intramuscular co‐administration
Authors: Moore David H. , Smallridge Robert C. , Von Bredow Jurgen D. , Lukey Brian J. 
Published: October 2006

AbstractThe purpose of this study was to determine whether the co‐administration of atropine and diazepam affect the rate and extent of absorption of either drug. A triple crossover pharmacokinetic study using adult sheep was conducted. Each of nine animals received single injections of atropine (2mg), diazepam (10mg), and a combination of the two compounds weekly over a 3‐week period. The combination of the drugs was injected into a single intramuscular site through a specially designed tandem syringe. Blood samples were obtained from time 0 to 300 min post‐injection. Serum samples were analyzed for atropine by radioimmunoassay and for diazepam by gas chromatography/mass spectrometry. Pharmacokinetic parameters were evaluated by non‐compartmental analysis. The co‐administration of atropine and diazepam intramuscularly in sheep caused a delay in the time to reach maximal concentration of atropine. However, at the time when a single injection of atropine reached its maximum serum concentration, 92 per cent of that concentration was reached by atropine in the presence of diazepam. Additionally, no difference was detected in the rate or extent of diazepam absorption when administered intramuscularly in combination with atropine at the same site.
Nonlinearities in amoxycillin pharmacokinetics I. Disposition studies in the rat
Authors: Torres‐Molina F. , Peris‐Ribera J. E. , García‐Carbonell M. C. , Aristorena J. C. , Granero L. , Plá‐Delfina J. M. 
Published: October 2006

AbstractSeveral features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady‐state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3·5 to 7·0 mg kg−1 for intravenous bolus, and from 4·6 to 20·0 μg min−1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intravenous dose is substantially increased (28·0 mg kg−1 bolus), plasma clearance tends to stabilize, probably because saturation of the active tubular secretion of amoxycillin takes place at these doses. Extrarenal clearance seems to remain linear throughout the entire dose range. On the basis of these observations and a review of selected bibliography, an interpretation of the kinetic disposition behaviour of amoxycillin in man is attempted.
Nonlinearities in amoxycillin pharmacokinetics II. Absorption studies in the rat
Authors: Torres‐Molina F. , Peris‐Ribera J. E. , García‐Carbonell M. C. , Aristorena J. C. , Plá‐Delfina J. M. 
Published: October 2006

AbstractMost factors influencing amoxycillin oral absorption are, even today, unknown. Since many dosage schedules have been shown to lead to incomplete absorption, it would be desirable to find a suitable animal model where these factors could be studied in depth. In this paper, it is shown that, in the rat, plasma level curves obtained after oral doses of 7 and 28 mg kg−1 are poorly fitted using first‐order absorption kinetics and that the best fit is obtained through the use of an input equation combining zero and first‐order kinetics. In contrast, plasma level curves found after intraduodenal administration of amoxycillin solutions (7 mg kg−1) are well fitted by first‐order input kinetics. It would seem that precipitation of some dose fraction of the orally administered antibiotic may occur in proximal gastrointestinal areas; this plays an important role in absorption profiles and prevents any possible saturation phenomena associated with active intestinal transport of the antibiotic. A comparative study of available human oral data revealed close similarities with those found in rats. As a result, the plasma level curve fitting was greatly improved by the use of the input function described here for the rat. Although oral bioavailability (as assessed from urinary excretion data) is lower in this latter species, the use of suitable correction factors led to superimposable plasma level curves in the two species, as occurred in previously reported disposition studies.
Pharmacokinetics and acetylation of sulfa‐2‐monomethoxine in humans
Authors: Vree Tom B. , Kolmer Eleonora W. J. Beneken , Hekster Yechiel A. , Shimoda Minoru , Ono Makoto , Miura Tadayoshi 
Published: October 2006

AbstractIn humans sulfa‐2‐monomethoxine (S) is metabolized by N4‐acetylation (39.9 ± 8.0 per cent). After an oral dose, S is eliminated biphasically (t½, 5·2 ± 1·6h and 13·2 ± 3·4h) which is similar in both fast and slow acetylators. The metabolite N4‐acetylsulfa‐2‐monomethoxine (N4) is eliminated monophasically (t½, 30·0 ± 5·7h). The intrinsic mean residence time (MRT) of NM4 is 33·5 ±8·8h. The mean total body clearance of S is 11·6 ±2·7 ml min−1, and the Vdss is 12·3 ± 1·01. The renal clearance of S during the first day was twice as high as on the following days for two of the six volunteers (8 vs 4 ml min−1). The renal clearance of N4 during the first day, for four out of the six volunteers, was twice as high as on the following days (8 vs 4 ml min−1). The protein binding of S is 95 per cent and that of its conjugate N4 98 per cent. Approximately 80 per cent of the oral dose of S is excreted in the urine as parent drug (41·0 ± 6·2 per cent) and as N4 acetyl conjugate (39·9 ± 8·0 per cent).
A pharmacokinetic and tolerance study of romazarit in patients with rheumatoid arthritis
Authors: Williams P. E. O. , Bird H. A. , Minty S. , Helliwell P. S. , Muirhead G. J. , Bentley J. , York A. 
Published: October 2006

AbstractRomazarit is a new drug for which animal pharmacology suggests a disease‐modifying action in rheumatoid arthritis (RA). These animal studies predict that plasma romazarit concentrations within the range 50–100 mg l−1 may be required for efficacy in the clinic. Therefore, a pharmacokinetic study was designed to estimate the dosage required to achieve these concentrations in man. Twenty‐four patients with RA entered a doubleblind controlled assessment receiving either placebo, 100 mg t.i.d., 350 mg b.i.d., or 350 mg t.i.d., for 6 days. Pharmacokinetic profiles were measured after single doses and after the last of the multiple doses. Adverse events were mainly trivial and were distributed almost equally between all three treatment and the placebo groups. Plasma romazarit concentrations were not dose‐proportional after the single doses. Mean peak plasma drug concentrations were 11·8, 66·7, and 159 mg l−1 at steady state after 100 mg t.i.d., 350 mg b.i.d., and 350 mg t.i.d. The mean urinary recovery of drug‐related material (mostly ester glucuronides) was 71 per cent of the dose during the dosage interval. The renal clearance of romazarit glucuronides correlated with creatinine clearance (p<0·01). Saturable tubular secretion of glucuronides coupled with reversible glucuronidation would explain these findings. It is predicted that oral doses of 450 mg romazarit given 12‐hourly will result in plasma concentrations within the target range of 50–100 mg l−1.
Brain regional pharmacokinetics of biperiden in rats
Authors: Yokagawa Koichi , Nakashima Emi , Ishizaki Junko , Hasegawa Mitsuru , Kido Hideki , Ichimura Fujio 
Published: October 2006

AbstractThe pharmacokinetic profiles of biperiden (BP) in blood and in specific brain regions were investigated in rats after acute i.v. administration. The regional brain‐to‐blood unbound concentration ratios (Kpf) were also determined after 16h intravenous infusion of BP. The Kpf values ranged from 30 to 75 in the different brain regions and showed decreasing concentrations in the following order: pons + medulla oblongata, basal ganglia, amygdala, hypothalamus, thalamus, mesencephalon, bulbus olfactorius + septum, hippocampus, frontal cortex, occipital cortex, cerebellum. The relationship between BP and acetylcholine (ACh) concentrations in the brain regions was examined. ACh levels in the various brain regions ranged from 8 to 44 ng g−1 tissue. There was a significant correlation between the Kpf values of BP and the levels of ACh in the brain regions except for the pons + oblongata. BP concentrations in the brain regions after BP administration were predicted based on the physiological pharmacokinetics. There was reasonable agreement between the model predictions and the observed data.
A simplified approach for evaluation of hepatic drugoxidizing activity with a simultaneous determination of caffeine and trimethadione and their demethylated metabolites in rats with a selective cytochrome P‐450 inducer
Authors: Tanaka Einosuke , Ishikawa Akio , Yamamoto Yuji , Uchida Eiji , Kobayashi Shinichi , Yasuhara Hajime , Misawa Shogo 
Published: October 2006

AbstractWe determined the blood concentrations of caffeine (CA) and its three primary dimethylxanthine metabolites: theobromine (TB), paraxanthine (PX), and theophylline (TP), and trimethadione (TMO) and its demethylated metabolite dimethadione (DMO) after the simultaneous administration of CA (10 mg kg−1) and TMO (4 mg kg−1) to rats pretreated with phenobarbital (PB: 40 and 80 mg kg−1 i.p. daily for 3 days) and 3‐methylcholanthrene (MC: 10 and 20 mg kg−1 i.p. daily for 2 days). After the oral administration of CA and TMO, the PB‐pretreated rats showed a significant increase in TMO metabolism, whereas the CA metabolism was greatly accelerated in rats pretreated with MC.In five pretreated groups, there were correlations which were determined 1 h after the administration of CA and TMO, between the plasma half‐life (t1/2) of CA and the TB/CA, PX/CA, and TP/CA ratios. The coefficients of correlation (r) ranged from −0·881 to −0·908, and the coefficients of correlation between the CL of CA and the TB/CA, PX/CA, and TP/CA ratios ranged from 0·959 to 0·989.There were high correlations between the t1/2 of TMO and the DMO/TMO ratio at 1 h after administration with r = −0·966, and between the CL of TMO and the DMO/TMO ratio with r = 0·971.The above results suggest that one blood sampling after the simultaneous administration of CA and TMO enables prediction of the degree of each hepatic drug‐oxidizing activity because the P‐450 isozymes involved in metabolism of CA and TMO are different.
Plasma disposition and hemo‐dynamic effects of a single oral dose of isosorbide dinitrate in human males and females
Authors: Nakatsu K. , Brien J. F. , Savard G. , Toffelmire E. B. , Abdollah H. , Bennett B. M. , Marks G. S. 
Published: October 2006

AbstractThe goal of the present work was to determine the plasma disposition and hemo‐dynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21·7±2·5 y (SD), and seven females, 20·7±3·4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmo‐manometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide‐2‐mononitrate (2‐ISMN) and isosorbide‐5‐mononitrate (5‐ISMN), were determined by large bore capillary column gas—liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2‐ISMN or 5‐ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0·5h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2‐ISMN and 5‐ISMN were maximal. These observations indicate that, for a single 10mg oral dose of ISDN, there were no gender‐dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.
Distribution of carbamazepine and its epoxide in blood compartments in adolescent and adult epileptic patients
Authors: Bonneton J. , Genton P. , Mesdjian E. 
Published: October 2006

AbstractCarbamazepine (CBZ) used in the treatment of epilepsy, is metabolized in man to an active metabolite: carbamazepine 10–11 epoxide (CBZ‐E). CBZ and CBZ‐E concentrations in the different blood compartments (plasma ultrafiltrate, plasma proteins, and red blood cells (RBC)) of epileptic patients on CBZ monotherapy were assessed using HPLC. The highest CBZ and CBZ‐E level to dose ratios were observed in the RBC. For CBZ and CBZ‐E significant correlations were found between some blood compartments particularly between RBC and plasma ultrafiltrate. The measurement of CBZ and CBZ‐E in all blood compartments may be interesting in uncontrolled patients and in patients presenting side‐effects which cannot be explained by total plasma concentration values.
Applicability of teicoplanin dosage adjustment guidelines for renally impaired patients over the range of 3 to 30MGKG−1
Authors: Smithers Jacquelyn A. , Thompson Gary A. , Kenny Michael T. , Dulworth Jacqueline K. , Kulmala Henrik K. , Lewis Eric W. , Ruberg Stephen J. , Shapiro Bruce E. , Keane William F. , Halstenson Charles E. 
Published: October 2006

AbstractThe pharmacokinetics of teicoplanin were investigated in 13 subjects with various degrees of renal impairment using a randomized two‐period crossover design; 11 subjects completed both periods. Doses of 3 and 30 mg kg−1 were administered as single dose, 60‐min constant rate intravenous infusions. Blood samples were obtained over 28 days and urine was collected over 48 h. Serum and urine were analyzed using a microbiological assay. As previously observed in studies conducted in renally impaired subjects, teicoplanin total and renal clearance significantly decreased with decreasing creatinine clearance (p<0·0001). However, for these parameters, no differences between doses were observed. Dosage adjustment guidelines for renally impaired patients are usually developed using the ratio of total clearance in renally impaired patients to the total clearance in patients with normal renal function. Since no dose‐related differences existed in the relationship between teicoplanin total clearance and creatinine clearance, initial dosage adjustment guidelines for renally impaired patients developed at 3 or 30 mg kg−1 are applicable over the range of 3 to 30 mg kg−1.
Sex‐differences in the disposition of substituted benzamides: Pharmacokinetics of a gastroprokinetic agent (4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl) ethoxy]‐N‐[2‐(diethylamino)ethyl] benzamide hydrochloride) (ML‐1035) in male and female New Zealand white rabbits
Authors: Rao Niranjan , Otis Kenneth W , Hwang Kin‐Kai 
Published: October 2006

AbstractThe disposition of 4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl)ethoxy]‐N‐[2‐(diethylamino) ethyl] benzamide hydrochloride (ML‐1035) following intravenous (10 mg kg−1) and oral (200 mg kg−1) dosing was investigated in male and female New Zealand white rabbits. After intravenous dosing ML‐1035 was eliminated with a half‐life of 1·45 ± 0·49 h in males and 0·79 ± 0·08 h in females. Volume of distribution at steady‐state was 2·08 ± 0·98 1 kg−1 in males and 9·11 ± 5·86 1 kg−1 in females. Clearance averaged 2·99 ± 1·11 1 h−1 kg−1 in males and 16·73 ± 7·29 1 h−1 kg−1 in females. All pharmacokinetic parameters were significantly different between males and females (p<0·05). Absolute bioavailability after oral administration was 7·35 per cent for males and 12·31 per cent for females, suggesting that ML‐1035 undergoes significant first‐pass elimination. Plasma area under the curve for the metabolites of ML‐1035 after both oral and intravenous administration were also different between the two sexes. These data suggest that the disposition of ML‐1035 shows significant differences between male and female rabbits.