bluuebunny/crossref_metadata_2025 huggingface dataset:
A pharmacokinetic evaluation of HIV protease inhibitors, cyclic ureas, in rats and dogs
Authors: Wong Y. Nancy , Burcham Deborah L. , Saxton Philip L. , Erickson‐Viitanen Susan , Grubb Mary F. , Quon Check Y. , Huang Shiew‐Mei
Published: October 2006

The pharmacokinetics of a series of novel cyclic, non‐peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC90, values of 0.03–1.0 μM (0.017–0.76 μg mL−1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21–1.88 μg mL−1 were detected within 1 h of oral administration of 10 mg kg−1 of the compounds. The elimination half‐lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 μg mL−1 and 48%, 1.07 μg mL−1 and 16%, and 1.48 mg mL−1 and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC90 for inhibition of viral replication after single doses of 10 mg kg−1 in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatment of HIV‐associated diseases.
The effect of different routes of administration on the metabolism of morphine: The disposition of morphine and its metabolites after topical application
Authors: Matsuzawa Takayasu , Wada Yoshio , Shimoyama Masaru , Nakajima Kae , Seki Toshinobu , Sugibayashi Kenji , Morimoto Yasunori
Published: October 2006

The disposition of morphine (MOR) and its metabolites in the rabbit was measured after topical administration of its hydrochloride salt (MOR · HCl), and their time course was compared with those after intravenous and oral administration. The area under the plasma concentration—time curve (AUC) ratio of metabolites/MOR after the topical application of MOR · HCl was similar to that after intravenous injection, but differed from that after oral administration. Pharmacokinetic parameters of the disposition of MOR and its metabolites were obtained by a general curve fitting of the time course of plasma concentrations of these compounds after intravenous injection of MOR · HCl and its metabolites, respectively. On the other hand, the time courses of plasma concentrations of the metabolites after intravenous, oral, and topical administration of MOR · HCl were simulated using a simple compartment model without consideration of enterohepatic circulation and the pharmacokinetic parameters obtained as above. The resulting curves of the metabolites agreed well with the observed values except for those after oral administration.

These results suggest that no first‐pass metabolism of MOR · HCl occurs after percutaneous administration, and that topical administration of this salt is more advantageous than oral administration in terms of bioavailability.
Effect of ‘unstirred’ water layer in the intestine on the rate and extent of absorption after oral administration
Authors: Chiou Win L.
Published: October 2006

The presence of an aqueous diffusion layer or ‘unstirred’ water layer adjacent to the intestinal membrane has long been regarded as a potential barrier for intestinal absorption of compounds. Theoretical analyzes were performed in the present study to quantitatively determine the effect of this layer on the rate and extent of absorption of passively absorbed compounds with different membrane absorption half‐lives (10 to 300 min) in humans, dogs, rabbits, rats and mice. Diffusion half‐lives across this (40 μm thick) layer were estimated to be 5.8, 2.5, 1.1, 0.65 and 0.32 min, respectively, in the distended intestine of the above five species. These half‐lives are reduced by about 5‐fold when the intestine is about 80% ‘flat’ in fasting state. The results of extensive analysis indicate that the presence of such a layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption. The study also indicates that an aqueous layer of 708 μm has practically no effect on the extent of absorption of progesterone, a highly lipophilic compound, in rats. For prediction of or correlation with the fraction of oral dose absorbed after oral administration, the present study indicates that use of apparent or effective permeability rather than unbiased or true wall (membrane) permeability, as advocated earlier by others, should generally suffice.
Comparative pharmacokinetics of oxaliplatin (L‐OHP) and carboplatin (CBDCA) in mice with reference to circadian dosing time
Authors: Boughattas Naceur A. , Hecquet Bernard , Fournier Charles , Bruguerolle Bernard , Trabelsi Hassen , Bouzouita Kamel , Omrane Belhadj , Lévi Francis
Published: October 2006

Carboplatin (CBDCA) and oxaliplatin (I‐OHP) are non‐nephrotoxic platinum (Pt) compounds, which exert their main respective toxicities on the bone marrow and on the intestinal mucosa in mice. Plasma and red blood cell (RBC) drug dispositions were investigated in 324 male B6D2F1 mice after a single IV injection of CBDCA (72 mg kg−1) or I‐OHP (17 mg kg−1). Since the toxicities of either drug largely depended upon circadian dosing time, such a pharmacokinetic study was performed following injection of either Pt complex at a time of low (16 h after light onset—HALO), intermediate (0 HALO) or high (8 HALO) toxicity.

Pt concentrations in plasma ultrafiltrate (PUF) and in total plasma declined in parallel and became barely detectable by 2 h following CBDCA injection. Conversely, free Pt became undetectable 1 h after I‐OHP injection, whereas sustained levels of total Pt were found 24 h post dosing. This suggested that I‐OHP had a high binding affinity for plasma proteins. Mean values of t1/2α and mean residence time (MRT) of free Pt for I‐OHP (6.7 min and 9.7 min respectively) were half those of CBDCA (12.5 min and 18.1 min respectively). The two drugs had a similar initial volume of distribution (Vdi) of free Pt (10.5 mL) in mice. However, plasma clearance of I‐OHP was twice as high (1.06 mL min−1) as that of CBDCA (0.58 mL min−1). Free Pt AUCs were eight to ten times lower for I‐OHP than for CBDCA. In contrast, erythrocyte Pt AUCs were three to four times as high for I‐OHP as for CBDCA. Circadian changes in pharmacokinetic parameters were large, yet limited to the initial distribution phase (C0, t1/2α, Vdi) as well as mean residence time. The smallest Vdi and the fastest plasma elimination occurred when either drug was injected at 0 HALO. The largest Vdi and the longest elimination were however observed at 8 HALO for CBDCA and 16 HALO for I‐OHP. No consistent relationship was found for both Pt complexes with regard to circadian changes in blood pharmacokinetics and in target organ toxicities.

The major pharmacokinetic differences between CBDCA and I‐OHP were related to both protein binding and RBC handling.
The bioavailability of diclofenac from enteric coated products in healthy volunteers with normal and artificially decreased gastric acidity
Authors: Van Gelderen Marjet E. M. , Olling Martin , Barends Dirk M. , Meulenbelt Jan , Salomons Peter , Rauws Adalbert G.
Published: October 2006

The relative bioavailability of four monolithic enteric coated (MEC) diclofenac products was compared in 16 healthy volunteers. Only one generic product was fully bioequivalent with the reference product Voltaren with regard to AUC, Cmax, and tlag. Two products showed significant differences in tlag.

In a second experiment with eight volunteers the influence of increased gastric pH (ranitidine treatment) on the two mutually most differing products was studied. They showed equivalence in AUC, but not in Cmax. Analysis of tlag suggests that the product with the low tlag disintegrates within the non‐acid stomach, whereas the product with the long tlag passes the non‐acid stomach intact.

Several in vitro dissolution tests were conducted. The European Pharmacopeia test did not detect any differences between the products. At pH 5, both with and without mechanical stress, only the product with the shortest tlag released diclofenac. The in vivo results were best predicted by the in vitro dissolution tests performed at several fixed pH values with mechanical stress.
The estimation of the plasma free fraction of cyclosporine in rabbits and heart transplant patients: The application of a physiological model of renal clearance
Authors: Shah Ajit K. , Brundage Richard C. , Lake Kathleen D. , Sawchuk Ronald J.
Published: October 2006

We estimated the free fraction (fu) of cyclosporine (CyA) in the plasma from concentrations of CyA in urine (Cu) and plasma (Cp), urine flow rate (UF), and glomerular filtration rate in rabbits and in heart transplant patients. Following intravenous administration of CyA (5–30 mg kg−1) in ten NZW rabbits and oral administration of CyA (4.8–12.1 mg kg−1) in nine heart transplant patients, CyA concentrations in urine and plasma were measured by HPLC. The ratios of Cu to Cp and UF data were fitted to a physiological model of renal clearance using NONMEM. The free fraction of cyclosporine in the rabbits and the heart transplant patients was 0.0122 and 0.14, respectively. Because of the relatively low permeability of CyA across the tubular epithelium, no apparent equilibrium between Cu and Cp at any urine flow rate was reached and, therefore, the Cu to Cp ratio will not be equal to fu.
Disposition kinetics of hepp in rats after intravenous, oral, and intraperitoneal administration. Correlation of plasma and brain levels with the anticonvulsant effects
Authors: Gómez Lisbeth E. , Cueva‐Rolón Rafael , Lehmann F. Pedro A.
Published: October 2006

D, L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropanamide (HEPP) is a synthetic drug with anticovulsant effects in a variety of seizure models. HEPP pharmacokinetics was studied after single 50 mg kg−1 intravenous (IV), intraperitoneal (IP), and oral (PO) administration in male albino Wistar rats. The plasma concentration against time curves showed a biphasic decay pattern with a similar distribution phase and the same terminal rate constant (β = 0.22 h−1) by all three routes. The apparent volume of distribution at steady state (VSS = 0.80 L kg−1) indicates that HEPP is extensively distributed in extracellular tissues. This finding agrees very well with its low binding to plasma protein (mean bound fraction = 19.3 ± 1.1%). The systemic clearance (Cl) was very low (3.30mL min−1 kg−1). The bioavailability after IP and PO administration was 0.80 and 0.60 respectively. In the pharmacokinetic‐pharmacodynamic studies a direct relationship was found between the protective effect of HEPP against pentylenetetrazole (PTZ) induced seizures and its concentration in plasma and/or brain. The concentrations at half‐maximal effect (EC50) with 95% confidence interval (Cl) were 70.6 (66–75.5) μg mL−1 in serum and 60.1 (55.4–65.1) μg g−1 in brain. There was a rapid uptake of HEPP into the brain, and after the distributive phase, the disappearances in plasma and brain were almost parallel [Cserum = 109 e−0.25t, r2 = 0.95; Cbrain = 38 e2.53t + 91 e−0.21t, r2 = 0.93], with a Cbrain/Cplasma ratio of 1.1.
Plasma lipoproteins as targeting carriers to tumour tissues after administraion of a lipophilic agent to mice
Authors: Tokui Taro , Kuroiwa Chitose , Muramatsu Shigeki , Tokui Yoko , Sasagawa Kazuhiko , Ikeda Toshihiko , Komai Toru
Published: October 2006

We synthesized 14C‐warfarin hexadecyl ether (14C‐WHE) by addition of a palmityl moiety to the hydroxyl group at the 4‐position of 14C‐warfarin, a compound known to bind to serum albumin. 14C‐WHE preferentially bound to the lipoproteins, low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL), in mouse plasma both in vitro and in vivo. 14C‐Warfarin mainly concentrated in the liver immediately after intravenous administration to mice bearing M5076 sarcoma, and was found at only low concentrations in other tissues including the tumour. 14C‐WHE highly distributed to the tumour, in other tissues including the tumour. 14C‐WHE highly distributed to the tumour, adrenal, and spleen, as well as the liver. These tissues coincided with those in which human 125I‐LDL was vigorously incorporated. The results indicate that chemical modification of an agent, giving it high lipophilicity, will enable it to bind to lipoproteins after intravenous administration. These modifications raise the possibility of lipoproteins as endogenous targeting carriers into tumour cells, which have high LDL‐receptor activity.
Pharmacokinetics of amoxicillin coadministered with a saline‐polyethylene glycol solution in healthy volunteers
Authors: Padoin C. , Tod M. , Brion N. , Louchahi K. , Le Gros V. , Petitjean O.
Published: October 2006

The pharmacokinetics of orally administered amoxicillin were investigated in 12 healthy volunteers in a crossover design. They received either a placebo or a saline—polyethylene glycol solution (SPG) for 4 d, the last dose being given simultaneously with 1 g amoxicillin; blood samples were drawn for the next 12 h. Amoxicillin kinetics were similar in the two treatments but small differences in some pharmacokinetic parameters reached significance. The mean±SD area under the curve was lower with SPG (43.8±6.8 against 47.8±8.2 mg h L−1, p<0.05) but the treatments were equivalent according to Westlake's test (95% confidence interval = 14.95%). Analysis of SPG against placebo amoxicillin absorption kinetics after fitting the data to a Weibull model revealed a longer duration of the absorption, a slower rate of absorption, and a different shape of the curve. No clinical consequences are expected from these minor variations but possible mechanisms could be relevant to other drugs.
The effect of food on the absorption of 14C‐SDZ FOX 988, an antidiabetic agent, in healthy human volunteers
Authors: Lau David T.‐W. , Kalafsky G. , Tse Francis L. S.
Published: October 2006

The objective of this study is to examine the effect of food on oral absorption of SDZ FOX 988 (FOX 988), an antidiabetic agent, and circulating levels of its active metabolite, SDZ 53–450 (53–450). Sixteen normal volunteers received a single 10 mg dose of 14C‐FOX 988, either as gelatin capsules or in a suspension (0.5% CMC). For subjects receiving each formulation, four subjects received a meal, consisting of 50% fat by calories, immediately following dosing, while the other four received the same meal at 2 h post‐dose. Serial blood, urine, and fecal samples were collected for 120 h and analyzed for total radioactivity. Blood concentrations of 53–450 were analyzed using an HPLC–UV method. Concomitant administration with food increased the extent of FOX 988 absorption from either suspension or capsule, as shown by an increase in AUC and in urinary recovery of radioactivity. Blood concentrations of 53–450 were only detected in subjects receiving food at dosing. No difference in absorption was observed between the capsule and the suspension. Results from this study showed that oral absorption of FOX 988 is enhanced by co‐administration of food in normal volunteers.
Pharmacokinetic analysis of diethylcarbonate prodrugs of ibuprofen and naproxen
Authors: Samara Emil , Avnir David , Ladkani David , Bialer Meir
Published: October 2006

The pharmacokinetics of ibuprofen diethylcarbonate (ibudice) and naproxen diethythylcarbonate (napdice), two new diethylcarbonate prodrgs of ibuprofen and naproxen, was investigated in dogs. The rationale for the development of ibudice and napdice was that esterification of the carboxylic moiety of the parent compounds would suppress gastrotoxicity without adversely affecting their anti‐inflamatory activity. In addition the biotransformation of the prodrugs to the parent compounds may be utilized to achieve rate and time controlled drug delivery of the active entities. Following oral administration the diethycarbonate esters were rapidly biotransformed to the parent compounds and no ibudice or napdice was detected in the plasma. The relative bioavailability of ibuprofen and naproxen, following oral administration of ibudice and napdice, was 96% and 74%, respectively, and the rate of absorption was not significantly different from that obtained following oral dosing of the parent compound. Stability studies in gastric and intestinal juice showed that, unlike napdice, ibudice was stable in gastric juice, with both prodrugs undergoing rapid biotransformation to their parent compounds in intestinal juice. This rapid conversion led to the lack of sustained release performance following oral administration of ibudice or napidice.
Disposition of [3H]fluvastatin following single oral doses in beagle dogs and rhesus monkeys with bile fistulae
Authors: Tse Francis L. S. , Dain Jeremy G. , Kalafsky Gaetana
Published: October 2006

The disposition of [3H]fluvastatin was examined following single oral doses in dogs (12.4 mg kg−1) and monkeys (0.48 45.5 mg kg−1) with bile fistulae. Serial plasma and complete urine, feces, and bile were collected at designated intervals for 3 or 4 d, and were analyzed for total radioactivity and unchanged fluvastatin. In the dog, peak radioactivity concentrations (Cmax) averaged 7260 ng equiv. mL−1 and the mean time to peak (tmax) was ∼ 9 h. In the monkey, the mean radioactivity tmzx values were ∼ 5 and 13 h following the low and high doses, the respective Cmax values being 116 and 10400 ng equiv. mL−1. The mean AUC of total radioactivity was proportional to the dose while that of fluvastatin was overproportional to dose, suggesting dose indepedent absorption but saturable first‐pass effect. The AUC ratio of unchanged fluvastatin versus total radioactivity was approximately 63% in the dog, and 9% and 13% for the low and high doses, respectively in the monkey. The bile was the major excretory route of radioactivity (dog, 56%; low‐dose monkey, 73%; high‐dose monkey, 69%) whereas the renal pathway accounted for < 5% of the dose in both species. Approximately 12% of the biliary radioactivity in the dog was due to intact fluvastatin, compared with 0% and 7.5% after the low and high doses in the monkey. These results showed a smaller extent of fluvastatin metabolism in the dog than in the monkey, and suggested that metabolism in the monkey was saturable in the dose range studied.
Mean residence time of drugs administered non‐instantaneously and undergoing linear tissue distribution and reversible metabolism and linear or non‐linear elimination from the central compartment
Authors: Cheng Haiyung
Published: October 2006

Based on disposition decomposition analysis (DDA), equations for the mean residence times (MRT) in the body are derived for a drug and its interconversion metabolite that undergo linear tissue distribution and linear or non‐linear elimination from the central compartment after non‐instantaneous administration of the drug. The MRT of the drug after non‐instantaneous input can be related to the MRT of the drug after intravenous administration, the ratio of the total area under the plasma concentration—time curve of the drug after non‐instantaneous administration to that after intravenous administration, the bioavailability of the drug, and the mean input time of the drug. Similar relationships also exist for the MRT of the interconversion metabolite after non‐instantaneous input of the drug. The application of these equations to a non‐linear reversible metabolic system is illustrated with computer simulations.
Pharmacokinetics and hepatic first‐pass effect of (−)‐carbovir in the anesthetized rat
Authors: Soria Inmaculada , Zimmerman Cheryl L.
Published: October 2006

Studies were designed to allow an in vivo estimation of the hepatic extraction ratio and to test the hypothesis that the pharmacokinetic parameters of (−)‐CBV are significantly different during anesthesia. (−)‐CBV was administered as an IV bolus followed by IV infusion into either the portal (n = 3) or the jugular (n = 3) veins of anesthetized male Sprague—Dawley rats These studies indicated that (−)‐CBV had a very low hepatic extraction ratio, in agreement with previous (−)‐CBV in situ liver perfusion studies. Additionally, anesthesia was shown to alter the pharmacokinetics of (−)‐CBV by reducing the total body clearance of this drug.
Pharmacokinetics of α‐dihydroergocriptine in rats after single intravenous and single and repeated oral administrations
Authors: Coppi G. , Silingardi S.
Published: October 2006

The pharmacokinetics of α‐dihydroergocriptine methane sulphonate in rats were investigated using an HPLC method for the detection of unchanged α‐dihydroergocriptine (DHEK) in plasma, organs (kidneys, heart, lungs, spleen, liver, and brain), and urine. The plasma profile of DHEK obtained after intravenous administration at a dose of 5 mg kg−1 (as base) of DHEK methane sulphonate showed a three compartment pharmacokinetic model with an elimination half‐life of 6.78 h. The kinetics of DHEK after a single oral administration at a dose of 20 mg kg−1 (as base) showed two peaks: the second peak, at about 6 h, was probably due to an enterohepatic cycle. The disposition of DHEK consisted of an absorption half‐life of 0.02 h, a distribution half‐life of 2.15 h and an elimination half‐life of 5.83 h. The pharmacokinetics of DHEK, after repeated oral administrations at the same dose, were similar to those after a single oral administration. The absolute bioavailability was 4.14% after a single oral administration and 3.95% after repeated oral administrations. The analysis of the organs showed that DHEK was rapidly absorbed and distributed in all tissues, mostly in lungs, kidneys, and liver, but it is interesting to observe that it also reached the brain. After repeated oral administrations plasma and tissue concentrations were similar to those obtained after a single administration; therefore it is possible to exclude the onset of autoinduction or accumulation phenomena of DHEK in rats' organs.

Urinary excretion of the unchanged drug was low (0.38% of the administered dose in the intravenous route and 0.04% in the oral route), being in agreement with a low oral bioavailability and a rapid and extensive metabolism (first‐pass effect).
Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding
Authors: Edwards D. M. F. , Pellizzoni C. , Breuel H. P. , Berardi A. , Castelli M. G. , Frigerio E. , Poggesi I. , Rocchetti M. , Dubini A. , Benedetti M. Strolin
Published: October 2006

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4 and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax⋍2h) and an elimination half‐life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F⋍29 mL min−1; Vz/F⋍32L); urinary excretion was ∼9% of dose, corresponding to a renal clearance of only 3 mL min−1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C‐labelled reboxetine, appeared to be dominated by α1‐acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL−1 (2.8–3.1% unbound with human plasma from three additional volunteers; 1.8–2.0% for 2gL−1 orosomucoid α1‐acid glycoprotein, and 46.4–47.4% for 40 gL−1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL−1 after a 5 mg dose).
Selective adherence of a sucralfate—tetracycline complex to gastric ulcers: Implications for the treatment of Helicobacter pylori
Authors: Yokel Robert A , Dickey Kenneth M. , Goldberg Arthur H.
Published: October 2006

The adherence of a sucralfate—tetracycline complex to gastric ulcers and to nearby nonulcer sites was determined in the rabbit antrum. Persistent gastric ulcers were produced by a previously described method. The presence of the complex was assessed 1 and 4 h after dosing. Drug adherence was determined by quantitation of aluminum in stomach wall biopsies. Significantly more aluminum adhered to ulcer sites than to nearby nonulcer sites. Adherence of the complex did not significantly decrease from 1 to 4 h. The complexation of tetracycline to sucralfate did not alter the selective adherence of sucralfte to gastric ulcers, providing a mechanism of ulcer site‐selective drug delivery in the treatment of Helicobacter pylori gastric ulcer disease.
Pharmacokinetics and relative bioavailability of selegiline in healthy volunteers
Authors: Mahmood Iftekhar , Marinac Jacqueline S. , Willsie Sandra , Mason William D.
Published: October 2006

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. A sensitive fluorimetric assay based on ibhibition of rat brain monoamine oxidase‐B (MAO‐B) in vitro has been developed to study the pharmacokinetics of selegiline. This method quantitates selegiline as low as 0.25 ng ml−1. The pharmacokinetics and relative bioavailability of selegiline were investigated in healthy volunteers following oral administration of 10 mg tablet or solution. A half‐life of approximately 70 min was observed following the administration of either dosage form. Although the two dosage forms exhibited a lag time, the absorption was rapid and peak plasma concentrations were observed between 30 and 45 min for the solution and 30 and 90 min for the tablets. Statistically no significant difference was found between Cmax, Tmax, AUC0‐∞ and MRT between the two dosage forms. Negligible renal clearance was found in both groups, but aparent oral plasma clearance was comparatively high and indicates rapid elimination of selegiline from the body.
Stability, tissue metabolism, tissue distribution and blood partition of azosemide
Authors: Lee Sun H. , Lee Myung G.
Published: October 2006

Stability of azosemide after incubation in various pH solutions, human plasma, human gastric juice, and rat liver homogenates, metabolism of azosemide after incubation in 9000g supernatant fraction of various rat tissue homogenates in the presence of NADPH, tissue distribution of azosemide and M1 after intravenous (IV) administration of azosemide, 20 mg kg−1, to rats, and blood partition of azosemide between plasma and blood cells from rabbit blood were studied. Azosemide seemed to be stable for up to 48 h incubation in various pH solutions ranging from two to 13 at an azosemide concentration of 10 μg mL−1; more than 93.4% of azosemide was recovered and a metabolite of azosemide, M1, was not detected. However, the drug was unstable in pH 1 solution: 75.8% of azosemide was recovered and 2.16 μg mL−1 of M1 (expressed in terms of azosemide) was formed after 48 h incubation in pH 1 solution at an azosemide concentration of 10 μg mL−1. Azosemide was stable in both human plasma and rat liver homogenates for up to 24 h incubation at an azosemide concentration of 1 μg mL−1, and in human gastric juice for up to 4 h incubation at an azosemide concentration of 10 μg mL−1. However,‐all rat tissues stdied had metabolic activity for azosemide in the presence of NADPH, with heart having a considerable metabolic acitivity: approximately 22% of azosemide disappeared and 9.32 μg of M1 was formed per gram of heart (expressed in terms of azosemide) after 30 min incubation of 50 μg of azosemide in 9000g supernatant fraction of heart homogenates. The tissue to plasma ratios of azosemide (T/P) were greater than unity only in the liver (1.26) and kidney (1.74); however, M1 showed high affinity for all tissues studied except the brain and spleen when each tissue was collected at 30 min after IV administration of azosemide to rats. The equilibrium plasma to blood cell concentration ratios of azosemide were independent of azosemide blood concentrations: the values were 2.78–4.25 at azosemide blood concentrations of 1, 10, and 20 μg mL−1 three rabbits. There was negligible ‘blood storage effect’ of azosemide, especially at low blood concentrations of azosemide, such as 1 and 10 μg mL−1.
Stability and pharmacokinetic studies of a new immunosuppressant, mycophenolate mofetil (RS‐61443), in rats
Authors: Sugioka Nobuyuki , Chen Shi Hu , Hayashida Kazuhisa , Koyama Hikaru , Ohta Toshio , Kishimoto Hideki , Yasumura Tadaki , Takada Kanji
Published: October 2006

Mycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The enzymatic and non‐enzymatic hydrolysis was studied in an artifical digestive fluid, rat plasma, and tissue homogenates. MPM was chemically stable in the artificial digestive fluid. In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA. The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver > kidney > plasma > small‐intestinal epithelial cells. After the intravenous injection of MPM at 16.7 mg kg−1, the terminal elimination half‐life,‐t1/2β, was 4.74 ± 0.33 (mean ± SD)h, and the area under the plasma concentration versus time curve, AUC, was 48.78 ± 6.01 μg h mL−1. After intraduodenal (ID) administration of MPM at 16.7 mg kg−1, t1/2β was 3.92 ± 1.05 h, and the AUC was 38.08 ± 8.30 μg h mL−1. The systemic availability of MPA after ID MPM dosing was 1.52 times higher than that after ID administration of MPA. This result supports the usefulness of MPM as an oral produrg of MPA as a new oral immunosuppressant.
Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state
Authors: Cardot J.‐M. , Degen P. , Flesch G. , Menge P. , Dieterle W.
Published: October 2006

A study was performed in ten patients, stabilized with oxcarbazepine monotherapy (450–750 mg bid) for two weeks minimum, to investigate the possibility of using saliva to monitor the oxcarbazepine therapy. Thirteen paired blood and saliva samples were taken over 24h. The saliva samples were obtained after stimulation.

The analysis performed on the data suggests a dose dependence for the relationship between plasma and saliva concentrations of the main active metabolite, 10, 11‐dihydro‐10‐hydroxycarbamazepine (MHD), and the importance of the type of stimulation for the saliva's production. Therefore it would be preferable to use plasma concentrations to monitor oxcarbazepine therapy, if necessary.
Pharmaceutical and biological properties of doxorubicin encapsulated in liposomes (L‐ADM): The effect of repeated administration on the systemic phagocytic activity and pharmacokinetics
Authors: Yachi Kiyoto , Kikuchi Hiroshi , Suzuki Norio , Atsumi Ryo , Aonuma Masashi , Kawato Yasuyoshi
Published: October 2006

We investigated the biodistribution and antitumour activity of doxorubicin (ADM) encapsulated in liposomes (L‐ADM) after two administrations in tumour bearing mice. The effect of the first administration on phagocytic activity was also examined.

The biodistribution of L‐ADM after the second dosing at an interval of 4d was remarkably different from that after the first. The concentration of ADM in plasma and tumour after the second injection was higher, but that in the liver was lower than after the first administration. This decrease in distribution to the liver is thought to have contributed to the difference in the biodistribution characteristics of L‐ADM. With regard to antitumour effect, the activity was similar between L‐ADM and a solution of ADM (F‐ADM).

To investigate the effect of the first administration of L‐ADM on biodistribution, systemic phagocytic activity was measured after the injection of F‐ADM, L‐ADM, or ‘empty’ liposomes not containing ADM. F‐ADM and L‐ADM (7.5 mg ADM/kg body weight) reduced phagocytic activity to approximately 50% and 30% of control, respectively. This finding suggests that entrapment of ADM in liposomes enhances both the distribution of the drug to the reticuloendothelial system (RES) and its suppressive effect on RES activity.

These results indicate that the decrease in RES activity by L‐ADM must be considered in estimation of the pharmacokinetics, antitumour activity, and toxicity of L‐ADM in clinical use when given by repeat administration or used in combination with other antitumour agents.
Pharmacokinetics of terbinafine and of its five main metabolites in plasma and urine, following a single oral dose in healthy subjects
Authors: Humbert H. , Cabiac M. D. , Denouël J. , Kirkesseli S.
Published: October 2006

The plasma pharmacokinetics, and the urinary excretion, of terbinafine and its five main metabolites have been investigated after a single oral dose administration of 125 mg to 16 healthy subjects.

In plasma, the highest concentrations are observed for the two carboxybutyl metabolites, with a predominance for the carboxybutylterbinafine. For this metabolite, as compared to terbinafine, the Cmax and AUC are 2.4 and 13 times higher respectively. The demethylterbinafine presents a plasma profile close to that of terbinafine. The two hydroxy metabolites are only found as glucuronide and are of minor importance. The apparent terminal half‐lives of terbinafine, demethylterbinafine, and the two carboxy metabolites appear to be similar (∼ 25h). As compared to the plasma concentration of total radioactivity observed after a single oral administration of the same dose of 14C‐terbinafine, the parent drug and these five metabolites, account for more than 80% of the total radioactivity in plasma over the 0–48 h interval following administration.

In urine, the major metabolite is demethylcarboxybutylterbinafine, which amounted to about 10% of the administered dose. Terbinafine and demethylterbinafine are only excreted as trace amounts in urine. Carboxybutylterbinafine and the two hydroxy metabolites are excreted in the range of 0.5–2% either as glucuronides or free. Urinary excretion over the 0–48h interval of terbinafine and of the five metabolites amounted to about 14% of the administered dose. This is far below the level of total radioactivity measured in urine over the same interval (∼ 57%), after administration of 14C‐terbinafine. This shows in contrast to plasma, that numerous other metabolites are present in urine.
Interspecies pharmacokinetic scaling of BSH in mice, rats, rabbits, and humans
Authors: Mehta Samir C. , Lu D. Robert
Published: October 2006

Sodium mercaptoundecahydrododecaborate or BSH is an important compound for boron neutron capture therapy (BNCT). The total clearance and steady state volume of distribution of BSH in humans and in laboratory animals were analyzed as a function of species body weight using the allometric equation for interspecies scaling. Significant linear relationships were obtained between log CLt (L h−1) and log W(kg) (r=0.972; p=0.028) as well as log VSS(L) and log W(kg) (r=0.999; p=0.0005). The corresponding allometric equations were CLt=0.127 W0.68 and VSS=1.557 W0.87, respectively. BSH clearance in various species was shown to be a constant fraction (0.26) of creatinine clearance, the relationship being independent of body weight. Thus BSH clearance in various species occurred at similar pace when measured by a physiological parameter (creatinine clearance) rather than chronological time. Interspecies scale‐up of plasma concentration—time data for the four species using a complex Dedrick plot resulted in similar profiles. Our results indicate that the BSH data obtained in laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.
Antibronchospasmic, tachycardiac, and hypokalaemic effects of L‐isoproterenol in guinea‐pigs
Authors: Ohtani Hisakazu , Yamamoto Koujirou , Sawada Yasufumi , Iga Tatsuji
Published: October 2006

The relationship between antibronchospasmic, tachycardiac, or hypokalaemic effects and plasma concentration of L‐isoproterenol (ISP) hydrochloride was investigated in guinea‐pigs in vivo. ISP was infused at the rate of 10, 30, 50, 100, and 300 ng kg−1 min−1. The antibronchospasmic effect was expressed as the attenuation of methacholine‐induced bronchospasm. The EC50 values of ISP for antibronchospasmic and tachycardiac effects were 5.12 nM and 3.95 nM, respectively. Although they were comparable to the values reported in vitro (7.23–0.358 nM, 1.77 nM), the concentration response relationship of ISP for antibronchospasmic effect was quite steep with a slope factor of more than six. Moreover, a decrease in plasma potassium level was not clearly detected. The experimental procedure in our present study was useful for evaluating antibronchospasmic and tachycardiac effects of beta‐agonists.
Niedergang der Vergleichenden Morphologie ‐ Verlust für die Botanik
Authors: Mollenhauer Dieter
Published: October 2006

Comparative or idealistic morphology can be taken for one of many different kinds of approaches in general biology. Its Golden Age was the era of Central European Romanticism, one late descendant of this tradition was Wilhelm Troll (1897‐1978). In the end of the 19th century morphology stood back. Its place in the front scene was taken by other general approaches. At present, however, aphilosophic or even antiphilosophic specialists with their materialistic ideologies (of which they are mainly unconscious) are setting the fashion in biology. General concepts are suspicious of natural philosophy and not wanted. If forwarded they have little influence on actual research. Desultory activity is characteristic of present‐day biology resulting in masses of incoherent data. However, history shows how much general concepts are needed for alignment of scientific research. One reason for the vanishing interest in general concepts can be found in professionalized science. Professionalism included the trend to confine to internal affairs. This ends up with a confrontation of two parties: scientists who dispose of knowledge and the public without such insight. Scientists, however, beware of surpassing their “proper spheres of responsibility” thus leaving the public in full obligation to decide on plans, enterprises, and operations. Positive science therefore turns out to be science in complete disengagement since it is pure expert knowledge. Biology must escape from positivism. It needs vital general concepts, otherwise it remains esoteric, exclusive and isolated. Science without interference with actual culture is as sterile and only for luxury as is art in its l'art‐pour‐l'art attitude.
Auflösung durch Unterwanderung
Authors: Schröder Susanne
Published: October 2006

Les raisons pour lesquelles la littérature comparée en Allemagne n'a pas réussi à s'établir en tant que discipline académique pendant l'époque de Wilhelm II et de la République de Weimar (1871‐1933) peuvent s'expliquer sous deux aspects différents.

‐ Si l'on tient compte de l'histoire des idées la ‘Geistesgeschichte’ vint remplacer le positivisme. Cette ‘Geistesgeschichte’ qui d'un cǒté refusait le mécanisme des études des influences et de la ‘Stoffgeschichte’, affirmait de son cǒté son engagement pour les intérêts du comparatisme (l'étude des grands courants européens).

‐ Du point de vue politique, c'est la germanistique avec ses buts nationalistes qui empecha le comparatisme, centré sur l'entente des peuples et les vrais échanges internationaux, de s'installer à l'Université.
Lavoisier, Lichtenberg und Heisenberg
Authors: Wagner Siegfried
Published: October 2006

The essay deals with the remarks on scientific revolutions, as well as on paradigms by some revolutionaries in science. ‐In 1772 Lavoisier remarked in his laboratory note‐book that he was going to make a revolution in chemistry and in physics by replacing the concept of phlogiston by oxygen. During the French revolution, Condorcet came to the conclusion that there are times of stagnation in science, whereafter a genius invents new methods. Both authors were among the three members of the Académie des Sciences who became victims of the Revolution. Lichtenberg was only a spectator of the Revolution. But the [revolutions on Earth] (as he called the Earth quakes) inspired him to contemplate scientific revolution. In the sketch of a textbook on science which he composed during the 1790's, and which he never completed, Lichtenberg returned to this topic. Here he introduced the concept of the paradigm as a tool in science. This term was defined according to its original meaning in classical Greek, i.e. as a model which is taken from a well established branch of science and is applied to a science as yet to be developed. In addition, Lichtenberg discussed several cases in which two scientific hypotheses were in contest. He believed that the future theory would contain a synthesis of the two opposing concepts rather than mark the victory of one over the other.

Heisenberg expressed, since 1932, his views on the development of science in several lectures adressed to the general public. His conclusion was that in sciences, from time to time, revolutions occur in which a given theory will be transformed in the sense of a metamorphosis; the new theory will then be based on a different system of basic concepts. The reasons for a revolutionary transformation are experimental data which do not fit the old theory. During this process the well established older theory is neither falsified nor completely replaced by the new one which, however, ordains the limits of its validity. Heisenberg signifies such theories (as the classical, the relativistic, or the quantum mechanics) as closed theories which are always true. He generalized his own experience in this way: A scientific revolutionary never starts with abandoning the older theory, on the contrary, he wants to save as much of it as possible‐and thus unwittingly he achieves a revolution.
Zum Verhältnis von ästhetischer Theorie und ästhetischer Psychologi
Authors: Menzen Karl‐Heinz
Published: October 2006

The goal of this essay is to point to the ambiguity of the aesthetic phenomenon in its receptivity as sui generis which is glissing away in modern discussion of aesthetics: On one side through the empiristic factualisation of the spiritual structuration of the human subject nevertheless receptive, on the other side through the evaporation of the world‐routed sensibility process in the human act of aesthetical experience. The beauty is neither subjective nor objective, nor interactively reducible to both of them; but: [Was aber schön ist, selig scheint es in ihm selbst] (Eduard Mörike). The base problems of constitution as it is vised in modern aesthetics, goals the conditio sine qua non of aesthetical experience, but just by doing this it is missing the ratio sufficiens, which for ever and ever is the beautiful in itself. The outcome of aesthetical history ends in a kind of subjectivism as loosing out of view the scopus of the beautiful in itself, where identity of both, subject and object of aesthetical experience, is coming forth, and what as such is set free and retributed to itself in the aesthetical act, which is an act of knowledge and acknowledge at once, unless it will never end to find itself in this maze of subject‐object‐dissimulation. Astonishment after all is just the verification of the unity of the different moments in this aesthetical act as such.
Romantische Naturkunde ‐ Die Doppelsinnigkeit der Naturbildung des Bernhard Heinrich Blasche (1766‐1832)
Authors: Trommer Gerhard
Published: October 2006

Naturbildung, written by B. H. Blasche in 1815, seems a typical philanthropic study about science education private organized. But it also demonstrates romantic philosophy influences, which led at least from describing natural history to biology. There was no success in Blasche's reformatory efforts: first reason because the idea of private education‐institution was out of discussion. Second reason was, on the way to stateorganized schoolsystem in Germany classic philology dominated and repressed deeply science education.
Gesundheitspolitik im 19. und frühen 20. Jahrhundert — Deutschland und England als Beispiele —Bericht über eine internationale Arbeitstagung am Zentrum für Interdisziplinäre Forschung der Universität Bielefeld, 7.–9. November 1986
Authors: Labisch Alfons , Spree Reinhard
Published: October 2006

Recent German publications on the social history of health policy stress longterm developments. Especially the preconditions, concepts, and anticipated as well as unexpected consequences must be elaborated more clearly. International comparison seems to be a valid scientific tool for this purpose. An international working group met at the Center for Interdisciplinary Studies/University of Bielefeld for a symposium on “Health Policy in the 19th and early 20th Century — Germany and England as examples”. The general subject was divided in several areas of discussion: social reactions to the cholera; hygienization of every‐day‐life; imperialism, armed forces and health policy; developments in occupational medicine.
Bildungsbegriff und Wissenschaftlichkeit als Bezugspunkte der Entwicklung der Rechtswissenschaften
Authors: Dilcher Gerhard
Published: October 2006

The 19th century offered a special challenge to law and legal profession in Germany: On the one side after the end of the Holy Roman Empire Germany was devided into dozens of sovereign states, on the other side there was a growing economic need for unified civil law. As there was no political possibility for a codification like in France, the German professors of law, led by F. C. von Savigny and his conception of a legal science (Rechtswissenschaft) on the basis of philosophy and history, formed the rules of civil law for a modern society founded on Roman and medieval German law. This effort, far from a mere interpretation of a legal code, joined the legal science to the flourishing German ancient and medieval history of that time, integrating the lawyers as well into the concept of higher education of the developing German middle class (Bildungsbürgertum) as into the political movements toward a national unification on the basis of a liberal constitution. At the same time the concept of a legal system, taken from the natural law theory of the 17th and 18th century, seemed to make law a science comparable to natural and technological sciences and integrated the legal profession the conception of progress (Fortschrittsgedanke). At the end of the century, the great national legal codifications brought the fulfillment of many of these aspirations; but, at the same time, the political and cultural ideals of this movement faded, giving place to a mere legal positivism. Only a small elite of scholars tried to use their historical legal education for developing a sociological and political conception of law (Th. Mommsen, Max Weber).
“Man ist nicht umsonst Philologe gewesen …”. Zur Bildungskritik Friedrich Nietzsches
Authors: Salaquarda Jörg
Published: October 2006

Up to now, Nietzsche's ideas on culture and education have been figured out mainly from his early writings. Accordingly, most authors ascribed to him a negative, at least reluctant attitude towards science and studies. On the contrary, in this paper it is argued that Nietzsche, from time to time, reconsidered and changed his thoughts and that he rather favoured science and studies. To be more specific, four periods may be distinguished. As a boy Nietzsche strived for a religious education. But while a pupil at Schulpforte he changed his mind and strongly pleaded for a secular, historically dominated erudition. Again during the seventies in Basle, he pointed out the dangers of a one‐sided historism, but in his later years he returned to his high esteem of history. — Basically Nietzsche was interested in a hermeneutical theory combining artistic vision and scholarly work.