Pharmacokinetic aspects of tert-butylaminoethyl disulfide, an experimental drug against schistosomiasis in mice

A preliminary study of the pharmacokinetic parameters of t-Butylaminoethyl disulfide was performed after administration of two different single doses (35 and 300 mg/kg) of either the cold or labelled drug. Plasma or blood samples were treated with dithiothreitol, perchloric acid, and, after filtration, submitted to further purification with anionic resin. In the final step, the drug was retained on a cationic resin column, eluted with NaCl 1M and detected according to the method of Ellman (1958). Alternatively, radioactive drug was detected by liquid scintillation counting. The results corresponding to the smaller dose of total drug suggested a pharmacokinetic behavior related to a one open compartment model with the following parameters: area under the intravenous curve (AUCi.v.): 671 +/- 14; AUCoral: 150 +/- 40 micrograms.min.ml-1; elimination rate constant: 0.071 min-1; biological half life: 9.8 min; distribution volume: 0.74 ml/g. For the higher dose, the results seemed to obey a more complex undetermined model. Combining the results, the occurrence of a dose-dependent pharmacokinetic behavior is suggested, the drug being rapidly absorbed and rapidly eliminated; the elimination process being related mainly to metabolization. The drug seems to be more toxic when administered I.V. because by this route it escapes first pass metabolism, while being quickly distributed to tissues. The maximum tolerated blood level seems to be around 16 micrograms/ml.     

Stereoselective disposition of ibuprofen and flurbiprofen in rats

(R)-2-Arylpropionates are often inverted to the pharmacologically active S-enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)- or (S)-ibuprofen (20 mg/kg), (R,S)-ibuprofen (40 mg/kg), (R)- or (S)-flurbiprofen (10 mg/kg), or (R,S)-flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two-compartment open model with conversion of the R- to S-enantiomers in the central compartment. There was 50 +/- 4% inversion of (R)-ibuprofen, a figure similar to that observed in man and (R)-ibuprofen had a higher clearance (12.6 +/- 1.3 ml/min/kg) than (S)-ibuprofen (7.7 +/- 0.7 ml/min/kg; P less than 0.01). The clearance of (R)-flurbiprofen after racemate (2.3 +/- 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 +/- 0.2 ml/min/kg; P less than 0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)-flurbiprofen as determined by area analysis (4.5 +/- 1.6%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pilot study with technosphere/PTH(1-34)--a new approach for effective pulmonary delivery of parathyroid hormone (1-34)

Sequential subcutaneous PTH injection therapy (repeated 14 days of PTH administration and a subsequent treatment pause for a few weeks) is known to increase bone mineral density in patients with osteopenic disorders. Alternative methods of drug delivery may be beneficial in increasing compliance. A pilot study was performed in 10 healthy volunteers (4 female/6-male, age: 25.6 +/- 3.5 years, BMI: 22.3 +/- 2.4 kg/m 2, mean +/- SD) to assess the pharmacokinetic profiles of 1600 IU of PTH(1 - 34) using the pulmonary Technosphere drug delivery system in comparison to a subcutaneous injection of 400 IU. The treatments were administered in the morning after an overnight fast and blood samples for measurement of PTH(1 - 34), PTH(1 - 84), and calcium and calcitonin were taken over a period of 6 hours. Both injection and pulmonary application of PTH(1 - 34) were well tolerated. After pulmonary administration of Technosphere/PTH(1 - 34), PTH(1 - 34) appeared in the serum with a faster concentration increase (T max: pulmonary 10 +/- 5 min vs. subcutaneous 28 +/- 8 min, p < 0.001) and with higher maximal concentrations (C max : pulmonary 309 +/- 215 pmol/l vs. subcutaneous 102 +/- 45 pmol/l, p < 0.05) as compared to the subcutaneous injection. The relative bioavailability of pulmonary Technosphere/PTH(1 - 34) was calculated to be 48 %. No differences were seen between pulmonary and subcutaneous application with regard to the PTH(1 - 84), calcitonin and calcium concentrations. In conclusion, pulmonary application of Technosphere/PTH(1 - 34) appears to be an effective and thus attractive candidate for PTH substitution therapy in osteoporosis and other conditions leading to a decrease in bone mineral density.     

Determination of perospirone by liquid chromatography/electrospray mass spectrometry: application to a pharmacokinetic study in healthy Chinese volunteers

Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT(1A) receptor agonism as well as 5-HT(2A) and D(2) receptor antagonism. A simple rapid and selective LC-MS method utilizing a single quadrupole mass spectrometer was developed and validated for the determination of perospirone hydrochloride in human plasma. N-hexane was used to extract perospirone hydrochloride and amlodipine benzenesulfonate (internal standard (IS)) from an alkaline plasma sample. LC separation was performed on a XTerra MS C(18) column (100mmx2.1mm, i.d. 3.5microm) using methanol -10mM ammonium acetate (84:16, v/v) as a mobile phase. The quantification of target compounds was obtained by using a selected ion monitoring (SIM) at m/z 427.5 [M+H](+) for perospirone hydrochloride, and at m/z 431.4 [M+Na](+) for IS (amlodipine benzenesulfonate). Perospirone and IS eluted as sharp, symmetrical peaks with retention times of 3.11+/-0.01min and 4.15+/-0.2min, respectively. Calibration curves of perospirone hydrochloride in human plasma at concentrations ranging from 0.10 to 21.1ng/mL exhibited excellent linearity (r(2)=0.9997). The mean absolute recovery of the drug from plasma was more than 85%. Intra- and inter-day relative standard deviations were less than 6.43% and 11.9% for perospirone hydrochloride at the range from 0.32 to 10.6ng/mL. Stability characteristics of the drug-containing plasma were thoroughly evaluated to establish appropriate conditions to process, store and prepare for chromatographic analysis without inducing significant chemical degradation. The following pharmacokinetic parameters were elucidated after administering a single dose of 8mg perospirone hydrochloride. The area under the plasma concentration versus time curve from time 0 to 24h (AUC(0-24)) was 15.48+/-4.23microg/Lh; peak plasma concentration (C(max)) was 2.79+/-0.78microg/L; time to C(max) (T(max)) was 1.79+/-0.45h; and elimination half-life (t(1/2)) 6.78+/-1.38h. The described assay method showed acceptable precision, accuracy, linearity, stability, and specificity and can be used for pharmacokinetic studies, therapeutic drug monitoring, and drug abuse screening.     

Intranasal midazolam in piglets: pharmacodynamics (0.2 vs 0.4 mg/kg) and pharmacokinetics (0.4 mg/kg) with bioavailability determination

Intranasal midazolam was studied in two series of piglets: series 1, n = 20 (18 +/- 3 kg), a randomized double blind pharmacodynamic study to compare doses of 0.2 mg/kg and 0.4 mg/kg; series 2, n = 9 (42 +/- 8 kg), a pharmacokinetic study with a 0.4 mg/kg dose administered either intravenously (i.v.) or intranasally (i.n.) in a cross-over protocol with a one-week wash-out period between each. In series 1, midazolam caused significant anxiolysis and sedation within 3 to 4 min, without a significant difference between 0.2 and 0.4 mg/kg doses for any of the studied parameters. In series 2, after intranasal midazolam administration of 0.4 mg/kg, plasma concentrations attained a maximum (Cmax) of 0.13 +/- 0.04 mg/l at 5 min (median Tmax) and remained higher than 0.04 mg/l until 60 min. The bioavailability factor (F) in this study was F = 0.64 +/- 0.17 by the intranasal route. The terminal half-life (T1/2 lambda z) = 145 +/- 138 min was comparable with the i.v. administration half-life (158 +/- 127 min). In conclusion, optimal intranasal midazolam dose in piglets was 0.2 mg/kg, which procures rapid and reliable sedation, adapted to laboratory piglets.     

Characterization of the pharmacokinetics of dioscin in rat

Dioscin (diosgenyl 2,4-di-O-alpha-l-rhamnopyranosyl-beta-d-glucopyranoside) is an important constituent of some traditional Chinese medicines with several bioactivities. We have investigated the pharmacokinetics of dioscin in rat after intravenous and oral administrations. Compartmental methods were used to perform pharmacokinetic data analysis. The dose-dependent pharmacokinetics of dioscin was characterized after intravenous administrations (0.064, 0.16, 0.4 and 1.0mg/kg) to rats. There was significant decrease in clearance with increasing dose (4.67+/-0.09 ml/min/kg (0.064 mg/kg) versus 3.49+/-0.23 ml/min/kg (1.0 mg/kg), P<0.05), and the plot of reciprocal clearance values versus the doses was linear (r=0.909, P<0.05). After an I.V. dose of 1mg/kg, simultaneous oral gavage of activated charcoal did not change the pharmacokinetic parameters indicating enterohepatic recycling of dioscin is not important in rat. The absolute oral bioavailability was very low (0.2%). In tissue distribution and bile excretion studies after I.V. and oral administrations, dioscin was shown to undergo a prolonged absorption from the intestinal tract and slow elimination from organs, and only a small amount of drug was recovered in bile. The cumulative amounts of dioscin in feces and urine indicated that the parent drug is mainly excreted in the feces.     

Impact of combined NO and PG blockade on rapid vasodilation in a forearm mild-to-moderate exercise transition in humans

We tested the hypothesis that nitric oxide (NO) and prostaglandins (PGs) contribute to the rapid vasodilation that accompanies a transition from mild to moderate exercise. Nine healthy volunteers (2 women and 7 men) lay supine with forearm at heart level. Subjects were instrumented for continuous brachial artery infusion of saline (control condition) or combined infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) and ketorolac (drug condition) to inhibit NO synthase and cyclooxygenase, respectively. A step increase from 5 min of steady-state mild (5.4 kg) rhythmic, dynamic forearm handgrip exercise (1 s of contraction followed by 2 s of relaxation) to moderate (10.9 kg) exercise for 30 s was performed. Steady-state forearm blood flow (FBF; Doppler ultrasound) and forearm vascular conductance (FVC) were attenuated in drug compared with saline (control) treatment: FBF = 196.8 +/- 30.8 vs. 281.4 +/- 34.3 ml/min and FVC = 179.3 +/- 29.4 vs. 277.8 +/- 34.8 ml.min(-1).100 mmHg(-1) (both P < 0.01). FBF and FVC increased from steady state after release of the initial contraction at the higher workload in saline and drug conditions: DeltaFBF = 72.4 +/- 8.7 and 52.9 +/- 7.8 ml/min, respectively, and DeltaFVC = 66.3 +/- 7.3 and 44.1 +/- 7.0 ml.min(-1).100 mmHg(-1), respectively (all P < 0.05). The percent DeltaFBF and DeltaFVC were not different during saline infusion or combined inhibition of NO and PGs: DeltaFBF = 27.2 +/- 3.1 and 28.1 +/- 3.8%, respectively (P = 0.78) and DeltaFVC = 25.7 +/- 3.2 and 26.0 +/- 4.0%, respectively (P = 0.94). The data suggest that NO and vasodilatory PGs are not obligatory for rapid vasodilation at the onset of a step increase from mild- to moderate-intensity forearm exercise. Additional vasodilatory mechanisms not dependent on NO and PG release contribute to the immediate and early increase in blood flow in an exercise-to-exercise transition.     

Effects of chronic beta-adrenergic blockade on exercise training in dogs

To assess the role of beta-adrenergic stimulation in cardiovascular conditioning we examined the effects of a beta-adrenergic blocker, propranolol, in mongrel dogs during an 8-wk treadmill-training program. Seven dogs were trained without a drug (NP), six were trained on propranolol 10 mg.kg-1.day-1 (P), and five served as caged controls (C). Effective beta-adrenergic blockade was documented by a decrease in peak exercise heart rate of 54 +/- 11 (SE) beats/min (P less than 0.05) and a one-log magnitude of increase in the isoproterenol-heart rate dose-response curve. Testing was performed before drug treatment or training and again after training without the drug for 5 days. Submaximal exercise heart rate decreased similarly in both NP and P (-26 +/- 4 NP vs. -25 +/- 9 beats/min P, P less than 0.05 for both) but peak heart rate decreased only with NP (-33 +/- 9 beats/min, P less than 0.05). Treadmill exercise time increased similarly in both groups: 3.4 +/- 0.6 min in NP and 3.0 +/- 0.2 min in P (both P less than 0.05). Blood volume also increased after training in both groups: 605 +/- 250 ml (26%) in NP and 377 +/- 140 ml (17%) in P (both P less than 0.05). Submaximal exercise arterial lactates were reduced similarly in both groups but peak exercise lactate was reduced more in NP (-1.4 +/- 0.3 NP vs -0.3 +/- 0.12 mmol/l P, P less than 0.05). Lactate threshold increased in both groups but the increase was greater in NP (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers.

The purpose of the present study was to examine the duration of caffeine's ergogenic effect and whether it differs between users and nonusers of the drug. Twenty-one subjects (13 caffeine users and 8 nonusers) completed six randomized exercise rides to exhaustion at 80% of maximal oxygen consumption after ingesting either a placebo or 5 mg/kg of caffeine. Exercise to exhaustion was completed once per week at either 1, 3, or 6 h after placebo or drug ingestion. Exercise time to exhaustion differed between users and nonusers with the ergogenic effect being greater and lasting longer in nonusers. For the nonusers, exercise times 1, 3, and 6 h after caffeine ingestion were 32.7 +/- 8.4, 32.1 +/- 8.6, and 31.7 +/- 12.0 min, respectively, and these values were each significantly greater than the corresponding placebo values of 24.2 +/- 6.4, 25.8 +/- 9.0, and 23.2 +/- 7.1 min. For caffeine users, exercise times 1, 3, and 6 h after caffeine ingestion were 27.4 +/- 7.2, 28.1 +/- 7.8, and 24.5 +/- 7.6 min, respectively. Only exercise times 1 and 3 h after drug ingestion were significantly greater than the respective placebo trials of 23.3 +/- 6.5, 23.2 +/- 7.1, and 23.5 +/- 5.7 min. In conclusion, both the duration and magnitude of the ergogenic effect that followed a 5 mg/kg dose of caffeine were greater in the nonusers compared with the users.     

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor

To investigate whether altered function of adenosine receptors could contribute to sinus node or atrioventricular (AV) nodal dysfunction in conscious mammals, we studied transgenic (TG) mice with cardiac-specific overexpression of the A1 adenosine receptor (A1AR). A Holter ECG was recorded in seven freely moving littermate pairs of mice during normal activity, exercise (5 min of swimming), and 1 h after exercise. TG mice had lower maximal heart rates (HR) than wild-type (WT) mice (normal activity: 437 +/- 18 vs. 522 +/- 24 beats/min, P < 0.05; exercise: 650 +/- 13 vs. 765 +/- 28 beats/min, P < 0.05; 1 h after exercise: 588 +/- 18 vs. 720 +/- 12 beats/min, P < 0.05; all values are means +/- SE). Mean HR was lower during exercise (589 +/- 16 vs. 698 +/- 34 beats/min, P < 0.05) and after exercise (495 +/- 16 vs. 592 +/- 27 beats/min, P < 0.05). Minimal HR was not different between genotypes. HR variability (SD of RR intervals) was reduced by 30% (P < 0.05) in TG compared with WT mice. Pertussis toxin (n = 4 pairs, 150 microg/kg ip) reversed bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ interval: 42 +/- 2 vs. 37 +/- 2 ms, P < 0.05), which was diminished but not abolished by pertussis toxin. Isolated Langendorff-perfused TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9 WT mice, P < 0.05). In conclusion, A1AR regulate sinus nodal and AV nodal function in the mammalian heart in vivo. Enhanced expression of A1AR causes sinus nodal and AV nodal dysfunction and supraventricular arrhythmias.     

Reversal of indomethacin-induced decreases in renal function by an isosterically-modified prostaglandin analog

A recently discovered isosterically-modified prostaglandin analog, 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl ] propyl) benzoic acid, was studied in conscious Na-deficient dogs to determine if this compound could reverse the deleterious renal effects induced by inhibition of renal cyclooxygenase. Indomethacin (2 mg/kg i.v.) reduced renal function significantly in all dogs studied: GFR decreased from 38 +/- 3 to 26 +/- 1 ml/min (P less than 0.01) and ERPF from 124 +/- 15 to 79 +/- 8 ml/min (P less than 0.01). On separate occasions, the six dogs used in this study were treated with a saline placebo intravenously or with the PG analog (0.1 mg/kg i.v.) 60 min after receiving indomethacin. After placebo treatments renal function remained suppressed for the duration of observation (2 hours). After treatment with PG analog, GFR was restored to pre-indomethacin levels within 1 hour (36 +/- 3 ml/min) and remained at this level or higher for the duration of the experiment. ERPF was restored to pre-indomethacin levels within 30 min of PG analog injection (140 +/- 7 ml/min) and subsequently rose ml/min) for the duration of the experiment. Urinary electrolyte excretion was suppressed by indomethacin and despite the large increase in ERPF, Na excretion was not augmented by PG analog. This study demonstrates that a synthetic, isosterically-modified prostaglandin analog can effectively reverse the hemodynamic effects of non-steroidal antiinflammatory drug treatment on renal function while not affecting renal Na excretion.     

Short-term effect of rate control on plasma endothelin levels of patients with tachyarrhythmias

Radiofrequency catheter ablation or modification of the atrio-ventricular junction is an effective therapy of drug refractory supraventricular tachyarrhythmias (ST). Higher endothelin (ET) levels were observed during nonsustained STs. We aimed to examine the effect of sustained STs and the applied rate-control therapy on plasma ET levels. Twenty-two patients (12 men; mean age, 64.4 +/- 13.2 years; ejection fraction, 41.8 +/- 11.2%; New York Heart Association (NYHA) class I: 3 cases, NYHA II: 11 cases, and NYHA III: 8 cases) suffering of atrial fibrillation (n = 11), atrial flutter (n = 7), atrial paroxysmal tachycardia (n = 3), or sinus tachycardia (n = 1) were studied, having coronary artery disease (n = 8), dilative cardiomyopathy (n = 5), or no underlying diseases (n = 9). All groups went under catheter ablation (same protocol, duration: 35 +/- 10.3 mins; rate before ablation, 100-170/min in every case; after ablation, 70-80/min in Groups I and II and 70-90/min in Group III). A pacemaker (PM) was implanted 2 months before ablation in Group I (n = 9) and during ablation in Group II (n = 7). No PM was implanted in Group III (n = 6). A control group (n = 13; 7 men; mean age, 66.15 +/- 6.7 years) with sinus rhythm got a PM without ST and ablation. Blood samples were collected from the cubital vein immediately before (control), and 5 mins and 24 hrs after ablation. Plasma ET-1 and big ET-1 levels were measured after immunoprecipitation with Western blot analysis. There were no differences between plasma ET-1 levels in the ST groups and the control group (Groups I, II, and III vs. control group: 0.66 +/- 0.04 fmol/ml, 0.93 +/- 0.12 fmol/ml, and 0.68 +/- 0.05 fmol/ml vs. 0.50 +/- 0.05 fmol/ml, respectively; P < 0.05). Comparing the control, 5-min, and 24-hr samples, ET-1 levels decreased significantly after supraventricular tachycardia ablation in Groups I and III (control vs. Group I, 5 mins and 24 hrs: 0.66 +/- 0.04 fmol/ml vs. 0.50 +/- 0.04 fmol/ml and 0.29 +/- 0.05 fmol/ml; control vs. Group III, 24 hrs: 0.68 +/- 0.05 vs. 0.34 +/- 0.05 fmol/ml; P < 0.05). No plasma big ET-1 changes were measured in any of the groups. The rapid decrease of ET levels after catheter ablation suggests that a high ventricular rate can be a trigger of ET production. PM implantation procedure seems to interfere with the ET decrease in ST patients.     

Route-dependent stereoselective pharmacokinetics of tramadol and its active O-demethylated metabolite in rats

The effects of route of administration on the stereoselective pharmacokinetics of tramadol (T) and its active metabolite (M1) were studied in rats. A single 20 mg/kg dose of racemic T was administered through intravenous, intraperitoneal, or oral route to different groups of rats, and blood and urine samples were collected. Samples were analyzed using chiral chromatography, and pharmacokinetic parameters (mean +/- SD) were estimated by noncompartmental methods. Following intravenous injection, there was no stereoselectivity in the pharmacokinetics of T. Both enantiomers showed clearance values (62.5 +/- 27.2 and 64.4 +/- 39.0 ml/min/kg for (+)- and (-)-T, respectively) that were equal or higher than the reported liver blood flow in rats. Similar to T, the area under the plasma concentration-time curves (AUCs) of M1 did not exhibit stereoselectivity after intravenous administration of the parent drug. However, the systemic availability of (+)-T was significantly (P < 0.05) higher than that of its antipode following intraperitoneal (0.527 +/- 0.240 vs. 0.373 +/- 0.189) and oral (0.307 +/- 0.136 vs. 0.159 +/- 0.115) administrations. The AUC of the M1 enantiomers, on the other hand, remained mostly nonstereoselective regardless of the route of administration. Pharmacokinetic analysis indicated that the stereoselectivity in the pharmacokinetics of oral T is due to stereoselective first pass metabolism in the liver and, possibly, in the gastrointestinal tract. The direction and extent of stereoselectivity in the pharmacokinetics of T and M1 in rats were in agreement with those previously reported in humans, suggesting that the rat may be a suitable model for enantioselective studies of T pharmacokinetics.     

ACE activity during the hypotension produced by standardized aqueous extract of Cecropia glaziovii Sneth: A comparative study to captopril effects in rats

To evaluate the effect of the standardized aqueous extract (AE) of Cecropia glaziovii Sneth on the plasma angiotensin I converting enzyme (ACE-EC 3.4.15.1) activity, rats were treated with a single dose of AE (1 g/kg, p.o.) or repeatedly (0.5 g/kg/bid, p.o.) for 60 days. Captopril (50 mg/kg, p.o.) was used as positive control on the same animals. The effects on the blood pressure were recorded directly from the femoral artery (single dose), or indirectly by the tail cuff method (repeated doses) in conscious rats. The plasma ACE activity was determined spectrofluorimetrically using Hypuril-Hystidine-Leucine as substrate. The arterial blood pressure, heart rate and plasma ACE activity were not significantly modified within 24 h after a single dose administration of AE. Comparatively, blood pressure in captopril treated rats was reduced by 7-16% and heart rate was increased by 10-20% from 30 min to 24 h after drug administration. ACE activity after captopril presented a dual response: an immediate inhibition peaking at 30 min and a slow reversal to 32% up-regulation after 24 h. To correlate the drug effects upon repeated administration of either compound, normotensive rats were separated in three groups: animals with high ACE (48.8+/-2.6 nmol/min/ml), intermediate ACE (39.4+/-1.4 nmol/min/ml) and low ACE (23.5+/-0.6 nmol/min/ml) activity, significantly different among them. Repeated treatment with AE reduced the mean systolic blood pressure (121.7+/-0.5 mm Hg) by 20 mm Hg after 14 days. The hypotension was reversed upon washout 60 days afterwards. Likely, repeated captopril administration decreased blood pressure by 20 mm Hg throughout treatment in all groups. After 30 days treatment with AE (0.5 g/kg/bid, p.o.) the plasma ACE activity was unchanged in any experimental group. After captopril (50 mg/kg/bid, p.o.) administration the plasma ACE activity was inhibited by 50% within 1 h treatment but it was up-regulated by 120% after 12 h in all groups. It is concluded that the hypotension produced by prolonged treatment with AE of C. glaziovii is unrelated to ACE inhibition.     

Pharmacokinetic profile of 3beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1), a potent androgen synthesis inhibitor, in mice

The objective of this study was to assess the pharmacokinetics and bioavailability of 3beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1) in normal male mice and in SCID mice bearing human LNCaP tumor xenografts. VN/87-1 is a novel potent steroidal inhibitor of human testicular 17-alpha-hydroxylase/C(17,20)-lyase. The steroid also shows anti-androgenic activity and inhibits the growth of human prostate cancer cell lines (LNCaP) in vitro and in vivo. Male Balb/c mice were given a single oral, subcutaneous (s.c.) or intravenous (i.v.) bolus dose of VN/87-1 (25, 50 or 100 mg/kg). Male SCID mice bearing LNCaP tumor xenografts were injected with a single s.c. dose of VN/87-1 (50 mg/kg). The animals were sacrificed at various times up to 24 h after drug administration and blood was collected. The plasma samples were prepared and analyzed by a reversed phase HPLC system equipped with a diode array detector. A non-compartmental pharmacokinetic approach was used to evaluate the plasma level versus time data. Following i.v. administration of VN/87-1, the plasma levels declined exponentially with an elimination half-life of 1.2+/-0.03 h. The absolute bioavailability of the 50 mg/kg dose after oral or s.c. administration was 12.08+/-2 or 57.2+/-4.5%, respectively. VN/87-1 is a high clearance (5.0+/-1.3 l/h per kg) compound in mice and its volume of distribution was relatively large (6.5+/-1.2 l/kg). The pharmacokinetic parameters of VN/87-1 were not significantly altered in SCID mice bearing human LNCaP tumor xenografts. VN/87-1 is well absorbed from the subcutaneous site compared with absorption from the gastrointestinal tract and shows linear kinetics at doses up to 100 mg/kg.     

Metabolism and acid secretory effect of sulfated and nonsulfated gastrin-6 in humans

The antral hormone gastrin is synthesized by processing progastrin into different peptides that stimulate gastric secretion. The effect on acid secretion depends mainly on the metabolic clearance rate of the peptides, but some of them may differ in potency and maximum acid output at similar concentrations in plasma. Sulfated and nonsulfated gastrin-6 are the smallest circulating bioactive gastrins in humans. Their effect and metabolism have now been investigated in nine normal subjects and compared with nonsulfated gastrin-17, a main product of progastrin. Maximum acid output after stimulation with gastrin-17, sulfated gastrin-6, and nonsulfated gastrin-6 were 28.3 +/- 2.0, 24.5 +/- 2.0 (P < 0.02), and 19.3 +/- 2. 3 (P < 0.05) mmol H(+)/50 min, respectively, and the corresponding EC(50) values were 43 +/- 6, 24 +/- 2 (P < 0.01), and 25 +/- 2 (not significant) pmol/l. The half-life of gastrin-17 was 5.3 +/- 0.3 min, the metabolic clearance rate (MCR) was 16.5 +/- 1.3 ml. kg(-1). min(-1), and the apparent volume of distribution (V(d)) was 124.3 +/- 9.6 ml/kg. The half-lives of sulfated and nonsulfated gastrin-6 were 2.1 +/- 0.3 and 1.9 +/- 0.3 min, the MCRs were 42.8 +/- 3.7 and 139.4 +/- 9.6 ml kg(-1) min(-1) (P < 0.01), and the V(d) were 139.0 +/- 30.5 and 392.0 +/- 81.6 (P < 0.01) ml kg(-1). All pharmacokinetic parameters differed significantly from gastrin-17 (P < 0.01). We conclude that gastrin 6 has a higher potency but a lower efficacy than gastrin-17. The efficacy of gastrin-6 is increased by tyrosine O-sulfation, which also enhances the protection against elimination.     

Effect of nimesulide co-administration on pharmacokinetics of lithium

In a crossover study, lithium was given orally at a dose of 56 mg/kg, prepared as suspension (0.5%) in carboxymethyl cellulose (CMC) and blood samples (1 ml) collected after 0-24 hr after drug administration. After a washout period of two weeks, nimesulide (10 mg/kg) was administered alongwith lithium (56 mg/kg) and blood samples were drawn at the same time intervals (0-24 hr) after drug administration. Plasma was separated and assayed for lithium by M 654 Na+/K+/Li+ analyzer and various pharmacokinetic parameters were calculated. C(max), K(el), t(1/2el) and AUC(0-alpha) of lithium were significantly increased when nimesulide was administered along with lithium as compared to control group.     

In vivo modulation of platelet deposition on human atherosclerotic lesions by various antiaggregatory prostaglandins

The influence of intravenous infusions of various prostaglandins on in vivo platelet function was studied after labelling of autologous platelets with 100 mu ci 111 indium-oxinesulfate in patients with peripheral vascular disease stage II according to FONTAINE. PGI2 (5 ng/kg/min) provoked a significant decrease of platelet deposition and a prolongation in platelet half-life time (74 +/- 6 vs 68 +/- 5 hours). PGE1 (25 ng/kg/min) failed to influence platelet deposition, but prolonged significantly platelet half-life time (82 +/- 6 vs 76 +/- 8 hours). CG 4203 (25 ng/kg/min) decreased significantly platelet deposition and prolonged significantly platelet half-life time (73 +/- 10 vs 67 +/- 11 hours). Iloprost (1 and 2 ng/kg/min) reduced significantly platelet deposition without dose relation. Half-life time was increased significantly after therapy compared to placebo (1 ng: 76 +/- 7 vs 69 +/- 7; 2 ng: 73 +/- 9 vs 67 +/- 9 hours).     

Pharmacokinetics and effects of intravenous infusion of somatostatin in normal subjects--a two-compartment open model

A direct radioimmunoassay of plasma somatostatin-like immunoreactivity (SRIF-LI) was developed and validated. The sensitivity was 16.0 pg/ml, and the specificity was good. The recovery of plasma SRIF-LI was 98.8 +/- 6.3%. The Scatchard plot of the antiserum binding data revealed a straight line, with a binding affinity of 3.52 X 10(-12) M and a binding capacity 4.06 X 10(-10) M. Synthetic SRIF (Stilamin), 250 micrograms, was infused intravenously over a 30-min period in 9 healthy volunteers. Plasma glucose, insulin (IRI), glucagon (IRG) and SRIF-LI were measured. A two-compartment open model was adopted to analyze the pharmacokinetic data of SRIF-LI. The results showed that plasma SRIF-LI rose from 192.2 +/- 16.2 pg/ml to a plateau of 2,129.8 +/- 288.2 pg/ml within 5-10 min after starting the infusion. The half disappearance time from plasma (Ta1/2) was 1.36 +/- 0.18 min, the half disappearance time from the 'remote' compartment (Tb1/2) was 49.6 +/- 10.9 min and the net half disappearance time from the two compartments together (Tn1/2) was 9.19 +/- 1.49 min. The metabolic clearance rate was 50.3 +/- 7.0 ml/kg/min. The plasma IRI, IRG and the IRI/IRG molar ratio were all suppressed during the infusion period. The recovery time of plasma IRG was mildly delayed in comparison to that of IRI. This indicates that there are dissociations between IRI and IRG in the extent and the duration of suppression caused by somatostatin infusion.     

Pharmacokinetics of methimazole in normal subjects and hyperthyroid patients

Serum and urinary concentrations of methimazole (MMI) were measured by high-performance liquid chromatography (HPLC) with an electrochemical detector (ECD) in 10 normal subjects and 43 hyperthyroid patients after intravenous and oral administration of the drug. The pharmacokinetic parameters of MMI were estimated in 5 normal subjects and 15 hyperthyroid patients according to a two-compartment model after intravenous injection of a 10 mg dose. The mean half-life of the distribution phase (T1/2 alpha) was 2.7 +/- 1.0 h (mean +/- SD) and 3.1 +/- 1.4 h and that of the slower-phase (T1/2 beta) was 20.7 +/- 9.6 h and 18.5 +/- 12.9 h in normal subjects and hyperthyroid patients, respectively. There were no significant differences between pharmacokinetic parameters of normal subjects and those of hyperthyroid patients. No correlations between free T4 index (FT4I) and pharmacokinetic parameters were observed. Maximum serum MMI concentrations (Cmax) (213 +/- 84 and 299 +/- 92 ng/ml) were attained 1.8 +/- 1.4 h and 2.3 +/- 0.8 h after a single dose of 10 mg in 5 normal subjects and in 15 hyperthyroid patients, respectively. In hyperthyroid patients the time taken to reach the peak concentration (Tmax) after a single dose of 10 mg was similar to that after a single 15 mg and 30 mg dose. The pharmacokinetic parameters, except Cmax and the area under the curve (AUC), were not affected by the administered dose and those, except Cmax, were not affected by the thyroid function. All urine was collected at intervals of 3 h for the first 12 h and then at 24 h and 48 h after intravenous and oral administration of MMI. In all subjects, MMI rapidly appeared in the urine and the rate of excretion was highest in the first 3 h. The cumulative urinary excretion of MMI was 5.5-8.5% of administered doses in normal subjects and hyperthyroid patients. These findings in the present study are compatible with the assumption that the extent of absorption of MMI is high, if not complete, and hyperthyroidism does not affect the kinetics of MMI, and that interindividual variation is observed in the time taken to reach the peak concentration after oral administration.