Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty-four healthy male subjects (28.5 +/- 5.2 years; 77 +/- 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four-way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high-pressure liquid chromatography method. The values (mean [CV, %]) for systemic clearance, volume of distribution at steady-state, and half-life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N-desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first-pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration-time data of CLZ can be described by either a one- or two-compartment pharmacokinetic model.     

Release of prolactin as well as adrenocorticotropin after administration of arginine-vasopressin to healthy men

The study was undertaken to obtain simultaneous measurements of circulating anterior pituitary hormone levels after the i.v. injection of arginine-vasopressin (AVP). Nine healthy men, mean age 31 years (range 24-41), received single blind with at least one week apart, after resting in the supine position for 30 min, AVP 0.26 microgram/kg body weight i.v. (Pitressin, Parke-Davis) or saline in randomized order. Blood samples were taken at 0, 10, 20, 30, 45 and 60 min for analyses of serum or plasma levels of ACTH, prolactin, TSH, GH, FSH, LH and AVP. The hormone responses after AVP or saline were calculated as the area under the curve (AUC) 0-60 min as well as the change in hormone levels from 0 to 10 min to pick up possible short lasting effects when there was no significant difference in AUC between AVP and control. As expected the highest plasma concentration of AVP was measured 10 min after the injection of AVP and well comparable to those in other studies where AVP was observed to release ACTH. The AUC:s for both ACTH and prolactin levels were significantly increased after AVP in comparison with saline (p = 0.008 and p = 0.038, respectively). The AUC:s for the other hormones measured were not significantly changed after AVP, but there were small but significant changes in the 0-10 min values for TSH and LH after AVP compared to saline. It is concluded that AVP has the potency to release not only ACTH but also prolactin in healthy men.     

Disposition of phenol in rat after oral, dermal, intravenous, and intratracheal administration

The absorption and elimination of [14C]-phenol (63.5 nmol) after oral, dermal, intratracheal, or intravenous administration in rat was rapid and extensive. Urinary elimination of radioactivity predominated, with a range of 75-95% of the dose detected in urine by 72 h post-exposure. Washing the dermal site 72 h post-exposure removed 14% of the dose. Two per cent of the dose was detected in the skin. The urinary metabolites at 4 and 8 h after administration by the four routes included phenyl sulphate and lower amounts of phenyl glucuronide. Phenol was poorly retained in the body after administration by the four routes. Phenol remaining in the body was widely distributed, with accumulation primarily in the liver, lung, and kidney.     

Disposition of methyl ethyl ketoxime in the rat after oral, intravenous and dermal administration

1. The disposition of 14C-methyl ethyl ketoxime (MEKO) was determined in the male F344 rat following oral, intravenous (i.v.) and dermal administration. 2. Oral doses of 2.7, 27 and 270 mg/kg were primarily excreted as CO2 (71-49%) in decreasing percentage as the dose increased. Excretion in urine (13-26%) and as volatiles (5-18%) increased as the dose increased. Five to 6% of the dose remained in the major tissues after 72 h. 3. An i.v. dose of 2.7 mg/kg was also principally excreted as CO2 (48.8%) with excretion in urine and as expired volatiles accounting for 21.4 and 11.4%, respectively. About 7% of the administered radioactivity remained in the tissues after 72 h. 4. Following dermal administration, 13 and 26% of a 2.7 and 270 mg/kg dose, respectively, were absorbed. Volatilization from the dose site prior to placement in the metabolism cage may account for the low absorption. 5. MEKO was biotransformed to at least five polar metabolites that could only be partially resolved by anion exchange chromatography. Incubation with glucuronidase, but not sulphatase, changed the urinary metabolic profile. Methyl ethyl ketone was a major component in the volatiles.     

Zatebradine: pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects

Although high-frequency low-intensity transcutaneous electric nerve stimulation (TENS) has been extensively used to relieve low back pain, experimental studies of its effectiveness have yielded contradictory findings mainly due to methodological problems in pain evaluation and placebo control. In the present study, separate visual analog scales (VAS) were used to measure the sensory-discriminative and motivational-affective components of low back pain. Forty-two subjects were randomly assigned to 1 of 3 groups: TENS, placebo-TENS, and no treatment (control). In order to measure the short-term effect of TENS, VAS pain ratings were taken before and after each treatment session. Also, to measure long-term effects, patients rated their pain at home every 2 h throughout a 3-day period before and 1 week, 3 months and 6 months after the treatment sessions. In comparing the pain evaluations made immediately before and after each treatment session, TENS and placebo-TENS significantly reduced both the intensity and unpleasantness of chronic low back pain. TENS was significantly more efficient than placebo-TENS in reducing pain intensity but not pain unpleasantness. TENS also produced a significant additive effect over repetitive treatment sessions for pain intensity and relative pain unpleasantness. This additive effect was not found for placebo-TENS. When evaluated at home, pain intensity was significantly reduced more by TENS than placebo-TENS 1 week after the end of treatment, but not 3 months and 6 months later. At home evaluation of pain unpleasantness in the TENS group was never different from the placebo-TENS group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of mivacurium isomers and their metabolites in healthy volunteers after intravenous bolus administration

BACKGROUND: Previous studies report the pharmacokinetics of mivacurium isomers after an infusion using venous blood sampling. Although the extent of the mivacurium arterial-venous gradient is not known, the sampling site is likely to influence mivacurium pharmacokinetic parameters because the drug is rapidly metabolized as it traverses the circulation. The objectives of this study were (1) to determine the pharmacokinetics of mivacurium isomers in healthy persons after intravenous bolus administration using intensive arterial blood sampling, and (2) to characterize the formation and elimination of mivacurium metabolites in human plasma. METHODS: Eight persons classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled to undergo elective surgery under balanced anesthesia received 0.15 mg/kg mivacurium chloride as an intravenous bolus. Arterial blood samples were collected every 10 s during the first 2 min and at frequent intervals for 4 h thereafter. Plasma concentrations of mivacurium isomers and their metabolites were determined by two stereoselective high-performance liquid chromatographic methods coupled with fluorometric detection and noncompartmental pharmacokinetic parameters. RESULTS: Mean elimination half-lives of the trans-trans, cis-trans, and cis-cis isomers were 2.4, 2, and 28.5 min, respectively, with corresponding mean plasma clearances of 29.2, 45.7, and 6.7 ml.min 1.kg-1. The volumes of distribution at steady state of the trans-trans, cis-trans, and cis-cis isomers were 0.047, 0.054, and 0.189 l/kg, respectively. Plasma concentrations of monoester and alcohol metabolites peaked 25 s (median) after mivacurium injection, with half-lives in the range of 90 min, except for the cis alcohol metabolite, which was only negligibly and transiently formed. CONCLUSIONS: Substantial hydrolysis of mivacurium isomers by cholinesterases was confirmed by the rapid appearance of mivacurium metabolites in plasma. The intensive arterial sampling proved to be critical for the trans-trans and cis-trans isomers because the area under the curve between 0 and 2 min accounted for 75% and 86% of the total, respectively.     

Pharmacokinetics of phenprobamate after oral administration to healthy subjects

Phenprobamate (CAS 673-31-4) is a centrally acting skeletal-muscle relaxant agent. There are only two studies in the literature about the pharmacokinetics of phenoprobamate in man. The inconsistency between the results of these studies can be attributed partly to the different analytical methodologies used. A sensitive, specific and reproducible HPLC-assay, which may increase the reliability of the pharmacokinetic studies of phenprobamate in plasma, has been developed recently. The objective of this investigation was to assess the single-dose kinetics of phenprobamate in human and to determine the pharmacokinetic parameters of clinical and regulatory concern. The plasma pharmacokinetics of phenprobamate have been investigated following single oral administration at a dose of 800 mg in eleven healthy volunteers.     

Pharmacokinetics and metabolic disposition of 14C-metronidazole-derived radioactivity in rat after intravenous and intravaginal administration

Urinary metabolites and the pharmacokinetics of radioactivity derived from 14C-metronidazole (14C-MTZ) were determined after intravenous (iv) or intravaginal (ivg) administration of 10 mg/kg to adult rats. Following iv or ivg administration, the disappearance of 14C from blood followed the kinetics of a two-compartment open-system model. The blood half-lives of 14C during the beta-phase were 10.9 +/- 1.6 and 13.6 +/- 4.2 hr, after iv and ivg administration, respectively. After ivg application, the MTZ-derived radioactivity was detected in tail blood at 5 min, peaked at 1 hr, declined rapidly to 6 hr and more slowly thereafter. The vaginal absorption half-life of 14C-MTZ was 0.28 +/- 0.09 hr. About 12% of the administered dose remained in the vagina after 1 hr and 1.5% after 24 hr. At 24 hr, the tissue distribution and concentration of 14C were similar in iv and ivg dosed rats, the highest 14C concentration being present in the kidneys and lowest in the fat. The percentages of the dose excreted in 24 hr in the urine and feces were 58 and 15 after iv administration, compared to 37 and 40 after the ivg route, respectively. Unchanged 14C-MTZ and five of its metabolites were detected in the urine irrespective of the route of administration. The results show that metronidazole is rapidly absorbed through the vaginal mucosa of the rat and the metabolism and excretion of this chemotherapeutic agent are influenced by the route of administration.     

A pharmacokinetic-pharmacodynamic model of d-sotalol Q-Tc prolongation during intravenous administration to healthy subjects

The objective of this study was to assess the pharmacokinetics and pharmacodynamics of the dextro (d-) isomer of sotalol, a class III antiarrhythmic agent, in healthy young men and women after a single intravenous bolus dose. The design was open-label, randomized, parallel group. Each group (4 men and 4 women) received either 0.5, 1.5, or 3.0 mg/kg d-sotalol as an intravenous infusion for 2 minutes. Serial measurements of the d-sotalol plasma concentration and the Q-Tc interval data were recorded before, during, and for 72 hours after drug administration. The pharmacokinetics of d-sotalol were found to be well described by a three-compartment model with linear elimination clearance from the central compartment. There were no significant differences in the elimination clearance or volume of the central compartment between dose levels or between men and women. However, women were found to have a lower steady-state volume of distribution than men (1.20 L/Kg versus 1.43 L/Kg). The Q-Tc versus d-sotalol plasma concentration data were fitted to a model that assumed a distinct "effect compartment" and sigmoidal Emax response. The baseline Q-Tc, determined from the fittings, was found to be significantly higher in women (0.40 versus 0.38 seconds). The effect compartment clearance was found to be highly variable, with a median of 12.3 (range, 0.2-671,300) L/h. There were statistically significant differences in the effect compartment clearance by dose among men and by gender at a dose of 1.5 mg/kg. There were no significant differences detected between dose groups or genders for the d-sotalol effect site concentration at one half the maximum Q-Tc prolongation from baseline (EC50), EMAX, (the maximum Q-Tc prolongation from baseline) or the Hill coefficient. In conclusion, the pharmacokinetics of d-sotalol after intravenous administration are independent of dose and gender, because the difference between men and women in volume of distribution at steady-state is not clinically significant. The pharmacodynamics of Q-Tc prolongation produced by d-sotalol appear to be independent of dose and gender; however, there is considerable variability in the time course of effects on Q-Tc between individuals.     

Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency

PURPOSE: The aim of the present study was to validate a simple MRI-procedure for semiquantitative assessment of regional cerebral blood flow. MATERIALS AND METHODS: Unilateral cerebral ischaemia (30 minutes) in the territory of the middle cerebral artery was induced in 14 anesthetised rates. The MRI-experiment consisted in an intravenous bolus injection of gadolinium-DTPA, recording of the cerebral contrast kinetics with a T2*-weighted pulse sequence, and measurement of the maximal concentration change at a chosen reference point of time. To measure perfusion quantitatively, a microsphere technique, an accepted reference technique was used. With both methods a perfusion index related to the contralateral side was calculated. RESULTS: In all cases decreased perfusion was detected by the MRI technique. The perfusion indices correlated with a coefficient of correlation of r = 0.89 (p < 0.001). CONCLUSION: The results demonstrate that contrast-enhanced MRI with bolus injection can be implemented with clinical potential as a semiquantitative instrument for the assessment of cerebral perfusion. Regional cerebral blood volume and collateral blood flow may interfere with the estimate of blood flow.     

Pharmacokinetics of dolasetron after oral and intravenous administration of dolasetron mesylate in healthy volunteers and patients with hepatic dysfunction

In previous studies, dolasetron was shown to have both renal and hepatic elimination mechanisms. This study was conducted to determine the impact of varying degrees of hepatic dysfunction on the pharmacokinetics and safety of dolasetron and its reduced metabolites. Seventeen adults were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child-Pugh class A; group II), and four patients with moderate to severe hepatic impairment (Child-Pugh class B or C1; group III). Single 150-mg doses of dolasetron mesylate were administered intravenously and orally, with a 7-day washout period separating treatments. After intravenous administration, no differences were observed between healthy volunteers and patients with hepatic impairment in maximum plasma concentration (Cmax), areas under the plasma concentration-time curve (AUC), or elimination half-life (t1/2) of intact dolasetron. No significant differences were found in Cmax, AUC, or apparent clearance (C(lapp)) of hydrodolasetron, the primary metabolite of dolasetron. The mean t1/2 increased from 6.87 hours in group I to 11.69 hours in group III. After oral administration, C(lapp) of hydrodolasetron decreased by 42%, and Cmax increased by 18% in patients with moderate to severe hepatic impairment. There were less changes in patients with mildly hepatic impairment. Total percentage of dose excreted as metabolites was similar for healthy volunteers and patients with hepatic impairment, although urinary metabolite profiles differed slightly. Dolasetron was well tolerated and there were no apparent differences in adverse effects between groups or treatments. Because hepatic impairment did not influence Cl(app) of hydrodolasetron after intravenous administration, and the range of plasma concentrations of hydrodolasetron after oral administration was not different from those observed in healthy volunteers, dosage adjustments are not recommended for patients with hepatic disease and normal renal function.     

The behaviour of healthy awake cats following intravenous and intramuscular administration of midazolam

The onset of action and behavioural effects following intravenous (i.v.) and intramuscular (i.m.) administration of 0.05, 0.5, 1.0, 2.0 and 5.0 mg/kg of midazolam were studied for 2 h in 20 awake, healthy cats. All cats, except one that received 0.05 mg/kg i.m., showed effects of the drug, whereas no effects were observed in cats administered only the vehicle in which midazolam was dissolved. The onset of action was rapid following both i.v. and i.m. administration, some cats became ataxic, while others assumed positions of sternal or lateral recumbency. Even after administration of the highest dose (5.0 mg/kg), anaesthesia was not induced, with swallowing reflexes and conscious perception of a clamp placed on the tail still present in all cats. An abnormal arousal state was observed in many cats after administration of midazolam. During the first hour, restlessness was more commonly observed, while from 1 to 2 h, sedation was more prominent in cats that received the highest dose. Ataxia occurred in all but one cat, was short-lived in cats that received the lower doses, but still present at 2 h in all cats that received 2.0 and 5.0 mg/kg. Midazolam caused some of the cats to behave differently when approached and restrained compared with behavioural patterns identified prior to administration of the drug. The cats were more likely to behave abnormally following i.v. administration rather than i.m. administration and, for the most part, abnormal behaviour was equally distributed between the two extremes; cats being easier to approach and restrain and cats being more difficult to approach and restrain. Food consumption increased significantly, during the 2 h period, following all i.m. doses and all but the highest (5.0 mg/kg) i.v. dose, with most of the food being consumed in the first hour after administration.     

Vancomycin cerebrospinal fluid concentrations after intravenous administration in premature infants

OBJECTIVE: Staphylococcal species are the most common cause of nosocomial infections in the neonate. Because of staphylococcal resistance patterns, vancomycin has become the drug of choice for treatment. Although the blood stream is the usual site of infection, premature infants are at increased risk for the development of meningitis. The aim of this study was to determine vancomycin cerebrospinal fluid (CSF) concentration and penetration following intravenous (IV) administration in critically ill premature infants. STUDY DESIGN: A multiple-dose, open-label, case series was performed at a level III neonatal intensive care unit in a university teaching hospital. Three critically ill premature infants, 26 to 31 weeks of gestation requiring a course of IV vancomycin for suspected or proved sepsis were studied. Vancomycin was administered intravenously at 20 mg/kg, every 18 to 24 hours over 60 minutes. Serum and CSF vancomycin concentrations were obtained and pharmacokinetic analysis and CSF penetration was calculated. RESULTS: Serum vancomycin pharmacokinetics were consistent with those previously reported. CSF vancomycin concentrations ranged from 2.2 to 5.6 micrograms/ml and the calculated vancomycin CSF penetration ranged from 26% to 68%. CONCLUSIONS: CSF penetration of vancomycin after IV administration was much higher than that reported in older infants and children. This higher penetration may improve clinical outcomes in neonates with central nervous system infections. These data should be encouraging to clinicians who choose to use IV vancomycin for neonatal meningitis.     

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.     

Formation of oxyadenine metabolites in the rabbit after intravenous administration of adenine

Adenine, 8-oxyadenine, and 2,8-dioxyadenine were analyzed, by Dowex-50 column chromatography, in rabbit urine four hours after IV infusion of the following doses of adenine in mg/kg: 2, 4, 8.75, 17.5, 35, 70, 140 and 210. The average excretion in mole percentage of the dose was: adenine, 11.1; 8-oxyadenine, 6.1; and 2,8-dioxyadenine, 6.2. The percentage of excretion of 8-oxyadenine and of 2,8-dioxyadenine was unrelated to the dose of adenine. At doses of adenine of 35 mg/kg and above more than 80 per cent of the 2,8-dioxyadenine in the urine was in the form of microscopic pale yellow spherical particles. The particulate 2,8-dioxyadenine was found in the kidney in a very small amount at the dose of 70 mg/kg and in much greater quantities at 140 and 210 mg/kg.     

Evaluation of lung function after intratracheal perfluorocarbon administration in healthy animals

OBJECTIVES: To investigate the effects of partial liquid ventilation (i.e., mechanical ventilation in combination with intratracheal administration of perfluorocarbon) on lung function, with particular attention to the integrity of the alveolocapillary membrane in healthy adult animals. DESIGN: Prospective, randomized, controlled study. SETTING: Laboratory at the Department of Experimental Anesthesiology, Erasmus University Rotterdam. SUBJECTS: Ten adult male New Zealand rabbits. INTERVENTIONS: Five rabbits were intratracheally treated with 12 mL/kg of perfluorocarbon while conventional mechanical ventilation (volume-controlled, tidal volume of 12 mL/kg, respiratory rate of 30 breaths/min, inspiration/expiration ratio of 1:2, positive end-expiratory pressure of 2 cm H2O, and an FIO2 of 1.0) was applied for 3 hrs. To assess the permeability of the alveolocapillary membrane, pulmonary clearance of inhaled technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) measurements were performed at 3 hrs and compared with data from the control group (n = 5) treated with mechanical ventilation only, using the same ventilatory parameters. MEASUREMENTS AND MAIN RESULTS: Pulmonary gas exchange and lung mechanical parameters were measured in both groups at 30-min intervals. Mean values for PaO2 in the perfluorocarbon group, although at adequate levels, were less than those values of the control group during the 3-hr study period (370 +/- 44 vs. 503 +/- 44 torr at 3 hrs [49.3 +/- 5.9 vs. 67.1 +/- 5.9 kPa]). Peak and mean airway pressures were higher in the perfluorocarbon group (ranging from 1.9 to 3.4 cm H2O and 0.7 to 1.3 cm H2O, respectively) compared with the control group, while end-inspiratory airway pressure was similar in both groups. The half-life of 99mTc-DTPA was 83.7 +/- 24.5 mins in the control group, which was significantly longer (p < .01) than in the perfluorocarbon group (49.8 +/- 6.1 mins). CONCLUSIONS: These findings suggest that partial liquid ventilation with perfluorocarbons lowers pulmonary gas exchange in healthy animals, and the increased pulmonary clearance of 99mTc-DTPA after 3 hrs of this type of ventilatory support may reflect minimal reversible changes in the lung surfactant system.     

Pharmacokinetics of acetaminophen after intravenous and oral administration to spontaneously hypertensive rats and normotensive Wistar rats

In our previous study, we reported the faster metabolism of intravenously administered furosemide, hence the smaller diuretic effect of furosemide in spontaneously hypertensive rats (SHRs) of 16 weeks of age than in the age-matched normotensive Wistar rats. In present study, in order to evaluate whether there is some alteration of the phase II metabolism including glucuronide and sulfate conjugations in 16-week-old SHRs and the age-matched Wistar rats, the pharmacokinetic parameters of acetaminophen (A), A-sulfate, and A-glucuronide were investigated after intravenous (iv) and oral 100 mg/kg administration of A to 16-week-old SHRs and the age-matched Wistar rats. After iv administration of A, the mean fraction of iv dose excreted in 24-h urine as A-sulfate (75.6 versus 67.8%) and the partial clearance of A to A-sulfate (8.10 versus 6.89 mL/ min/kg) were significantly greater in SHRs than in Wistar rats. Conversely, the mean fraction of iv dose excreted in 24-h urine as A-glucuronide (9.39 versus 15.0%) and the partial clearance of A to A-glucuronide (1.01 versus 1.49 mL/min/kg) were significantly smaller in these SHRs. Similar results were also obtained after oral dosing of A. The in vitro sulfotransferase activity toward A was significantly smaller (0.397 versus 0.331 microg/min/mg of protein) in 16-week-old SHRs than in the age-matched Wistar rats, whereas, the glucuronyltransferase activity toward A was not significantly different between these SHRs and Wistar rats. On the other hand, there was no significant difference in the both sulfotransferase and glucuronyltransferase activity toward A between 6-week-old SHRs and age-matched Wistar rats. Therefore, the alterations in sulfation and perhaps glucuronidation of A between 16 -week-old SHRs and normotensive Wistar rats suggested that some physiological factors derived from the chronic hypertensive status in SHRs might affect the disposition of drugs.     

Stereoselective pharmacokinetics of bisoprolol after intravenous and oral administration in beagle dogs

We report 81 of 107 cases of hemolytic uremic syndrome (HUS), admitted between July 1994 and February 1996, following an outbreak of Shigella dysenteriae type 1 dysentery in Kwazulu/Natal. All patients, excluding 1, were black with a mean age of 38 months (range 1-121); 50 (61.7%) were males. The mean duration of dysentery was 11.3 days (range 1-41) and HUS 15 days (range 1-91). Most patients had acute oliguric renal failure (90.1%), 42 (51.6%) required peritoneal dialysis. Complications included encephalopathy 30 (37.0%), convulsions 12 (14.8%) and hemiplegia 2 (2.3%), gastrointestinal perforation 8 (9.9%), protein losing enteropathy 26 (32.1%), toxic megacolon 4 (4.9%), rectal prolapse 5 (6.2%), hepatitis 11 (13.6%), myocarditis 5 (6.2%), congestive cardiac failure 3 (3.7%), cardiomyopathy 3 (3.7%), infective endocarditis 1 (1.2%), septicemia 15 (18.5%), disseminated intravascular coagulation 17 (21%). Leukemoid reactions were found in 74 (91.3%) patients, hyponatremia in 56 (69.1%), and hypoalbuminemia in 67 (82.7%). Stool culture for Shigella dysenteriae type I was positive in only 7 (8.6%) patients; Shiga toxin assays were not performed. Outcome was as follows: recovery 32 (39.5%), impaired renal function 8 (9.9%), chronic renal failure 26 (32.1%), end-stage renal disease 1 (1.2%), and death 14 (17.3%) patients.     

Relative bioavailability of different butamirate citrate preparations after single dose oral administration to 18 healthy volunteers

The action of purified cathepsin D on hemoglobin was examined using micellar electrokinetic chromatographic separation of peptide products. Purified cathepsin D was incubated with hemoglobin in 40 mM Na-formate pH 3.1 at 37 degrees C for varying lengths of time. The reaction was stopped by the addition of the inhibitor pepstatin, and the peptide products were isolated from the reaction mixture by ultrafiltration with a 10,000 molecular weight cut-off (MWCO) microfuge type filter. Filtered samples were then separated in 100 mM Tris-Cl pH 8.5 containing sodium dodecyl sulfate (SDS) or Na-deoxycholate at micellar concentrations using a 50-microns (i.d.) fused-silica capillary. Detection was performed at 214 nm. It was found that Na-deoxycholate containing separations were superior in resolution and required less time. This technique was used to determine initial velocity (expressed as peak area per unit time) for nine peptides. Several peptides resulted after very short incubation times (< 10 min). This suggests that this approach may be useful for the determination of cathepsin D activity.