Osmolality changes in perilymph after systemic administration of glycerin

Blood osmolality was altered in guinea pigs by intravenous administration of glycerin (glycerol). After glycerin administration, serum osmolality increased rapidly, reaching a plateau within 15 minutes. Perilymph osmolality lagged significantly behind the increase of serum osmolality and equalled serum osmolality only after one hour. While perilymph osmolality responded to changes of serum osmolality, there was some time lag noted in the response of perilymph, suggesting the existence of a blood-labyrinth barrier. It was observed that this barrier is permeably to glycerin and water, suggesting the possibility of transient reduction of hydrostatic pressure in the labyrinth by the injection of an osmotic agent into the systemic circulation.     

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.     

Contractility of the rabbit abdominal aorta 4 days after endothelium denudation

The purpose of this study was to evaluate contractility of the rabbit abdominal aorta 4 days after de-endothelialization by balloon catheter. The isometric tension of ring-segments in response to vasoactive agents was monitored. A significant enhancement of contraction to noradrenaline and serotonin was found in aortas 4 days after endothelium denudation as compared with controls with endothelium. The enhancement, however, did not differ from that found already in acutely denuded vessels (immediate denudation). No significant difference in contractility to potassium chloride was found in either group of denuded preparations as compared with controls. The sensitivity to all three vasoactive agents (EC50) was not influenced by denudation. These results indicate that changes in the contractility of denuded vessels are predominantly a consequence of lacking the endothelium as a producer of endothelium-derived relaxing factor. The access of mitogens to the media does not seem to interfere with the magnitude of contraction 4 days after denudation.     

Structural changes in the tissues of white rats after capsaicin administration

Attitudes to health and illness may differ between rural and urban dwellers. Issues that may relate to the provision of health services to rural dwellers are raised for consideration. The response of urban dwellers to illness or disability has often been linked to discomfort caused by pain or cosmetic attractiveness, while for rural dwellers the response to illness or disability is often related to the degree to which the illness or disability affects productivity. Often the rural resident will postpone seeking medical or associated services until it is economically or socially convenient. The notion of exposing their private lives to strangers or acquaintances from the local based services or to undertake the journey to distant services where the cultural or behavioural differences could be misunderstood, may impact on rural dwellers' well-being. Health service providers in rural areas need to understand such differences and difficulties when offering services.     

Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmacokinetics and 6 beta-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5 mg of doxylamine succinate, placebo, or 30 mg of phenobarbital administered orally every 6 h for 17 days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45 mL/h/kg) and nonrenal (35 versus 44 mL/h/kg) clearances and 6 beta-hydroxycortisol excretion (338 versus 529 micrograms) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.     

Comparative bioavailability of two atenolol tablet formulations in healthy male volunteers after a single dose administration

The bioavailability of 2 atenolol tablet formulations (Angipress from Laboratórios Biosintética, and Atenol from Wellcome ICI Laboratory, Brazil) were compared in 18 healthy male volunteers who received a single 50 mg dose of each atenolol formulation. The study was conducted following an open randomized 2-period crossover design with a 14-day washout interval between doses. Plasma samples were obtained over a 24-hour interval and atenolol concentrations were determined by HPLC with fluorimetric detection. From the plasma atenolol concentration vs time curves the following pharmacokinetic parameters were obtained: AUC(zero-24) (area under the concentration vs time curves from 0-24 h), ke (terminal elimination constant), t1/2 (terminal first order elimination half-life), AUC (area under the concentration vs time curves extrapolated to infinity), Cmax (maximum achieved concentration), Tmax (time to achieve Cmax) and Cmax/AUC. All these variables were analyzed using both parametric and nonparametric statistics. Geometric mean Angipress/Atenol individual percent ratios were 99.6% for AUC(zero-24), 99.7% for AUC, 98.0% for Cmax, 102.8% for t1/2, 97.2% for ke and 97.8% for Cmax/AUC, with all their 90% confidence intervals within the bioequivalence range 80-125%, thus showing similar patterns of absorption and disposition. Arithmetic mean for individual Tmax differences was 0.8 h, and the 90% confidence interval did not include the zero value. Based on these results and in accordance with the European Union and the US Food and Drug Administration bioequivalence requirements we conclude that both atenolol formulations are bioequivalent for both the extent and the rate of absorption.     

Application of a first-pass effect model to characterize the pharmacokinetic disposition of venlafaxine after oral administration to human subjects

Venlafaxine (VEN), a drug used in the treatment of depression, undergoes significant first-pass metabolism after oral dosing to O-desmethylvenlafaxine (ODV), a metabolite with comparable therapeutic activity to that of parent drug. The pharmacokinetic disposition of VEN was characterized using a "first-pass" model that incorporates a presystemic compartment (liver) to account for the first-pass metabolism of VEN to ODV. A series of differential equations were simultaneously fitted to plasma concentrations of parent and metabolite. A good fit of the model to observed data was demonstrated, generating estimates for the following parameters: ka (1.31 +/- 0.009 hr-1), VVEN (252 +/- 87.6 liters), CLint (65.8 +/- 39.7 liters/hr), RL (liver:plasma partition coefficient, 29.6 +/- 18. 3), VODV (181 +/- 84.1 liters), and CLODV (23.5 +/- 12.5 liters/hr). Parameter estimates correlated closely with those obtained through noncompartmental methods. These results indicate that the time-course disposition of a compound undergoing first-pass hepatic metabolism after oral dosing can be successfully modeled.     

Effects of anesthetics on somatosensory evoked potentials by median nerve stimulation in human--analyses after single administration in volunteers

In the present study, effects of midazolam, thiopental sodium, propofol, and nitrous oxide upon SEP in a clinically used dose were investigated on 24 male volunteers. In addition, antagonistic actions of flumazenil and naloxone against effects of midazolam and nitrous oxide, respectively, on SEP were studied. Midazolam had no effect on latencies of N 20 and P 25, but increased latency of P 45 and attenuated P 100 amplitude. Flumazenil reversed these effects of midazolam of P 45 latency and P 100 amplitude to their control values. While thiopental sodium and propofol suppressed P 100 amplitude, they had no effect on N 20, P 25, P 45 latencies. Nitrous oxide elongated latencies of N 20, P 25, P 45 and decreased P 100 amplitude. Naloxone reversed the effects of nitrous oxide on N 20 and P 25 latencies without affecting increased P 45 latency and attenuated P 100 amplitude. These results suggest that midazolam might have an analgesic action of suppressing cortical sensory neurons, whereas thiopental sodium and propofol have no effect on neurons in the primary sensory cortex. The finding that naloxone antagonized the increased latencies of N 20 and P 25 by nitrous oxide could be explained by the analgesic action of nitrous oxide that could be mediated by opioid receptors. The results also indicate that electrical activities of the cortical neurons in the associated area are more susceptible to psychotropic agents than those in the primary sensory cortex. The effects of anesthetics on SEP appear to reflect their characteristics of functioning mechanisms on cortical neurons. Analysis of SEP is, therefore, useful for the assessment of the mechanism and the acting site of anesthetics in the sensory cortex.     

EEG pharmacodynamics upon single administration of seduxen in healthy volunteers

We have examined the type I collagen protein, RNA, and cDNA of 2 children with moderately severe (type IV) osteogenesis imperfecta (OI). They have in common a non-lethal form of OI with ambulatory potential, overmodification of type I collagen protein, and a substitution of serine for glycine in the collagen chain produced by one alpha 1(I) allele. The first child (Marini et al.: J Biol Chem 264:11893-11900, 1989) is now 7 years old, with the height of a 3-year-old. Her course includes significant remodeling of lower long bones and 4 femur fractures. She walks independently. A mishmatch was detected in her alpha 1(I) mRNA using RNA/RNA hybrids; it was demonstrated to be due to a G-->A point mutation in one allele of alpha 1(I), resulting in the substitution of serine for glycine 832. The second child is now 6 1/2 years old, with the height of 1 1/2-year-old. Her history includes significant bowing of femurs and tibias, 6 femur fractures, S-curve scoliosis, compression of all lumbar vertebrae, and limited short-distance walking with braces. Her alpha 1(I) mRNA has also been studied by RNA hybrid analysis; there is a single G-->A change in one alpha 1(I) allele causing the substitution of serine for gly 352. Both children have moderately severe OI. However, the serine substitution at gly 352 is associated with a more severe phenotype then is the serine substitution at gly 832. Compared to substitutions described in other cases of OI, the serine 352 is located in the middle of a cluster of cysteine substitutions associated with non-lethal OI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sleep fantasy in normal and schizophrenic persons.

Used the Dream-like Fantasy Scale of D. Foulkes to assess the bizarreness of the fantasy content from the REM and NREM sleep reports of 3 groups of Ss: 8 19-22 yr. old schizophrenic patients, 10 "normal" college students with MMPI Schizophrenia (ScK) scores above 70, and 14 college students with MMPI ScK scores below 70. It was hypothesized that hallucinatory fantasy would be confined to REM sleep least for patients, next for normals with high ScK scores, and most for normals with low ScK scores. REM fantasy was found to be significantly different between groups, with low-ScK normals scoring highest. NREM fantasy was also significantly different between groups, with high-ScK normals scoring highest. Patients who were actively hallucinating during the day showed no difference between REM and NREM fantasy scores. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blood-flow velocities in the extraocular vessels in normal volunteers

PURPOSE: To determine normal values of blood-flow velocities in extraocular vessels. METHODS: In one eye each in 189 healthy adult volunteers, blood-flow velocities in the ophthalmic artery (OA), central retinal artery (CRA), central retinal vein (CRV), short lateral posterior ciliary artery (LPCA), and short medial posterior ciliary artery (MPCA) were measured by color Doppler imaging. In the arteries, peak systolic velocity (PSV), end diastolic velocity (EDV), and resistivity index (RI) were calculated. In the CRV, maximal and minimal blood-flow velocities were measured. Influence of age, gender, blood pressure, and heart rate on blood-flow velocities and the resistivity index were analyzed. RESULTS: Mean outcomes +/- S.D. cm/sec were as follows: in the OA, PSV was 39.2 +/- 5.3, EDV was 9.1 +/- 2.5, and RI was 0.77 +/- 0.05. In the CRA, PSV was 11.0 +/- 1.8, EDV was 3.3 +/- 0.9, and RI was 0.71 +/- 0.05. In the short LPCA, PSV was 11.2 +/- 1.7, EDV was 3.7 +/- 1.0, and RI was 0.68 +/- 0.06. In the short MPCA, PSV was 11.2 +/- 11.7, EDV was 3.6 +/- 0.9, and RI was 0.68 +/- 0.05. In the CRV, mean maximal velocity was 4.5 +/- 0.9, and mean minimal velocity was 3.3 +/- 0.7. Age, gender, systolic blood pressure, diastolic blood pressure, and heart rate had no consistent statistically significant influence on the measured and calculated variables. CONCLUSION: Normal values for blood-flow velocities in the extraocular vessels serve as a basis in deciding whether a measured value of a patient is normal or abnormal.     

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.     

Cardiorespiratory and electrolytic changes in status asthmaticus after intravenous administration of magnesium sulfate

The authors studied cardiorespiratory effects of MgSO4 infusion in 30 randomized patients with status asthmaticus. They found, that after having the drug administered, values of VC, FEV1, FIV1, PaO2 and pH increased, the respiratory and heart rate, diastolic blood pressure reduced. Other ventilation, blood gas and ECG parameters were unchanged. Among the electrolytes, serum Ca2+ level has reduced, both plasma and intracellular Mg2+ concentrations increased. It is apparent from the results, that broncholytical ability of MgSO4 given in therapeutical dose i.v. does not reach the level of beta-stimulating agents. However, this completed with the cardioprotective, sedative effect as well as more advantageous ion-distribution, influences favourably the asthmatic dyspnoea.     

Hormonal responses to consecutive days of heavy-resistance exercise with or without nutritional supplementation

Nine resistance-trained men consumed either a protein-carbohydrate supplement or placebo for 1 wk in a crossover design separated by 7 days. The last 3 days of each treatment, subjects performed resistance exercise. The supplement was consumed 2 h before and immediately after the workout, and blood was obtained before and after exercise (0, 15, 30, 45, and 60 min postexercise). Lactate, growth hormone, and testosterone were significantly (P 相似文献   

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.     

Antibacterial activity of ofloxacin in urine for 4 days after a single oral dose of 400 mg

Antibacterial activity of ofloxacin in urine after a single oral dose of 400 mg was evaluated in ten healthy female volunteers. Urine was collected over six periods, i.e., 0-6 h, 6-12 h, 12-24 h, 24-48 h, 48-72 h, and 72-96 h postdose. Ofloxacin levels were assayed in all samples using a microbiological method and HPLC. Urinary ofloxacin MICs were determined for five bacterial strains recovered from urine, two E. coli strains of which one was susceptible and the other resistant to nalidixic acid (Nal-A), one Klebsiella pneumoniae resistant to nalidixic acid (Nal-B), one Staphylococcus saprophyticus strain, and one Enterococcus faecalis strain; MICs were 0.06, 0.25, 1, 0.25, and 2 mg/L, respectively. Mean urinary ofloxacin levels by the microbiological method during the six collection periods were 193.3 +/- 30.3, 138.1 +/- 31, 53.2 +/- 7.3, 8.3 +/- 0.8, 1.4 +/- 0.2, and 0.6 +/- 0.1 mg/L, respectively. HPLC provided similar results: 216.7 +/- 31.6, 130.7 +/- 20.5, 56.5 +/- 7.1, 8.3 +/- 0.9, 1.5 +/- 0.3, and 0.5 +/- 0.05 mg/L, respectively. Mean urinary ofloxacin excretion over 96 h was 67.4 +/- 3.6% of the dose by the microbiological method was 72.5 +/- 2.5% of the dose by HPLC. On the first day, bacteriostatic activity of urine against enterobacteria exceeded 32 and was greater than 8192 for the nalidixic acid-susceptible E. coli strain; on the next day, overall values were equal or greater than 8 for the nalidixic acid-resistant E. coli and K. pneumoniae strains. Bacteriostatic activity was equal to or greater than 32 for the S. saprophyticus strain during the first two days and equal to 8 on the first day and 4 on the second day for the E. faecalis strain.     

Hemodynamic and pathological changes in the normal rabbit brain after linac stereotactic irradiation

A number of clinical reports on stereotactic radiosurgery using a linear accelerator have been published. So far, however, basic studies using the experimental animals have been comparatively few in number. Changes of cerebral hemodynamics and pathohistology in the animal brain after stereotactic, large dose irradiation was studied in this experiment. Fourteen pure imbred Japanese white rabbits, weighing approximately 5 kg, were used. As the landmark for irradiation targeting, a small silicone ball, 2 mm in diameter, was implanted aseptically in the right frontal bone. A month after placing the landmark, stereotactic irradiation was given in a single dose of 100 Gys by a linear accelerator with a 10 mm collimator. In all animals, dynamic CT was carried out before and immediately after irradiation, and thereafter, it was repeated at various intervals. Time density curve which has two parameters of peak-time (PT) and peak-height (PH), was drawn with the help of Sprine function. The ratios of PT, PH, and CBF were calculated for their values in the irradiated area/values in the contralateral corresponding area. Two animals were sacrificed immediately, 1, 3, 7, 21, 90 and 180 days respectively after irradiation, and one animal was killed 1 year after radiation followed by another animal killed 2 years after irradiation. Brains were removed and formalin-paraffin sections were made. All sections were stained with hematoxylin-eosin and GFAP (glial fibrillary acidic protein). In the brain of day 3, cerebral hemorrhage and an increase of astrocyte were demonstrated in the irradiated area. The increase of astrocyte had persisted for approximately 3 weeks. On the other hand, neurons and vessels appeared intact, even i the brain of day 90. In the brain of day 180, brain necrosis had developed in the irradiated area and necrosis had become wider and more prominent in the brains of 1 and 2 years after irradiation. Fibrinoid degeneration of capillaries was evident in the irradiated area and its adjacent areas. Regional cerebral blood flow (r-CBF) in the irradiated area decreased for 3 days and continued to remain at a lower level for a week. However, r-CBF increased thereafter again at 3 weeks. Then it gradually continued to decrease and finally it became unmeasurable at one or 2 years after irradiation. To interpret the fact that there is a biphasic time course for r-CBF, the early decrease was attributed to local edema, and the later decrease was attributed to changes in the wall of vessels.