Comparison of short-term immunosuppressive therapy with cyclosporine and FK 506 in small-bowel transplantation.
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Animals↗
Biomedical subjects
A Hoffman
Publications and source records attributed to A Hoffman.
A simple technique for artificial cardiac pacing in closed chest anesthetized rats.
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Anesthesia↗
Transplantation of the small intestine: the pathologist's perspective.
Small-bowel transplantation is now ready for clinical trials. The surgical techniques and methods for immunosuppression and monitoring bowel status have been developed in animal models over the past 30 years. Several attempts at small-bowel transplantation in humans have already been reported. In the course of future trials, pathologists will be involved in the monitoring of the posttransplant course by mucosal biopsies and functional studies, including maltose and xylose absorption tests. The morphology of rejection has been studied in canine and rat models. Activated lymphocytes and plasma cells infiltrate the lamina propria and invade crypt epithelium, causing "cryptitis." Villous blunting ensues, resulting eventually in necrosis. Graft survival without immunosuppression is about 10 days. Under Cyclosporine immunosuppression, a lymphoplasmacytic infiltrate has been noted around nerves and vessels in the submucosa. The overlying mucosa may be relatively normal. End-stage bowel is characterized by a contracted, scarred mass. Due to the large amount of lymphoid tissue in the allograft, graft-versus-host disease is a significant problem in small-bowel transplantation.
Graft Rejection↗
Endothelium-dependent basilar and aortic vascular responses in normotensive and coarctation hypertensive rats.
The responsiveness of acetylcholine (ACh), nitroglycerin (NG) and norepinephrine (NE) (aorta only) in both basilar arteries (BA) and thoracic aortic (TA) rings from coarctation hypertensive rats (CHR) were studied and compared to their sham-operated normotensive control rats (SNR). The effects of these agents were also evaluated in TA or BA with and without endothelium from naive normotensive rats (NNR). Blood pressure (BP) and plasma renin activity (PRA) of CHR were significantly higher than their time-matched SNR. Endothelium removal from TA of NNR significantly enhanced NE and NG sensitivity and reduced the maximum ACh relaxation. Removal of BA endothelium of NNR abolished ACh-induced relaxation but had no effect on NG-induced relaxation. In BA from CHR at any stage of hypertension studied, the sensitivity and maximum relaxation induced by ACh or NG were not significantly different than their respective time-matched SNR. ACh sensitivity of TA did not change in 1 Day CHR but decreased in 4 and 14 Day CHR. NG sensitivity increased, did not change and decreased in 1, 4 and 14 Day CHR, respectively. NE sensitivity increased in all stages of hypertension. These data suggest that in coarctation-induced hypertension there is a complex progression of events in TA which is modulated by different mechanisms as evidenced by the changes in the effects of NE, ACh and NG at various stages of hypertension. The results also suggest that the vascular endothelium of TA but not of BA may provide an acute protective mechanism to counteract the imbalance created by the increased sensitivity of smooth muscle cells to contractile agonists in the early stage of hypertension. However, persistent hypertension appears to override this mechanism.
Animals↗
Endothelin induces an initial increase in cardiac output associated with selective vasodilation in rats.
The systemic and regional hemodynamic effects of endothelin (ET), a novel endothelial derived vasoconstrictor peptide were studied in Wistar Kyoto rats. A bolus of 1 nmol/Kg ET intravenously induced a transient 43% decrease in blood pressure associated with a 57% decrease in systemic resistance and a 30% increase in cardiac output (p less than 0.01 for all parameters). This was followed by an increase of 20% in arterial pressure and of 71% in systemic resistance and a decrease of 30% in cardiac output at 10 minutes. The initial fall in blood pressure was not abolished by pretreatment with verapamil, captopril, indomethacin, ketanserin, atropine, methylene blue or ethanol. Verapamil abolished the hypertensive phase by markedly decreasing cardiac output. ET had selective effects on the arterial tree; during the hypotensive phase it caused a transient increase in blood flow in the carotid and femoral arteries (+41% and +83% respectively, p less than 0.01) but a decrease in flow in the renal and mesenteric arteries (-53% and -44% respectively, p less than 0.05). Accordingly, there was a decrease in resistance in the carotid and femoral beds (-55% and -67% respectively, p less than 0.01) and an increase in resistance in the renal and mesenteric beds (+102%; p less than 0.01 and +23%; p = N.S. respectively). Subsequently there was an increase in resistance in all vascular beds to variable degrees. The maximal increase in resistance was in the renal bed (+156%). Thus, ET causes initially a potent systemic vasorelaxation and an increase in cardiac output later progressing to systemic vasoconstriction and a decrease in cardiac output. The initial vasodilation is selective, appearing in musculocutaneous beds but not in visceral beds.
Animals↗
Effect of enoxacin on theophylline neurotoxicity.
Concomitant use of the bronchodilator theophylline and the antibacterial agent enoxacin has been associated with significant neurologic and other adverse effects. Enoxacin and certain other quinolones are known to inhibit the biotransformation of theophylline, thereby increasing the plasma concentrations of the bronchodilator. It was considered possible that this may not be the only interaction because theophylline as well as enoxacin are known to have neurotoxic potential. To explore the possibility of a pharmacodynamic interaction, rats pretreated orally with enoxacin or water (controls) were slowly infused i.v. with theophylline until the onset of a maximal seizure. Neither 100 nor 400 mg/kg enoxacin 1 hour before the infusion had any significant effect on the infused dose or on the concentrations of theophylline in serum, brain and cerebrospinal fluid at onset of seizures. On the other hand, 400 mg/kg enoxacin reduced the total serum clearance of a 12 mg/kg i.v. bolus dose of theophylline from 2.56 +/- 0.37 to 1.00 +/- 0.13 ml min-1kg-1 (mean +/- SD). It is concluded that acutely administered enoxacin in a dose sufficient to inhibit the elimination of theophylline has no direct effect on theophylline neurotoxicity in rats.
Animals↗
Gender differences in the pharmacodynamics of barbiturates in rats.
There is considerable evidence of gender differences in the pharmacokinetics of numerous drugs, particularly in rodents, but very limited information concerning the effect of gender on pharmacodynamic characteristics (concentration-activity relationships). In this study, heptabarbital or phenobarbital was administered to male and female rats and the concentrations of these drugs in the brain, cerebrospinal fluid and serum at onset or offset of loss of righting reflex were determined. For heptabarbital, offset concentrations were determined in Lewis rats and onset concentrations in Wistar rats. Onset concentrations of phenobarbital were determined in Wistar rats. In all cases, the barbiturate concentrations in males were significantly lower than those in females at the pharmacologic endpoint. The biologic (serum) half-life of heptabarbital is much shorter in males (approximately 10 min) than in females (approximately 90 min) and this pharmacokinetic difference is reflected by the considerably longer duration of effect of the drug in females.
Animals↗
Normal atrial natriuretic peptide release after acute and chronic stimuli in hypophysectomized rats.
To test the hypothesis that the pituitary gland has a role in modulating the release of atrial natriuretic peptide (ANP) from atrial myocytes, we applied different stimuli of both acute and chronic nature to rats 8-10 days after hypophysectomy (Hypx). Acute rapid cardiac pacing at a rate of 500 beats/min in anesthetized rats caused a marked increase in plasma levels of ANP (from 76 +/- 7 to 237 +/- 60 pg/ml, P less than 0.05) despite a marked decrease of blood pressure. This response was similar to that of paced control rats, but because the basal levels were lower in Hypx rats, the relative increase in ANP was larger in the experimental group. Studies were also done in a chronic model of high-output congestive heart failure produced by an aortocaval fistula in hydrocortisone-supplemented rats. Although these rats had low blood pressure 2-3 days after surgery, there were marked increases in right atrial pressures associated with high plasma levels of ANP (194 +/- 24 pg/ml) that were not significantly different from controls (221 +/- 26 pg/ml, P greater than 0.05). These results indicate that the role of the pituitary in ANP release is indirect, and no specific hypophyseal factor is required for this response. Hemodynamic parameters are the important determinants of ANP secretion, even in hypophysectomized rats.
Animals↗
A retrospective cost-effectiveness analysis of colorectal cancer screening in a public hospital. Savings from reduced hospitalization.
We compared the actual diagnosis and treatment costs for nine colon cancer and 19 polyp patients detected by occult blood screening with excess hospitalization costs incurred by a comparable group of traditionally detected patients. Program benefits were calculated from data on group differentials in surgical length of stay, readmissions in the year following surgery, and preventive polypectomies. A sensitivity analysis was performed to evaluate varying estimates of the percentage of polyps that may have become cancers, the urgency of presentation of clinically apparent cancer, and the inclusion or exclusion of the observed differences for hospitalization in the year after surgery. Two year program benefits varied from 59% to 185% of program costs. Adjusting estimates with DRG weightings for resource intensity produced considerably higher benefits. All estimates of program benefits are conservative because screened patients were compared with the 15-20% least severely ill, most favorably staged of all traditionally detected colon cancer patients admitted. Results indicate that occult blood screening programs may produce significant benefits derived from outpatient diagnosis, preventive polypectomies, coordination of care between medical and surgical services, and enhanced patient education.
Chicago↗
Kinetics of drug action in disease states. XXIX. Effect of experimental nephrotic syndrome on the pharmacodynamics of heptabarbital: implications of severe hypoalbuminemia.
The purpose of this investigation was to determine the effect of nephrotic syndrome (NS) on the pharmacodynamics of a barbiturate. NS was induced in male rats by puromycin aminonucleoside; it caused hypoproteinemia, increased liver and kidney weight and elevated serum creatinine and urea nitrogen concentrations. Serum albumin concentration decreased from 3.5% in controls to 0.90% in NS animals. The rats were infused i.v. with heptabarbital, 1 mg/min, until they lost their righting reflex. The total dose (mean +/- S.D.) required by rats with NS, 40.2 +/- 4.2 mg/kg, was substantially lower than that required by normal animals (68.6 +/- 6.2 mg/kg, P less than .001). Serum protein binding of heptabarbital was reduced from 49% in controls to 26% in NS rats. However, the drug concentration in cerebrospinal fluid (CSF) at the pharmacologic endpoint was not significantly different in controls and NS rats (18.9 +/- 1.5 vs. 18.3 +/- 1.4 mg/l). Serum, CSF and the brain contained appreciable concentrations of a metabolite of heptabarbital. To determine if the metabolite contributes to the pharmacologic effect of the parent drug, rats received an i.v. injection of 46, 60 or 100 mg/kg of heptabarbital. Concentrations of heptabarbital in CSF at return of righting reflex (which occurred after 15, 25 and 50 min, respectively) were independent of dose whereas metabolite concentrations increased with increasing dose. Thus, the metabolite of heptabarbital in male rats is pharmacologically inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Therapeutic effectiveness of lidocaine in patients with ventricular arrhythmias estimated relative to measurements of drug concentration in serum].
Therapeutic effectiveness of lidocaine intravenous infusions preceded by an initial intravenous dose was studied in 29 patients with ventricular arrhythmias in a course of ischemic heart disease admitted to CCU. Clinical effects were evaluated in correlation with obtained lidocaine concentrations and basic pharmacokinetic parameters. Regression of cardiac arrhythmias was stated in 23 patients (79.3%), inclusive of all acute MI cases. Partial therapeutic effect was observed in 4 patients (13.8%) and no effect in 2 (6.9%). In 12 patients (52.2%) with stated regression of ventricular arrhythmias the full therapeutic effect was observed after initial dose administration. Serum drug concentrations were above the lower limit of the therapeutic range in all cases. Side effects were observed in 3 cases with high serum lidocaine levels caused by impaired drug metabolism or elimination due to the patient's clinical state. Correlation between the infusion rate and obtained stationary condition of drug concentration within therapeutic range seemed to be highly effective in management of ventricular premature beats caused by acute myocardial ischemia but less effective in cases of ischemic and postinfarction cardiomyopathy with heart failure.
Aged↗
Cigarette smoking and attitudes toward quitting among black patients.
A sample of 1,388 black patients attending the medical clinic of a general public hospital were interviewed regarding smoking habits and attitudes toward quitting. Current smokers constituted 30% of respondents of both sexes, and approximately half of the sample were ex-smokers. Rates of current smoking were lower, and cessation rates higher, among older individuals and men. Two thirds of current smokers expressed a desire to quit, and of those an equal proportion wanted to participate in a formal cessation program. A majority of smokers reported attempting to quit on their own, and most had made more than one attempt. Given the large burden from cigarette-related disease in the black population, and the current absence of effective primary prevention efforts, smoking intervention in the clinical setting will remain an important obligation of health providers caring for black patients. This article demonstrates moderately high smoking prevalence rates of black individuals already under care for chronic illness, and a concomitant high level of desire to quit. The absence of effective programs appears to be the obstacle preventing significant progress in this important area of health promotion.
Adult↗
Design and release kinetic pattern evaluation of indomethacin microspheres intended for oral administration.
Indomethacin has been incorporated into either ethylcellulose (EC) or Eudragit RL microspheres by a solvent-evaporation process. Production variables have been tested in an attempt to produce indomethacin microspheres having adequate oral controlled-release properties. In spite of high drug content in the ethylcellulose microspheres, the indomethacin release rate was too slow and incomplete. Although the addition of an hydrophilic polymer, poly(ethylene glycol), to the EC polymer enhanced the indomethacin release rate, it was not possible to reach release profiles suitable for oral use. Therefore, indomethacin was incorporated into a more permeable polymer, Eudragit RL. While incorporation efficiency decreased with increasing initial concentration of indomethacin, adequate oral-release profiles were achieved. It was found that all the global-release profiles yielded by the indomethacin-loaded Eudragit RL microspheres conformed to the Higuchi diffusional model of dispersed drug particles in spherical micromatrices and not to the desorption kinetic model of a dissolved drug from a monolithic spherical device.
Administration, Oral↗
Relation between individual and ensemble release kinetics of indomethacin from microspheres.
Indomethacin microspheres based on a combination of ethylcellulose and polyethyleneglycol were prepared using the solvent evaporation process. Release profiles of ensemble and individual microspheres were measured. Both were found to follow first-order kinetics, in contrast to what was expected. This was attributed to the fact that all the particles showed the same kinetic pattern and had a greater degree of homogeneity in the payload, mean particle size and shape, and k1 values than in ensembles of microcapsules.
Indomethacin↗
Effects of atrial natriuretic factor in rats with experimental high-output heart failure.
The effects of atrial natriuretic factor (ANF) were evaluated in rats with chronic aorto-caval (A-V) fistula. In this experimental model of high-output heart failure, the animals display elevated atrial pressure and systemic vasodilation, but avidly retain sodium. Experiments were performed on Munich-Wistar rats, 8 to 14 days after placement of an infrarenal surgical anastomosis (side-to-side, 0.9 +/- 0.2 mm) and on sham operated controls. Infusion of synthetic ANF (3-28) intravenously (5 micrograms/kg prime; 0.17 microgram/kg.min) resulted in increases in urine flow (V) and fractional sodium excretion (FENa) and decreases in blood pressure (BP) that were significantly attenuated in rats with A-V fistula compared to controls. To control for the lower baseline BP that was present in rats with A-V fistula, a second series of studies was performed in which renal perfusion pressure was reduced in normal rats to 110 mm Hg with a servocontrolled pneumatic cuff. ANF infusion to this group led to significant increases in glomerular filtration rate (GFR), V and FENa that were greater than those seen in rats with A-V fistula (FENa = 2.7 +/- 0.3% vs. 0.48 +/- 0.12%, P less than 0.05). Thus, the moderately reduced BP in rats with A-V fistula did not account for the blunted response to ANF. To investigate whether the renal sensitivity to ANF is altered in this model, an additional series of experiments were performed in which ANF was infused over a range of doses (0.08 to 2.5 micrograms/kg.min) to both groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neutralization of mouse xenotropic virus by lipoproteins involves binding to the virions.
We examined the properties of the mouse serum lipoprotein responsible for specific neutralization of the endogenous mouse xenotropic (X-tropic) type C retrovirus. The anti-X-tropic virus activity of the mouse lipoprotein neutralizing factor (NF) could not be blocked by sugars or lectins. Moreover, neutralization did not involve rupture of the virion core. Sucrose density gradient analysis of X-tropic virus mixed with various lipoprotein preparations demonstrated that the binding of complete virions to NF is associated with the neutralization.
Animals↗
Variation of population release kinetics in polydisperse multiparticulate systems (microcapsules, microspheres, droplets, cells) with heterogeneity of one, two or three parameters in the population of individuals.
Release kinetics of active substances from ensembles of microparticles such as microcapsules, cells, droplets and liposomes constituted of individual entities releasing their contents at constant rates may follow zero order, first order, sigmoid or biphasic equations. The release equation observed depends upon the statistical distribution of release-determining parameters among the population. Typical cases are presented in terms of the distribution of two parameters, payload (m infinity) and time for complete payload release (t infinity) which also define the release rate constant (k). Heterogeneity of the two parameters generally leads to first order ensemble behaviour, whereas heterogeneity of one parameter only may lead to different ensemble release equations, viz. zero order (m infinity heterogeneous) or first order (t infinity heterogeneous). Biphasic distribution can lead to an apparent 'burst' effect, with apparent change of kinetics. The presence of a third heterogeneous parameter, lag time, yields a sigmoid ensemble release curve. These conclusions are demonstrated by simulations or experimentally, and are also valid for linearized curves of microparticles following matrix kinetics.
Capsules↗
Hormonal determinants of sodium excretion in rats with experimental high-output heart failure.
The present study evaluates the inter-relationship between the alteration in atrial natriuretic factor (ANF) and the renal handling of Na in rats with chronic aortocaval (a-v) fistula, an experimental model of congestive heart failure. Balance studies in these animals showed two distinct patterns of Na excretion: some rats developed progressive Na retention [urinary sodium excretion (UNaV) less than 100 mueq/24 h], whereas others compensated and returned to normal Na balance (UNaV greater than 1,200 mueq/24 h). Base-line plasma ANF levels were equally elevated in Na-retaining and compensated rats with a-v fistula (588 +/- 70 vs. 621 +/- 114 pg/ml, P, NS). However, the response of the two groups to exogenous administration of synthetic rat ANF-(101-126) in incremental doses varied greatly. ANF infusion increased the fractional Na excretion (FENa) in compensated animals from 0.12 +/- 0.03 to 2.6 +/- 0.5%, whereas the rise in FENa in Na-retaining animals was markedly blunted (0.11 +/- 0.06 to 0.89 +/- 0.35%). A similar pattern of ANF action was observed on the glomerular filtration rate and urine flow. The blunted response to ANF in the Na-retaining animals was associated with a marked increase in plasma renin activity (PRA) (35.6 +/- 6.9 vs. 4.5 +/- 0.7 ng ANG I.ml-1.h-1 in sham control rats, P less than 0.05) and plasma aldosterone levels (729.3 +/- 28.2 vs. 42.6 +/- 18.4 ng/dl in sham control rats, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗