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1.
The effects of a glutathione depletor, buthionine sulphoximine (BSO) and biliary cannulation on the nephrotoxicity of p-aminophenol (PAP) have been investigated in the F344 rat. Preatment with BSO completely protected against the nephrotoxicity of a 50 mg/kg dose of PAP, assessed by clinical chemistry, renal histopathology, and 1 H-NMR urinalysis. Biliary cannulation partially protects against nephrotoxicity induced by 100 mg/kg PAP. These data suggest that the nephrotoxicity of PAP may be due in part to the formation of a proximate toxic metabolite in the liver which is excreted in the bile, subsequently reabsorbed and transported via the systemic circulation to the kidney where the toxic effects occur. 相似文献
2.
The acute toxicological effects of the nephrotoxic antibiotic cephaloridine (CPH, 0–1500 mg/kg) in male Fischer 344 (F344) rats, have been investigated over 48 h using clinical chemistry, histopathology and proton nuclear magnetic resonance ( 1H NMR) spectroscopy of urine and plasma. High field (400 and 600 MHz) 1H NMR urinalysis revealed increased excretion of lactic acid, acetoacetate, alanine, valine, lysine, glutamine and glutamate and a severe, time-dependent glycosuria. A major change observed in urine of CPH-treated animals was the dose-dependent increase in HB which may relate to altered energy metabolism. CPH also caused dose-dependent decreases in the urinary excretion of hippurate, allantoin and protein (conventional assay). This abnormal metabolic profile is consistent with a functional defect in the S 1/S 2 regions of the proximal tubule, and was confirmed by histology post mortem. Functional changes observed included elevations in blood urea nitrogen (BUN) and urine flow rate (UFR) and dose-related decreases in urine osmolality. Spin-echo 1H NMR spectroscopic analysis of lyophilised plasma, reconstituted with 2H 2O revealed an abnormal phase modulation of the methyl signal from free alanine and it is postulated that this is due to the release of transaminases from damaged tissue which via a reversible conversion to pyruvate, cause variable deuteration of alanine at the -CH position. This observation suggests that 1H NMR spectral patterns are also dependent on the level of plasma transaminases and this may provide a novel indicator of tissue damage. 相似文献
3.
4-Aminophenol ( para-aminophenol; PAP) causes selective necrosis to the S 3 segment of the proximal tubule in experimental animals. The mechanism of PAP nephrotoxicity has not been fully elucidated, although it has been suggested to involve glutathione (GSH)-dependent S-conjugation followed by processing by the enzyme -glutamyl transpeptidase (GT) to the corresponding cysteine S-conjugate. This proposed toxicity mechanism was probed further by administering L-( S,5 S)--amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), a potent GT inhibitor, to Fischer 344 (F344) rats before treatment with PAP (100 mg/kg). AT-125 pretreatment did not appear to protect against PAP-induced nephrotoxicity as assessed by renal histopathology, clinical chemistry and proton nuclear magnetic resonance ( 1H NMR) spectroscopy of urine. These data suggest that renal GT activity is not a prerequisite for PAP nephrotoxicity and that the generation of a cysteine S-conjugate is not a unique requirement for the induction of PAP nephrotoxicity. 相似文献
4.
High resolution 1H NMR spectroscopy of urine and plasma, conventional clinical chemical methods and histopathology have been applied to investigate
the effects of uranyl nitrate (UN) on renal function and biochemistry in the Fischer 344 (F344) rat. Administration of UN
(5 – 20 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy assessed conventionally by histopathology
and urinary excretion of N-acetyl- β- d-glucosaminidase (NAG), and related to changes in the patterns of low MW metabolites observed in 400 MHz 1H NMR spectra of urine. The changes in urinary metabolite profiles included elevations in glucose accompanied by minor elevations
in certain amino acids (alanine, valine and glutamate). 1H NMR urinalysis also revealed altered excretion of low MW metabolites which are not routinely measured, such as l-lactate, acetate, citrate, succinate and 2-oxoglutarate (2-OG). In addition, the striking appearance of high concentrations
of 3- d-hydroxybutyrate (HB) in the urine was noted, in the absence of acetoacetate or acetone, and it is suggested that this may
provide a new marker of proximal tubular damage for certain types of nephrotoxic mechanism. Broadening of the 1H NMR signals of citrate following 10 mg/kg UN was shown to be due to a dynamic exchange process involving chelation with
urinary Ca 2+ and Mg 2+ ions. Conventional biochemical analysis of plasma from UN-treated rats revealed dose-related increases in creatinine, urea
and HB concentrations. 1H NMR-detected evidence of raised alanine aminotransferase (ALT) levels in rats administered the highest dose of UN was indicated
by the partial deuteration of alanine in lyophilised plasma reconstituted in 2H 2O. The degree of 1H NMR-detected abnormalities agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity
and more fully characterised the renal changes produced by UN. The significance of HB-uria in UN-induced proximal nephropathy
is discussed in relation to biochemical observations on other proximal nephrotoxins.
Received 7 June 1993/Accepted 23 August 1993 相似文献
5.
4-Aminophenol ( p-aminophenol, PAP) causes selective necrosis to the pars recta of the proximal tubule in Fischer 344 rats. The basis for this selective toxicity is not known but PAP can undergo oxidation in a variety of systems to form the 4-aminophenoxy free radical. Oxidation or disproportionation of this radical will form 1,4-benzoquinoneimine which can covalently bind to cellular macromolecules. We have recently reported that a glutathione conjugate of PAP, 4-amino-3-S-glutathionylphenol, is more toxic to the kidney than the parent compound itself. In this study we have examined the distribution and covalent binding of radiolabel from 4-[ring 3H]-aminophenol in the plasma, kidney and liver of rats 24 h after dosing and related these findings to the extent of nephrotoxicity. In addition, we have examined the effect of ascorbic acid which will slow the oxidation of PAP; acivicin, an inhibitor of -glutamyltransferase and hence the processing of glutathione-derived conjugates; and probenecid, an inhibitor of organic anion transport on the nephrotoxicity produced by PAP. Administration of a single dose of PAP at 458 or 687 mol kg –1 produced a dose-related alteration in renal function within 24 h which was associated with proximal tubular necrosis. The lesion at the lower dose was restricted to the S 3 proximal tubules in the medullary rays, while at the higher dose it additionally affected the S 3 tubules in the pars recta region of the cortex. Administration of ascorbic acid protected rats against the nephrotoxicity produced by PAP, markedly reducing the effect on renal function, and the extent of renal tubular necrosis. Associated with this protection was a reduction in the concentration of both total and covalently bound radiolabel from PAP in the kidney. In contrast, prior treatment with acivicin slightly potentiated the nephrotoxicity of PAP at the lower dose of 458 mol kg –1, by increasing the extent of proximal tubular necrosis and azotemia. In association with this potentiation the concentration of both total and covalently bound radiolabel from PAP in the kidney was increased. Prior treatment with probenecid had little or no effect on the nephrotoxicity of PAP or on the distribution of radiolabel from PAP in the kidney. These studies indicate that oxidation of PAP to form a metabolite which can covalently bind to renal proteins may be an important step in the nephrotoxic process and that treatment with ascorbic acid reduces this and thereby affords protection.This work was presented in part at the Society of Toxicology Meeting, 23–27 February 1992 in Seattle, Washington, USA 相似文献
6.
The renal tubular toxicity of various halogenated xenobiotics has been attributed to their enzymatic bioactivation to reactive
intermediates by S-conjugation. A combination of high resolution proton nuclear magnetic resonance ( 1H NMR) spectroscopy of urine, renal histopathology and more routinely used clinical chemistry methods has been used to explore
the acute toxic and biochemical effects of S-(1,2-dichlorovinyl)- L-cysteine (DCVC), S-(1,2-dichlorovinyl)- L-homocysteine (DCVHC) and 1,1,2-trichloro-3,3,3-trifluoro-1-propene (TCTFP) up to 48 h following their administration to male
Fischer 344 (F344) rats. In the absence of gross renal pathology, 1H NMR urinalysis revealed increased excretion of the tricarboxylic acid cycle intermediates citrate and succinate following
DCVC administration. In contrast, both DCVHC and TCTFP produced functional defects in the S 2 and S 3 segments of the proximal tubule that were confirmed histologically. In these cases, 1H NMR urinalysis revealed increased excretion of glucose, L-lactate, acetate and 3- D-hydroxybutyrate (HB) as well as selective amino aciduria (alanine, valine, glutamate and glutamine). The significance of
the proximal nephropathies induced by DCVHC and TCTFP is discussed in relation to biochemical observations on other xenobiotics
that are toxic by similar mechanisms.
Received: 25 April 1994 / Accepted: 13 June 1994 相似文献
7.
Teriparatide acetate, a synthetic polypeptide fragment consisting of human parathyroid hormone residues 1-34 [hPTH(1-34)], is a bone anabolic agent used to treat osteoporosis. The present study was conducted to characterise the pharmacokinetics of teriparatide acetate in rats after subcutaneous administration. Teriparatide was rapidly absorbed into the circulation and eliminated immediately. No intact teriparatide was detected in the urine. To elucidate the mechanism of teriparatide metabolism, we performed in vivo and in vitro studies using the radiolabelled bioactive analogue, [125I]-[Nle8,18,Tyr34]-hPTH(1-34). After subcutaneous administration, the concentration of analogue metabolites increased in the plasma time-dependently. The concentration in the kidneys was more than 3-fold the concentration in the liver. In vitro analyses suggested that kidney radioactivity was associated with degraded bioactive analogue. In model rats, renal failure, but not hepatic failure, affected the pharmacokinetics of teriparatide acetate, which accounted for the decrease in the clearance of teriparatide. In conclusion, our results suggest that after subcutaneous administration of teriparatide acetate, teriparatide is rapidly absorbed and distributed to the liver or kidneys, where it is immediately degraded. The kidneys play a particularly important role in the distribution and metabolism of teriparatide, but not its excretion. 相似文献
8.
Summary Patients suffering from congestive heart failure received maintenance doses of digitoxin (N=10) or digoxin (N=8). The plasma glycoside concentration was determined, and after a single dose of 3H-digitoxin or 3H-digoxin, the decline and excretion of radioactivity were measured over a period of 7 (digitoxin) and 3 days (digoxin). Plasma radioactivity declined with a
x
T 1/2 between 77 and 234 h (mean 138 h) in the case of digitoxin and with a
x
T 1/2 between 9.2 and 38.6 h (mean 23.5 h) for digoxin. A close correlation between
x
T 1/2 and excreted radioactivity and
x
T 1/2 and total plasma level was found for digitoxin. In 4 patients TLC of urine showed that interindividual variations in digitoxin elimination could possibly be attributed to variation in metabolism, resulting in the production of different metabolites. Predicted digitoxin plasma levels agreed well with measured values. The maintenance dose could be calculated from the total body clearance ( V Cl) and a presumed plasma glycoside level. The recommended technique facilitates dosage calculations in patients treated with digitoxin.Abbreviations AUC
0
x
area under curve
-
average steady state plasma concentration
- F
fraction of the dose which is absorbed
- D
dose
- D M
maintenance dose
- V Cl
plasma (body) clearance
-
dosage interval
-
kinetic parameter of the corresponding
-
3H
glycoside 相似文献
9.
Renal papillary necrosis (RPN) was induced in Fischer 344 (F344) rats ( n=4) using 2-bromoethanamine hydrobromide (BEA) dosed at 150 mg/kg, and in multimammate desert mice ( Mastomys natalensis) at 150 and 250 mg/kg ( n=4) per group). Control rats and Mastomys were dosed with 0.9% saline ( n=4 per group). Urine was collected at regular intervals for up to 4 days post-dosing and analysed for low MW metabolites using
high resolution 1H NMR spectroscopy. The urinary activity of lactate dehydrogenase, γ-glutamyl transpeptidase and alkaline phosphatase was
determined using conventional biochemical assays. On termination, histopathological examination of papillae was performed
showing the development of extensive lesions in F344 rats at 150 mg/kg BEA. Mastomys appeared much more resistant to BEA and showed normal renal histology at 150 mg/kg and patchy lesions at 250 mg/kg BEA. Enzyme
analysis of control urine showed F344 rats to have > 1000% higher γ-glutamyl transpeptidase activity than Mastomys. 1H NMR spectroscopic analysis showed that BEA caused a substantial decrease in urinary concentrations of succinate and citrate
(0–24 h p.d.) and an increase in creatine (0–96 h p.d.) in both animal models. A decrease in the urinary concentration of
2-oxoglutarate with a subsequent increase by 72–96 h p.d. was also noted in both animal models. Glutaric and adipic aciduria
were also induced in both F344 rats and Mastomys 0–24 h post-BEA treatment, indicative of an enzyme deficiency in the acyl CoA dehydrogenases. Urinary taurine levels were
elevated in Mastomys following the administration of BEA, indicating some degree of liver toxicity. Urinary taurine was not elevated in F344 rats
following BEA administration, demonstrating further species difference in BEA toxicity. 相似文献
10.
The effect of acute and repeated
8-THC administration on alcohol-induced sleeping time was studied in male albino rats. We have observed that acute pretreatment with
8-THC markedly potentiates alcohol-induced sleeping time in a dose-related manner. This potentiation of the alcohol sleeping time is shortened significantly after repeated prior treatment with
8-THC and can be observed 72 hrs post-chronic treatment. The effect of
8-THC on alcohol-induced sleeping time is not associated with an altered alcohol metabolism rate. 相似文献
11.
Summary After oral administration of 3H-digoxin, 3H- (= 16)-acetyldigoxin, 3H- (=15)-acetyldigoxin and 3H-(15,16)-diacetyldigoxin water-soluble metabolites have been found in the urine of three persons. A maximum is reached after 4–5 h. These metabolites are very polar and are not identical with neither digoxigenin nor with its mono- and bis-digitoxosides. 相似文献
12.
Purpose. The primary objective of this study was to determine the rate and extent of transdermal absorption for systemic delivery of diclofenac from Pennsaid (Dimethaid Research, Inc.) topical lotion into the systemic circulation after the lotion was applied to human volunteers, in an open treatment, non-blinded, non-vehicle controlled study. In addition, the in vivo metabolism of this topical diclofenac lotion has also been studied.
Methods. Human volunteers were dosed with topical [ 14C]-diclofenac sodium 1.5% lotion on the knee for 24 h. Sequential time blood and urine samples were taken to determine pharmacokinetics, bioavailability and metabolism.
Results. Topical absorption was 6.6% of applied dose. Peak plasma 14C occurred at 30 h after dosing, and peak urinary 14C excretion was at 24–48 h. The urinary 14C excretion pattern exhibits more elimination towards 24 h and beyond, as opposed to early urinary 14C excretion. This suggests a continuous delivery of [ 14C]-diclofenac sodium from the lotion into and through skin which only ceased when the dosing site was washed. Skin surface residue at 24 h was 26 ± 9.5% dose (remainder assumed lost to clothing and bedding). Extraction of metabolites from urine amounted to 7.4–22.7% in untreated urine, suggesting substantial diclofenac metabolism to more water soluble metabolites, probably conjugates, which could not be extracted by the method employed. Two Dimensional TLC analysis of untreated urine showed minimal or no diclofenac, again emphasizing the extensive in vivo metabolism of this drug. Treatment of the same urine samples with the enzymes sulfatase and (-glucuronidase showed a substantial increase in the extractable material. Three spots were consistently present in each sample run, namely diclofenac, 3hydroxy diclofenac and an intermediate polar metabolite (probably a hydroxylated metabolite). Therefore, there was significant sulfation and glucuronidation of both diclofenac and numerous hydroxy metabolites of diclofenac, but many of the metabolites/conjugates remain unidentified.
Conclusions. There was a continuous delivery of diclofenac sodium from the lotion into and through the skin, which ceased after the dosing site was washed. The majority of the material excreted in the urine were conjugates of hydroxylated metabolites, and not the parent chemical, although further identification is required. 相似文献
13.
Summary Potassium transport was measured in -cell-rich islets from ob/ob-mice using the K +-analogue 86Rb +. Both tetracaine (0.1 mM) and glibenclamide (0.1 M) reduced the oubain-resistant 86Rb + influx but did not significantly affect the oubain-sensitive portion (Na +/K + pump). Tetracaine (0.5–1 mM) or glibenclamide (0.2 mM) decreased the 86Rb + equilibrium content and glibenclamide (1 M) transiently reduced the 86Rb + efflux rate but 0.1 mM tetracaine had only a slight effect on this flux rate. The results suggest that a change in ouabain-resistant (passive) K + fluxes, but not the Na +/K + pump, is involved in stimulation of insulin secretion by glibenclamide and tetracaine. Both drugs may exert similar effects on the -cell plasma membrane. 相似文献
14.
Bilateral microinjection of morphine (0.003–3 g/side) into the caudate putamen enhances the behavior induced by the IP injection of 1 mg/kg d-amphetamine phosphate in a dose-related manner. The duration of activity was prolonged and ambulation was changed to d-amphetamine stereotypy, a behavior normally associated with higher doses of d-amphetamine. The opioid activity was stereospecific in that levorphanol was active, whereas dextrorphan was not. The enhancement of d-amphetamine-induced behavior by the opioids was blocked by naloxone. d-ala 2- met-Enkephalin also enhanced the amphetamine-induced behavior. This enhancement appears to be specific to the caudate putamen because the oral stereotypy observed appears to be a unique action of amphetamine in this region of the brain. 相似文献
15.
Male Wistar rats exposed to atmospheric n-hexane excreted in their urine substances which gave rise to absorption spectra like those of pyrroles after the reaction with Ehrlich's reagent. A simple spectrophometric assay was developed to determine these pyrrole-like substances in urine. Their excretion kinetics were evaluated by exposing rats for 8 h to atmospheric n-hexane concentrations between 50 and 3000 ppm. The dose-response curve revealed saturation kinetics according to Michaelis-Menten, V max being 1.12 [ E
526ml urine/8 h n-hexane exposure] and Km, the atmospheric n-hexane concentration at V max/2, being 250 ppm. The excretion of pyrrolelike substances closely correlated with that of 2,5-hexanedione measured by Fedtke and Bolt (1987). Pyrrole-like substances were also found in the urine of a male volunteer. When exposing the person for 3 h to atmospheric n-hexane at a concentration of 146 ppm (equivalent to 55 ppm/8 h) the excreted amount was twice the background value. Due to the sensitivity of this assay it is possible to determine pyrrole-like substances in urine according to the present German MAK or US TLV conditions for n-hexane (50 ppm/8 h). 相似文献
16.
A study of the rates and routes of excretion of 3-fluoro-[U-14C]aniline following intraperitoneal administration to male bile-cannulated rats by liquid scintillation counting (LSC) gave a total recovery of ~ 90% in the 48?h following dosing, with the majority of the dose being excreted in the urine during the first 24?h (~ 49%). The total recovery as determined by 19F-nuclear magnetic resonance (19F-NMR) was ~ 49%, with the majority of the dose excreted in the first 24?h (~ 41%). The comparatively low recovery in comparison to that obtained from LSC was due to matrix effects in bile and a contribution from metabolic defluorination. High-performance liquid chromatography with radiometric profiling of urine and bile revealed a complex pattern of metabolites with the bulk of the dose excreted as a single peak. Ultra-performance liquid chromatography-orthogonal acceleration time of flight mass spectrometry profiling also showed a complex pattern of metabolites, detecting ~ 21 metabolites of 3-fluoroaniline (3-FA) with six of these detected only in urine and four solely in bile. 19F-NMR revealed the presence of the parent compound and 15 metabolites in urine collected during the first 24?h after -dosing. The matrix effects of bile on 19F-NMR spectroscopy made metabolite profiling impractical for this biofluid. The major metabolite of 3-FA was identified as 2-fluoro-4-acetamidophenol-sulfate. 相似文献
17.
Summary In a comparative study the neuronal and extraneuronal metabolism of several 3H-catecholamines (all of which were tritiated in the C-7 position of the side chain only) was determined in isolated rat hearts perfused at a concentration of the 3H-amines of 50 nmol/1. While the neuronal MAO activity was determined after inhibition of extraneuronal uptake (100 mol/1 OMI) and COMT (10 mol/1 U-0521), the extraneuronal MAO activity was estimated after inhibition of neuronal uptake (30 mol/1 cocaine) and COMT. The extraneuronal COMT activity was determined under conditions of inhibition of both neuronal uptake and MAO (pretreatment with pargyline). Hearts were perfused with the 3H-catecholamines until the rate of appearance of the various 3H-metabolites in the venous effluent has reached a steady state. From these rates ( v
st-st) and the steady-state content of the unchanged 3H-catecholamines in the tissue ( S
i), the rate constants ( V
max/ K
m) for the unsaturated intracellular enzymes COMT ( COMT) and MAO ( MAO) were calculated. The COMTvalues for all four catecholamines, (–)-noradrenaline, dopamine, (–)-adrenaline and (±)-isoprenaline exhibit a range from 0.24 to 0.78 min –1; the metabolism of the catecholamines by the COMT differs: (-)-noradrenaline = dopamine < (–)-adrenaline < (±)-isoprenaline. The extraneuronal MAO activity was low for all three catecholamines, (–)-adrenaline, (–)-noradrenaline and dopamine (range of MAOfrom 0.05 to 0.28 min –1) and declined in the order: (–)-adrenaline < (–)-noradrenaline < dopamine. The neuronal MAO activity for (–)-adrenaline, (–)-noradrenaline and dopamine was slightly higher than that in the extraneuronal cells (range of kMAO from 0.08 to 0.35 min –1), but the ranking order showed the same pattern: (–)-adrenaline < (–)-noradrenaline = dopamine.Abbreviations MAO
monoamine oxidase
- COMT
catechol-Omethyltransferase
- NMN
normetanephrine
- MN
metanephrine
- MT
3-methoxytyramine
- OMI
3-O-methyl-isoprenaline
- DOPEG
dihydroxyphenylglycol
- DOPET
dihydroxyphenylethanol
- DOMA
dihydroxymandelic acid
- DOPAC
dihydroxyphenylacetic acid
- U-0521
3,4-dihydroxy-2-methyl propiophenone 相似文献
18.
Summary To support the increasing use of intravenous -blockers during cardiovascular emergency and surgery, dose proportionality of pharmacokinetics of nadolol was evaluated after intravenous administration of 14C-nadolol at doses of 1, 2 and 4 mg to nine healthy volunteers. There were no observed differences in the excretion or the pharmacokinetics of nadolol with respect to the dose administered. Over a 72-h period after drug administration, an average of about 60% of the dose was excreted in the urine and about 15% was excreted in the feces. The range of values for total body clearance (219 to 250 ml·min –1), renal clearance (131 to 150 ml·min –1), mean residence time (10.5 to 11.3 h), half-life (8.8 to 9.4 h), and steady-state volume of distribution (V ss) (147 to 157 l) indicated that nadolol was extensively distributed and slowly cleared from the body. There was a linear correlation ( r
2=0.97) between the area under the plasma concentration of nadolol versus time curve (AUC) and the dose. All pharmacokinetics parameters, except V ss, were slightly, but significantly, different at the 4 mg dose. Superposition of the dose-normalized average concentrations indicated that despite these minor differences in parameters, the pharmacokinetic behavior of nadolol was linear with respect to dose. Urinary excretion of nadolol was dose independent. 相似文献
19.
The purpose of this investigation was to explore theoretically certain strategies for optimizing the therapeutic index of drugs and to assess these strategies experimentally with two diuretics. Diuretic agents allow dosing rate flexibilities because the temporal profile of diuretic action can vary considerably as long as the total diuretic effect per day is the same. They can also be used in combination. Experiments were designed to determine if the therapeutic index of furosemide and hydrochlorothiazide can be optimized by administering one or the other at a certain rate or by administering the two drugs together in a certain ratio and at a certain rate. Male Lewis rats received one or the other drug, or combinations of the two, by i.v. infusion at different rates. Several timed urine collections were made under steady-state conditions, with excreted urine replaced volume for volume by i.v. lactated Ringer's solution. The urine flow rates and the urinary excretion rates of the diuretics and of Na + and K + were determined. The relationship between the diuretic effect of either of the two drugs given alone and the respective drug excretion rate could be described by the Hill equation. The ratio of urine flow rate to K + excretion rate exhibited a marked dependence on hydrochlorothiazide excretion rate (highest ratio at high excretion rates), whereas the K +/Na + excretion rate ratio was constant over a wide range of hydrochlorothiazide excretion rates. There was no significant change of these ratios with changing excretion rate of furosemide. Infusion of the two diuretics in combination of different ratios and at different combined rates under steady-state conditions revealed proportionality between the urinary excretion rates of Na + and urine over a wide range and a decreasing K + /urine excretion rate ratio with increasing urine flow rate. Hence, a favorable increase in the Na +/K + excretion rate ratio was attained with increasing urine flow rate. These experiments and computer simulations demonstrate in principle the feasibility of optimizing the therapeutic index by appropriate selection of a drug's dosing rate or by dosing a combination of two drugs at an appropriate ratio and rate. 相似文献
20.
Four rats were trained to barpress for water reinforcement under a variable interval 60 sec schedule. Nine acute administrations of (–)
9- trans-tetrahydrocannabinol, in amounts ranging from 0.25 to 16.0 mg/kg, produced dose-related effects on responding; overall response rate increased at lower doses, while higher doses produced ataxia and a complete suppression of responding. Increased response rates reflected changes both in response spacing and in the lengths of post-reinforcement pauses. It was concluded that marihuana has a biphasic effect on variable interval water-reinforced behavior in rats.The authors thank Reid Vandell for his assistance in collecting the data. Research supported by National Institute of Mental Health Grant MH20363-01 to D. P. Ferraro. Synthetic
9-THC obtained by approval of the FDA-NIMH Psychotomimetic Agents Advisory Committee. The animals involved in this study were maintained in accordance with Guide for Laboratory Animal Facilities and Care as published by the National Academy of Sciences-National Research Council. 相似文献
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