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DRUG INTERACTIONS |
From AstraZeneca R&D Södertälje, Södertälje, Sweden (Dr Strid); AstraZeneca R&D Södertälje, Medical Neuroscience, Södertälje, Sweden (Dr Nilsson); Borgå PK Consulting, S-211 16 Malmö, Sweden (Dr Borgå); Xendo Drug Development Services, Groningen, the Netherlands (Dr Wemer); and Quintiles AB, S-753 23 Uppsala, Sweden (Professor Grahnén).
Address for reprints: Stig Strid, PhD, AstraZeneca R&D, Södertälje, SE-151 85, Södertälje, Sweden; e-mail: stig.strid{at}astrazeneca.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Acute ischemic stroke • furosemide • neuroprotectant • NXY-059 • pharmacodynamics • pharmacokinetics
Neuroprotection offers an alternative strategy for the treatment of acute ischemic stroke. Neuroprotective agents are postulated to preserve viable brain cells in the ischemic penumbra, an area of compromised tissue surrounding the ischemic core, thereby reducing the area of infarction and improving patient outcome. NXY-059 is a novel, free radical-trapping neuroprotectant, and preclinical studies have shown that it reduces infarct size5,6 and preserves brain function in animal models of acute ischemic stroke.7-9 NXY-059 is currently being evaluated in the Stroke Acute Ischemic NXY-059 Treatment (SAINT) clinical trial program, which comprises 2 large placebo-controlled phase III trials (SAINT I and SAINT II). These studies are designed to assess the efficacy of a continuous 72-hour intravenous NXY-059 infusion (including an initial 1-hour loading infusion, which was 3 times the maintenance infusion rate) on disability and neurologic recovery and to evaluate safety when administered to patients within 6 hours of onset of acute ischemic stroke. Results from SAINT I have demonstrated a reduction in global disability as measured by the modified Rankin Scale after 90 days.10 In addition, patients randomized to receive NXY-059 had a reduced incidence of hemorrhagic transformation subsequent to rt-PA administration. Treatment with NXY-059 was well tolerated with an overall safety profile not different from placebo.
After a single dose, the distribution phase of NXY-059 had a half-life of approximately 1 hour in healthy young and elderly subjects.11 NXY-059 is renally eliminated unchanged, and the mean terminal elimination half-life was 2.6 hours in young subjects and 3.9 hours in elderly subjects.11 A study in subjects with renal impairment demonstrated a strong correlation between total plasma clearance and glomerular filtration rate (GFR) (r2 = .93).12 The absence of a positive intercept for GFR equal to zero indicated that virtually all elimination of NXY-059 occurs renally.12 In both young and elderly healthy subjects, renal clearance (CLR) due to active tubular secretion was approximately 30% of the overall CLR.11 A recent phase I study has demonstrated that the active tubular secretion of NXY-059 is blocked by oral pretreatment with probenecid,13 a drug that is known to block the active renal secretion of many acidic drugs, for example, furosemide.14 The fact that the renal excretion of the 2 drugs is affected by probenecid suggests that they may be sharing the same excretion pathway.
Cardiac insufficiency and hypertension are common comorbidities requiring treatment in patients who have experienced an acute ischemic stroke and are often managed with diuretic therapy. Furosemide is a commonly prescribed diuretic in these patients and is secreted actively by an organic anion transporter, a pathway that can be inhibited by simultaneous treatment with probenecid.14 Furosemide exerts its diuretic action from the luminal side of the nephron, where it blocks the reuptake of sodium ions in the ascending loop of Henle.15 Thus, the higher the furosemide concentration in the urine, the higher the saluretic and diuretic effects. An interacting drug that inhibits the renal elimination of furosemide may therefore acutely diminish the effect of furosemide as amply demonstrated by the interaction with probenecid.13
However, it is of greater interest to look at the overall diuretic or saluretic effect of furosemide, for example, milliliter of urine per microgram of furosemide or millimolar of sodium per microgram of furosemide, a parameter called the overall efficiency of the drug. Thus, the efficiency of furosemide actually increased from 0.23 mL/µg to 0.44 mL/µg when a bolus dose of furosemide was combined with probenecid.14 Furthermore, an increased efficiency was noted when furosemide was given as an infusion instead of as a bolus. The authors concluded that slowing the rate of delivery of furosemide to its site of action, either by administration by constant infusion or by combining it with probenecid, increased the efficiency of the drug.14
When the elimination of furosemide is slowed down and consequently the elimination of furosemide gets more prolonged, then the curve describing the concentration of urinary furosemide will stay within a region of concentration close to that of maximum efficiency over a longer time period than during normal conditions. Hence, the efficiency of a bolus dose of furosemide was considerably increased in the presence of probenecid.14
It is possible that a pharmacokinetic interaction between NXY-059 and furosemide would have pharmacodynamic consequences similar to those described. The present study was designed to investigate this possibility and especially to investigate any risk of reduced saluretic and diuretic effects due to a possible pharmacokinetic interaction.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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During the study days at the clinic, all meals (breakfast, lunch, dinner, and snacks) and drinks were standardized with a strict control of sodium, potassium, and volume of fluids. Intake of acetyl salicylic acid and caffeine-containing beverages was not allowed. Exercise outside normal daily or weekly amounts for the individual subject was not allowed, otherwise no physical constraint was imposed on the subjects. During the intensive periods of measurements and sampling, the subjects stayed in bed. The study was approved by the Independent Ethical Committee at Faculty of Medicine, Uppsala University, Uppsala, Sweden.
Subjects
The study enrolled 24 (13 male and 11 female) healthy volunteers aged between 18 and 45 years. There were no significant differences in baseline demographics between subjects randomized to the 2 treatment sequences. Twenty-two subjects completed the study and were eligible for pharmacokinetic and pharmacodynamic assessments.
Drug Treatment
NXY-059 solution for infusion (15 mg/mL) was prepared by diluting the NXY-059 concentrate (400 mg/mL) in 500 mL of commercially available sodium chloride (9 mg/mL). The prepared solution was protected from light and used within 24 hours of preparation. The infusion rate of the loading dose was 3 times the maintenance dose. The mean loading dose range was 2753 to 3433 mg/h for the loading dose and 915 to 1142 mg/h for the maintenance dose. The dose chosen was based on a previous study to achieve the intended therapeutic plasma concentration of NXY-059.16 Placebo was identical to the phosphate-buffered NXY-059 infusion with the exception of the active substance. Commercially available furosemide solution for injection (Impugan, Alpharma AS, Lierskogen, Norway; 10 mg/mL) was given as a 30-mg intravenous bolus dose.
Pharmacokinetic and Pharmacodynamic Analyses
Blood Sampling for Pharmacokinetic Analysis
Blood sampling (5 mL) for plasma analysis of NXY-059 was performed immediately before the start of infusion and then after 1, 3, and 5 hours (that is, before the furosemide dose) and then 6 hours 10 minutes, 6.5 hours, 6 hours 50 minutes, 7 hours 10 minutes, 7.5 hours, 7 hours 50 minutes, 8.5 hours, 9.5 hours, and 11.5 hours after start of the NXY-059 infusion.
For furosemide analysis, samples were also taken immediately before NXY-059 infusion and then after the 30-mg bolus dose of furosemide at 6 hours 10 minutes, 6.5 hours, 6 hours 50 minutes, 7 hours 10 minutes, 7.5 hours, 7 hours and 50 minutes, 8.5 hours, 9.5 hours, and 11.5 hours after start of the NXY-059/placebo infusion. Mean unbound fractions of NXY-059 were determined by analysis of extra blood samples taken at 5, 7.17, and 11.5 hours after start of infusion during each treatment period.
Blood samples for NXY-059 and furosemide measurement were collected into heparinized vacuum tubes (Terumo Venoject, Terumo Medical Corp, Tokyo, Japan) from the arm not used for infusion of the investigational product. Blood samples were centrifuged within 45 minutes at 2000g to 2500g for 15 minutes. The plasma was transferred into storage tubes (Nunc CryoTube, 3.6 mL; Nunc A/S, Roskilde, Denmark) and immediately frozen at -20°C, protected from light.
Urine Sampling for Pharmacokinetic and Pharmacodynamic Analyses
Urine samples for NXY-059, furosemide, and sodium analysis were collected immediately before NXY-059/placebo infusion, between 0 and 2 hours, 2 and 4 hours, 4 and 6 hours (before furosemide dose), and then 6 hours and 6 hours 20 minutes, 6 hours 20 minutes and 6 hours 40 minutes, 6 hours 40 minutes and 7 hours, 7 hours and 7 hours 20 minutes, 7 hours 20 minutes and 7 hours 40 minutes, 7 hours 40 minutes and 8 hours, 8 and 9 hours, 9 and 10 hours, 10 and 11 hours, and 11 and 12 hours after start of the NXY-059/placebo infusion.
The samples were divided into 10-mL aliquots for analysis of NXY-059 (1 aliquot), furosemide (2 aliquots), and sodium (1 aliquot). An oral rehydration fluid (Pripps Sport Fluid, Carlsberg Sverige AB, Stockholm, Sweden) was administered to compensate for the voided urine, by isovolumetric replacement. Dark-colored collection containers were used (to prevent breakdown of NXY-059 from light). Aliquots were transferred into storage tubes (3.6 mL) and then frozen at -70°C.
Pharmacokinetic Evaluation
Analysis of Plasma and Urine Data for NXY-059
The total plasma concentration, amount excreted unchanged in the urine (Ae), excretion rate (µmol/min), and CLR of NXY-059 in each interval were determined. CLR was defined as the excretion rate for each urine collection interval divided by the plasma concentration in the middle of the collection interval. The CLR of NXY-059 before and after the furosemide dose was assessed by comparing the mean CLR between 4 and 6 hours with the mean CLR between 6 and 8 hours. The CLR of furosemide in the presence and absence of NXY-059 was assessed by comparing the mean CLR between 6 and 12 hours.
The fraction unbound (fu) of NXY-059 in plasma was calculated from the ratio between ultrafiltrate concentration and total plasma concentration. The unbound plasma concentration was calculated as fu x total plasma concentration.
Analysis of Plasma and Urine Data for Furosemide
For furosemide, the plasma concentration, the Ae, excretion rate (µmol/min), and the CLR were determined. CLR was defined as the excretion rate of furosemide for each urine collection interval divided by its plasma concentration at the middle of the collection interval.
Pharmacodynamic Evaluation
Analysis of Urine Volume and Urine Content of Sodium
The urine concentration, Ae (mmol/L excreted), and the excretion rate (µmol/min) of sodium in each interval were determined. The following variables were calculated:
Saluretic response was evaluated as sodium excretion rate and total Ae for the 6-hour interval.
Saluretic efficiency of furosemide (mmol/L sodium per µg furosemide) was evaluated as the net saluretic response over 6 hours/Ae of furosemide.
Diuretic response was evaluated as the excretion rate (mL/min) and the total volume excreted for the 6-hour interval.
Diuretic efficiency of furosemide (mL urine per µg furosemide) was evaluated as net diuretic response over 6 hours/Ae of furosemide over 6 hours.
Analysis of Drug Concentrations in Plasma and Urine
Concentrations of NXY-059 in plasma and urine were analyzed by Analytical Services, Quintiles AB, Uppsala, Sweden, using column-switching highperformance liquid chromatography (HPLC) with an external standard. The ultraviolet absorbance of NXY-059 at 299 nm was used to detect and quantify the substance. The limit of quantification (LOQ) was 0.04 µmol/L, with a coefficient of variation (CV) of 9.0% for the concentration of 0.4 µmol/L and <0.9% in the concentration range 175 to 750 µmol/L for plasma samples, and 1.6 µmol/L with a CV <4.1% in the concentration range 5 to 2000 µmol/L for urine samples. Unbound concentrations of NXY-059 in the blood were determined by ultrafiltration (LOQ = 1.0 µmol/L, with a CV <2.6% in the concentration range 51-339 µmol/L).
Concentrations of furosemide in plasma and urine were determined by Analytical Services, Quintiles AB, Uppsala, Sweden, using HPLC with fluorescence detection. The LOQ was 0.04 µmol/L, with a CV <11.2% in the concentration range 0.075 to 6.0 µmol/L for plasma samples. For urine samples, the LOQ was 0.18 µmol/L, with a CV <8.7% in the concentration range 0.35 to 22.5 µmol/L.
Concentrations of sodium in urine were determined using a sodium ion-selective electrode in a closed electrochemical cell, whereby the electric potential is proportional to the logarithm of the concentration of sodium in the sample. The measuring range was 10 to 176 mmol/L, with a CV <1.2% in the concentration range 124 to 161 mmol/L.
Safety and Tolerability
Physical examination, 12-lead electrocardiogram (ECG), vital signs, and laboratory measurements were performed throughout the study. Adverse events were reported throughout the study by subjects or from nonspecific questioning by investigators. Study staff recorded the onset, resolution, and intensity of the events. Adverse events were recorded within 2 hours before the start of infusion (baseline), 12 hours after the start of infusion, and at follow-up visits 4 to 7 days after the last infusion.
Statistical Analysis
The total urine volume and content of sodium before and after the furosemide dose were compared. The saluretic and diuretic responses were analyzed in a multiplicative 2 x 2 crossover model with lognormal residuals and fixed effect factors for treatment (NXY-059 or placebo), period, furosemide (before and after administration), and sequence and a random effect of subject within sequence. The treatment effect was evaluated using a noninferiority approach facilitated by using a symmetric 2-sided 90% confidence interval (CI) for the treatment ratio. For the amount of excreted sodium, a CI located entirely above 0.7 was interpreted as evidence of absence of relevant treatment effect, and noninferiority was concluded. No correction for multiple comparisons was made for any analysis. The mean values for the CLR of NXY-059 were analyzed by a multiplicative model with lognormal residuals and having fixed effect factors of furosemide (before and after furosemide administration) and sequence and a random effect of subject within sequence. The mean values for CLR of furosemide were analyzed in a multiplicative model with fixed effects for period, treatment (placebo or NXY-059), and sequence and a random effect of subject within sequence.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetic Analyses
The mean total plasma concentration of NXY-059 at 5 hours (1 hour before the dose of furosemide) was 538 µmol/L, and the mean unbound concentration of NXY-059 was 341 µmol/L. Treatment with furosemide at 6 hours caused a small, transient increase in the plasma concentration of NXY-059, which reached its maximum mean total concentration, 622 µmol/L, 70 minutes after administration of furosemide.
The unbound fraction of NXY-059 averaged 0.63 at 5 hours (that is, before furosemide administration). Mean values of 0.60 and 0.61 were found at 7.17 and 11.5 hours, respectively. Administration of furosemide significantly reduced the CLR of NXY-059 to 91.6% (95% CI, 86.3%-97.1%; Figure 2), compared with clearance before the furosemide dose. Similarly, the CLR of furosemide was significantly attenuated during treatment with NXY-059 to 81.0%, compared with placebo (95% CI, 68.2%-96.2%; Figure 3). Therefore, the 19% reduction in CLR should be equivalent to a corresponding increase in area under the concentration-time curve (AUC) and half-life, but the diuretic and saluretic effects are not related to AUC.
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Pharmacodynamic Analyses
The mean urine volumes collected during the first 6 hours were 803 mL for the NXY-059 arm and 881 mL for the placebo arm. After the 30-mg bolus dose of furosemide, the mean urine volume increased to 5142 mL and 5026 mL during the following 6 hours, respectively. Furosemide therefore increased urine volume by 4340 mL during infusion of NXY-059 and by 4150 mL during infusion of placebo.
The mean urine content of sodium collected during the first 6 hours was 87.8 mmol/L for the NXY-059 arm and 61.2 mmol/L for the placebo arm. After the bolus dose of furosemide, the urine content of sodium increased to 265.7 mmol/L for NXY-059 and to 250.8 mmol/L for placebo during the following 6 hours. Thus, furosemide increased sodium excretion by 178 mmol/L during infusion of NXY-059 and 190 mmol/L during infusion of placebo. There were no significant differences between treatment groups in the effects of furosemide on saluresis (95% CI, 0.89-1.26; Figure 4) or diuresis (95% CI, 0.83-1.23; Figure 5). The analysis plan stated that a CI entirely above 0.7 was interpreted as evidence of absence or relevance of treatment effect.
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The saluretic efficiency of furosemide was not affected by treatment with NXY-059, nor was the diuretic efficiency. In the presence of NXY-059, the mean saluretic activity was 0.010 mmol/µg (SD, 0.003), which was not different from the value in the presence of placebo, 0.010 mmol/µg (SD, 0.002). In the presence of NXY-059, the mean diuretic efficiency was 0.243 mL/µg (SD, 0.049), which was similar to the value in the presence of placebo, 0.221 mL/µg (SD, 0.049).
Safety and Tolerability
Twelve subjects experienced a combined total of 33 adverse events of mild to moderate intensity. Adverse events occurred before, during, between, and after the 2 infusion periods. If a subject experienced the same adverse events more than once, this was counted as a single event, which resulted in 23 unique adverse events (Table I).
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Seven subjects had in total 7 unique adverse events during the NXY-059 12-hour infusion period, and in addition, 1 subject had 1 adverse event during the 36-hour time period after infusion (Table II). The most significant adverse events occurring during treatment with NXY-059 were moderate abdominal pain and vomiting, each occurring in 1 subject. Three subjects had in total 8 unique adverse events during the placebo 12-hour infusion period, and 1 subject had 1 adverse event during the 36-hour time period after infusion (Table II). Two subjects discontinued because of adverse events occurring during placebo administration. Of these, 1 suffered urinary retention after furosemide treatment, which was judged to be a serious adverse event, and another suffered a migraine attack (headache, nausea, and vomiting).
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All adverse events were resolved on their own with the exception of the urinary retention whereby a catheter was inserted temporarily to remove the urine. No additional interventions were necessary.
The physical examination observations, ECG, and vital signs were all judged to be normal. Although variations were observed in laboratory assessments, these findings were not clinically significant.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Preliminary estimates have indicated that approximately 30% of the renal elimination of NXY-059 may be due to active tubular secretion.11 Because active tubular secretion of NXY-059 is mediated by a secretion process sensitive to probenecid,13 there is a possibility that it uses the same transporter as furosemide, which is also probenecid sensitive.14 Data in the present study show that the 2 drugs reduce the clearance of each other, which is likely because of competition for the same transporter. However, the magnitude of the interaction was small and without clinical relevance, as the diuretic and saluretic properties were unaltered. The saluretic efficiency of furosemide with and without NXY-059 was 0.01 mmol/µg, which is similar to the 0.009 mmol/µg previously reported after a 30-mg bolus dose of furosemide.14 Also, the present diuretic efficiency values in the present study are similar to those of the previous report, 0.23 mL/min.14 In contrast, the same study demonstrated that simultaneous treatment with probenecid 2g increased the saluretic efficiency to 0.015 mmol/µg and the diuretic response to 0.44 mL/µg.14
The lack of a clinically relevant interaction between NXY-059 and furosemide in the present study is an important finding, as patients who have had a stroke may also receive furosemide for the treatment of heart failure or hypertension. The mean total plasma concentration of NXY-059 in the present study was 538 µmol/L and the mean unbound plasma concentration was 341 µmol/L. These values are in the upper range of concentrations observed when using the intended therapeutic dose.10 The plasma concentrations at 6 hours are similar to those at steady state. Therefore, it is possible to theoretically extrapolate the present results to the clinic, bearing in mind the limitations associated with data obtained from healthy volunteers compared with the more complex situation when treating a patient. In addition, no safety concerns were highlighted during this study, and all adverse events in the NXY-059 treated group were of mild or moderate intensity. NXY-059 had no clinically significant effect on vital signs, ECG, or laboratory assessments in healthy volunteers.
In conclusion, these findings suggest that NXY-059 does not significantly interact with or alter the saluretic and diuretic effects of furosemide to any degree of clinical importance, which is an essential consideration for the potential treatment population for this novel neuroprotectant. The results suggest that no dose adjustment of furosemide is necessary when used concomitantly with NXY-059.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. World Health Organization. The World Health Report 2004. Geneva, Switzerland: The World Health Organization; 2004.
2. American Heart Association. Heart Disease and Stroke Statistics: 2006 Update. Dallas, Tex: American Heart Association; 2006.
3. NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333: 1581-1587.
4. Furlan AJ, Katzan IL, Caplan LR. Thrombolytic therapy in acute ischemic stroke. Curr Treat Options Cardiovasc Med. 2003;5: 171-180.[Medline] [Order article via Infotrieve]
5. Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjö BK. Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 1999;19: 778-787.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Sydserff SG, Borelli AR, Green AR, Cross AJ. Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window. Br J Pharmacol. 2002;135: 103-112.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Marshall JW, Duffin KJ, Green AR, Ridley RM. NXY-059, a free radical-trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke. 2001;32: 190-198.
8. Marshall JWB, Cummings RM, Bowes LJ, Ridley RM, Green AR. Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke. 2003;34: 2228-2233.
9. Wang CX, Shuaib A. NXY-059: a neuroprotective agent in acute stroke. Int J Clin Pract. 2004;58: 964-969.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Lees KR, Zivin JA, Ashwood T, et al: NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354: 588-600.
11. Edenius C, Strid S, Borga O, Breitholtz-Emanuelsson A, Vallen KL, Fransson B. Pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent, in healthy young and elderly subjects. J Stroke Cerebrovasc Dis. 2002;11: 34-43.[Medline] [Order article via Infotrieve]
12. Strid S, Borga O, Edenius C, Jostell KG, Odergren T, Weil A. Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based, free-radical trapping agent developed for the treatment of acute stroke. Eur J Clin Pharmacol. 2002;58: 409-415.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Cheng Y-F, Strid S, Borga O, Nilsson D, Wemer J. Effects of cimetidine and probenecid on renal clearance of NXY-059, a novel neuroprotectant: a phase I study to determine the transporter responsible for active secretion. Clin Pharmacol Ther. 2006;79: 72.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Wakelkamp M, Alvan G, Paintaud G. Natriuretic efficiency of frusemide as a consequence of drug input rate. Br J Clin Pharmacol. 1997;43: 481-491.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Burg M, Stoner L, Cardinal J, Green N. Furosemide effect on isolated perfused tubules. Am J Physiol. 1973;225: 119-124.
16. Werner J, Cheng Y-F, Nilsson D, et al. Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects. Curr Med Res Opin. 2006;22: 1813-1823.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16: 31-41.[Web of Science][Medline]
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