Selecting an equation to estimate glomerular filtration rate for use in renal dosage adjustment of drugs in electronic patient record systems

STUDY OBJECTIVE: To identify a variant of the Cockcroft-Gault equation whose estimate would agree with the Modification of Diet in Renal Disease (MDRD) estimate of glomerular filtration rate (GFR) since the MDRD equation may not be programmable in some electronic patient record systems. DESIGN: Prospective case series. SETTING: A 625-bed, adults-only, private, tertiary care teaching hospital. PATIENTS: Two hundred eight consecutive hospitalized patients with MDRD-estimated GFRs less than 90 ml/minute/1.73 m 2 . Seventeen patients were black (includes native African immigrants). INTERVENTION: Chemistry assays were performed, and patients' records were reviewed for age, ethnic background, height, and actual weight. Ideal weight, corrected weight, body mass index, body surface area (BSA), and GFR by the original MDRD equation were calculated for each patient. MEASUREMENTS AND MAIN RESULTS: Cockcroft-Gault estimates of renal clearance were calculated by using actual weight, ideal weight, and corrected weight both with and without correction for BSA. These estimates, as well as an estimate of GFR by the abbreviated MDRD equation, were compared with the original MDRD estimate. The results obtained with the abbreviated MDRD equation and with the Cockcroft-Gault equation that used corrected weight and BSA adjustment had the best agreement; both were within +/- 30% of the original MDRD equation in 80% of the 208 patients' results. All other Cockcroft-Gault variants tested were less accurate. CONCLUSION: Electronic patient record databases may not contain a nominal variable database field for black or non-black status, which is required by the MDRD equations. The Cockcroft-Gault equation that used corrected weight and BSA adjustment performed about as well as the abbreviated MDRD equation and can be programmed into electronic patient records. Given the small number of black patients included in this study, further study in this patient population is recommended before applying this Cockcroft-Gault variant to this subgroup.     

Comparison of dosing recommendations for antimicrobial drugs based on two methods for assessing kidney function: cockcroft-gault and modification of diet in renal disease

STUDY OBJECTIVES: To quantify the difference between glomerular filtration rates (GFRs) estimated by using the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations, and to determine whether dosing recommendations for four commonly prescribed antimicrobial agents are discordant when determined by using these equations. DESIGN: Prospective, observational study. SETTING: Tertiary-care medical center. PATIENTS: Two hundred seven consecutive adults without normal renal function but not receiving dialysis who were admitted to a non-intensive-care ward and had two consecutive serum creatinine concentration (S(cr)) values measured 20-24 hours apart. MEASUREMENTS AND MAIN RESULTS: The patients' mean +/- SD S(cr) was 1.41 +/- 0.95 mg/dl. Kidney function was estimated by using two versions of the four-variable MDRD equation and four versions of the Cockcroft-Gault equation. Mean estimated GFRs ranged from 52.3-73.1 ml/minute. Dosing for cefepime, levofloxacin, meropenem, and piperacillin-tazobactam was determined using the two equations that had the highest level of correlation; these were the MDRD equation unadjusted for body surface area and the Cockcroft-Gault equation adjusted for ideal body weight and S(cr). When the total daily doses based on these two equations for the four antimicrobials were compared, the discordance rate was 22.8-36.3%, and statistically significant differences were observed for most of the discordant doses. When discordance was present, the MDRD equation resulted in a higher dose of the drug. CONCLUSION: Discordance rates for drug dosing ranged from 22.8-36.3% between the MDRD and Cockcroft-Gault methods for estimating GFR. Although use of the MDRD equation is a well-accepted and accurate method of estimating GFR to stage chronic kidney disease, our results demonstrated a significant difference in drug dosing regimens between the MDRD method and the Cockcroft-Gault method.     

肾动脉阻力指数和搏动指数对移植肾功能的预测作用

目的运用彩色多普勒超声早期测量肾动脉和叶间动脉的阻力指数和搏动指数,观察两者能否预测无明显并发症同种异体肾移植患者术后1年的肾功能。方法对100例无并发症肾移植患者,应用彩色多普勒超声,于肾移植术后1周内,测量移植肾肾动脉和叶间动脉的阻力指数和搏动指数,并与术后1年的移植肾肾小球滤过率(GFR)进行相关分析。结果术后1周测得的肾动脉的阻力指数和搏动指数与术后1年的GFR无明显的相关关系;叶间动脉的阻力指数和搏动指数与术后1年的GFR呈明显的负相关,叶间动脉阻力指数和(或)搏动指数升高,移植后1年肾功能下降,如果叶间动脉阻力指数≥0.7或者搏动指数≥1.2,移植后1年肾功能有明显的下降。结论早期多普勒彩超测量叶间动脉的阻力指数和搏动指数能够预测无明显并发症的移植肾的术后1年肾功能。     

血清胱抑素-C和肾小球滤过方程在慢性肾脏病患者临床应用的实用性探讨

目的探讨血清胱抑素-C（Cys-C）和各种肾小球滤过方程在诊断慢性肾脏病（CKD）患者中的临床意义。方法双血浆法^99mTc-DTPA清除率测定肾小球滤过率（rGFR）作为标准,MDRD方程7、简化MDRD方程、简化改良MDRD方程、Cockcroft-Gault公式计算的GFR及Cys-C与^99mTc-DTPA清除率测定肾小球滤过率做比较,观察它们的相关性。结果在CKD1、2期,简化的MDRD方程和Cockcroft-Gault公式明显低估了GFR,简化的MDRD方程低估GFR的程度高于Cockcroft-Gault公式;改良简化MDRD方程,其相关系数为0.812、0.867,显示了改良简化MDRD方程评估CKD患者早期肾功能的变化具有优势;在CKD3期,改良简化MDRD方程与rGFR比较,其相关性最强。在CKD4、5期,各种方程均能很好地评估GFR。结论肾功能轻中度损害时,使用改良简化MDRD方程和Cystatin-C预测肾小球滤过率,肾功能重度损害时,可以根据当地医院的条件选用目前的各种方程评估GFR。     

Pharmacokinetics of digoxin-specific Fab: effects of decreased renal function and age

Aims To study the influence of age and renal function on digoxin-specific Fab (DS-Fab) pharmacokinetics.
Methods Sixteen patients (35–91 years) with creatinine clearance ranging from 10.6 to 122.1  ml  min⁻¹ who had been admitted to hospital with severe digoxin or digitoxin self-poisoning were treated with DS-Fab (80 to 800  mg). Plasma DS-Fab concentrations were determined by radioimmunoassay.
Results The mean (±s.d.) distribution and elimination half-lives, apparent volume of distribution and total body clearance were 1.1±0.4  h, 20.2±7.3  h, 13.1±5.8  l, and 17.6±10.8  ml  min⁻¹ , respectively. Interindividual variability of DS-Fab total body clearance was linked linearly with the decrease in creatinine clearance or with the increase in age and DS-Fab distribution volume was not dependent on creatinine clearance or age.
Conclusions The data suggest that DS-Fab should be given to elderly and renal-impaired patients at doses similar to those given to younger or normal renal function patients.     

(−)-Timolol is a more potent antagonist of the positive inotropic effects of (−)-adrenaline than of those of (−)-noradrenaline in human atrium

1 The affinity of (−)-timolol for β₁- and β₂-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol were measured.
2 The antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol (0.1–100 nm) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93±0.09 for (−)-adrenaline, 0.97±0.09 for (−)-noradrenaline].
3 The inotropic effects of (−)-adrenaline were antagonized significantly more by each concentration of (−)-timolol than those of (−)-noradrenaline. K _B-values (-log m) were 10.10±0.09 against (−)-adrenaline and 9.43±0.07 against (−)-noradrenaline ( P <0.001).
4 Blocking kinetics of (−)-timolol for the β-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times K _B of (−)-timolol were approximately 30  min for both (−)-adrenaline and (−)-noradrenaline; offset times were similar.
5 It is concluded that (−)-timolol has a higher affinity for the β₂-adrenoceptor than for the β₁-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the β₂-adrenoceptor hypersensitivity induced by cardiac β₁-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug.     

Validation of estimated renal function measurements compared with the isotopic glomerular filtration rate in an HIV-infected cohort

We performed a cross-sectional study to determine the best method for estimating the glomerular filtration rate (GFR) in HIV-infected subjects. Isotopic GFR was correlated with 24-h urine creatinine clearance, cystatin C levels, and 3 creatinine-based equations-the Modification of Diet in Renal Disease (MDRD), Cockcroft-Gault (CG), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-in 15 patients. Cystatin C showed the strongest correlation with isotopic GFR (r=-0.760, p=0.001). When cystatin C was used as the reference variable for all 106 patients, CKD-EPI proved to be superior to the other equations (r=-0.671, p<0.001). Time with HIV infection, unsuppressed viral load, low CD4 T-cell counts, and use of protease inhibitors are related to an increased risk of renal impairment, leading us to recommend early initiation of antiretroviral therapy accompanied by a regular renal study.     

Impaired renal function and atherosclerosis in a Pakistani cohort

OBJECTIVE: To investigate the relationship of creatinine and calculated glomerular filtration rate (GFR) with coronary arterial disease (CAD) in Pakistani patients. SUBJECTS: Four hundred individuals with chest pain; 200 with angiographic disease matched with 200 without occlusive disease. DESIGN: A prospective case-control study. SETTING: A tertiary referral cardiology unit in Pakistan. RESULTS: Impaired renal function as estimated by calculated GFR was common in this population. Creatinine and glomerular filtration rate, as calculated by the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae, were associated with CAD and atherosclerotic burden in Pakistani patients. Calculation of creatinine clearance, correcting for age, sex and body mass index, showed that clearance was 81 (17-257) mL/min/1.73 m2 in patients with CAD compared with 88 (23-167) mL/min/1.73 m2 in controls with a significant number of patients (18.5 vs. 6.5%; RR = 2.85; p < 0.001) showing significant renal impairment (< 60 mL/min/1.73 m2) by CG and more by the MDRD equation (26 vs. 9%; RR = 2.88; p < 0.001). The unadjusted odds ratios for CAD for a GFR < 60 mL/min/1.73 m2 were 3.66 (1.87-7.16) and 3.29 (1.81-6.01), respectively and, after adjustment for diabetes, smoking, insulin resistance, inflammation and apolipoprotein A1, 1.04 (1.02-1.09) and 1.04 (1.02-1.09), respectively. CONCLUSIONS: Impaired renal function is common in Pakistani patients with coronary arterial disease and is strongly associated with a risk of atherosclerosis independent of insulin resistance.     

Measurement of glomerular filtration rate and effective renal plasma flow in the conscious beagle dog by single intravenous bolus of iohexol and p-aminohippuric acid.

The objective of this study was to validate a kinetic approach for the simultaneous measurement of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in the dog. Six healthy male Beagle dogs were randomly assigned in a three-period cross-over study of intravenous bolus administration of iohexol (64.7 mg/kg), PAH (10 mg/kg), and an iohexol/PAH mixture. PAH and iohexol were determined simultaneously by a validated high-performance liquid chromatographic method. The iohexol and PAH data obtained after intravenous administration were analyzed using noncompartmental and bicompartmental approaches. A simplified iohexol plasma clearance was also calculated from the terminal elimination phase of the plasma iohexol concentrations versus time profile. The total plasma clearance values for PAH and exo-iohexol were 13+/-2.3 mL/kg/min and 2.9+/-0.3 mL/kg/min, respectively. No significant (or biologically relevant) effect of coadministration of PAH and iohexol was observed on the pharmacokinetic parameters of either drug. The calculation of simplified plasma clearance led to an overestimation of the true plasma clearance. In conclusion, GFR and ERPF can easily and rapidly be measured in the dog by this approach which is relatively noninvasive.     

Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N-1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N-acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios (CL(ratio)) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA (CL(rNAPA)) was better predicted from the renal clearance of NMN (CL(rNMN)) than from GFR. A mathematical equation was also constructed to estimate the CL(rNMN) from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.     

Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function

1 The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function.
2 After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0±3.0, 11.1 ± 3.0, 8.7 ± 3.7 and 6.7 ± 2.1 l h^-1 (means ± s.d.) in patients with creatinine clearances (CL_cr) of > 100, 41-100, 21-40, and 8-20 ml min^-1, respectively.
3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CL_cr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CL_cr < 40ml min^-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups.
4 This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.     

Estimation of the initial dose setting of vancomycin therapy with use of cystatin C as a new marker of renal function

In recent years, it has been suggested that the glomerular filtration rate (GFR) can be predicted on the basis of serum cystatin C concentrations and that this measurement is more sensitive than serum creatinine concentration as a marker of renal function. In this study, to investigate the clinical utility of the initial dose setting of vancomycin by the population mean method with use of serum cystatin C as a marker of renal function, we compared the correlations between measured vancomycin concentrations and predicted vancomycin concentrations based on serum cystatin C or serum creatinine concentrations in elderly (>/=65 years old) and nonelderly (<65 years old) patients. An analysis of prediction accuracy (bias) and precision was evaluated by calculating the mean prediction error (ME), the mean absolute error (MAE), and the root mean squared prediction error (RMSE). For nonelderly patients (n = 50), there was no significant difference in the MAE based on the use of serum creatinine or serum cystatin C concentration. However, for elderly patients (n = 105), the MAE based on serum cystatin C concentration was significantly better than that based on serum creatinine level. These results suggest that serum cystatin C is a good marker of renal function in comparison with serum creatinine for dose setting of vancomycin, especially in an elderly population.     

Clinical trial: a randomized controlled cross-over study of flupenthixol + melitracen in functional dyspepsia

Background  Functional dyspepsia is a prevalent condition associated with diminished quality of life (QoL) and high economic burden.
Aim  To study the efficacy of a combination of flupenthixol and melitracen (F + M) with anxiolytic and antidepressant properties in functional dyspepsia using a randomized controlled cross-over design.
Methods  Patients met the Rome III criteria for functional dyspepsia and a validated questionnaire was used to exclude those with anxiety or depression. Moreover, patients had to have failed a trial of acid-suppressive therapy and Helicobacter pylori eradication when positive. End points included subjective global symptom relief and QoL assessed by the Nepean Dyspepsia Index (NDI).
Results  Twenty-five patients (14 females, 11 males; mean age = 34.3 ± 9.9 years) were enrolled and 24 completed the 8-week study. There was a significant improvement in subjective global symptom relief with F + M vs. placebo (ITT: 73.9% vs. 26.1%, P  = 0.001) and a significant drop in the NDI score vs. placebo (ITT: −9.0 ± 11.9 vs. −2.4 ± 8.9, P  = 0.03). No difference was noted whether the initial treatment was F + M or placebo. No significant side effects were noted.
Conclusions  A combination of F and M is safe and effective in the short-term treatment of functional dyspepsia. F + M is associated with significant improvement in QoL independent of the presence of anxiety or depression.     

Pharmacokinetics of the S(+) and R(−) enantiomers of vigabatrin during chronic dosing in a patient with renal failure

Aims To study the pharmacokinetics of vigabatrin in a patient affected with tuberous sclerosis who developed major agitation and aggression, while receiving vigabatrin orally (1.5  g every 12  h) and in whom impaired renal function was diagnosed.
Methods The patient received vigabatrin (0.5  g  day⁻¹ ). A pharmacokinetic study of the S(+) and R(−) enantiomers of vigabatrin was performed before and during dialysis. Plasma concentrations were measured at 0, 1, 2, 3, 4, 6, 12, 18 and 24  h by a specific GCMS assay.
Results Before dialysis, the maximum and minimun plasma concentrations of vigabatrin at steady-state were lower for the S(+) than for the R(−) enantiomer, while the apparent oral clearance was higher for the S(+) than for the R(−) enantiomer (2.97 vs 0.48 l  h⁻¹ ). In addition, the haemodialysis clearance was similar for the two enantiomers (4.96 vs 5.15 l  h⁻¹ ).
Conclusions Vigabatrin is an irreversible inhibitor of GABA-transaminase, effective in the treatment of drug-resistant epilepsy and reported to be eliminated unchanged by renal excretion. Although vigabatrin is known to have stereoselective kinetics, the difference in plasma dry concentrations and pharmacokinetics of the S(+) and R(−) enantiomers that we observed during long term administration at high doses in a patient with impaired renal function, has not been reported before. The question remains of the potential toxicity of the high levels of the R(−) enantiomer.     

Pharmacokinetic study of amphetamine elimination in dogs and swine

The kinetics of amphetamine elimination were studied in healthy and nephrectomized mongrel dogs and healthy swine. A similar dose of dl-amphetamine sulfate (0.66 mg/kg, free base) was administered intravenously to each animal. The drug concentration in the biological fluids was determined by a sensitive and specific gas Chromatographic method. Amphetamine was extracted from alkaline biologic fluid into cyclohexane. The trichloroacetamide derivative was prepared and detected by electron capture. The biological half-life of the drug (mean ± S.E.M.) was significantly shorter in swine (1.05 ± 0.05 hr) than in dogs (4.50 ± 0.24 hr) (Student's t-test, P < 0-001). This was believed to be due to the faster rate of biotransformation of the drug in swine. Diffusion equilibrium was attained rapidly in both species, and the apparent specific volumes of distribution were large. The disappearance of amphetamine from plasma and the appearance of unchanged drug in urine and bile were first-order processes. An appreciable amount of unchanged amphetamine was excreted in urine while the cumulative amount in bile was small. The renal clearance values in dogs (2.80–5.07 ml min⁻¹ kg⁻¹) provide evidence that amphetamine probably undergoes glomerular filtration and tubular reabsorption. Extent of reabsorption was pH dependent. Anaesthesia with pentobarbital sodium (ca. 28·5 mg/kg) did not affect overall clearance (9.18 ml min⁻¹ kg⁻¹) in intact dogs. The biological half-life of the drug (mean ± S.E.M.) was significantly longer in nephrectomized dogs (5.69 ± 0.20 hr) than in intact dogs (4.50 ± 0.24 hr) (Student's t-test, P < 0.001). Nephrectomy did not significantly change the extent of plasma protein binding or the apparent specific volume of distribution of the drug. The mean biliary clearance values (0.012 ml min⁻¹ kg⁻¹) were similar in intact and nephrectomized dogs. The renal clearance value, the per cent of dose excreted unchanged in urine and the highly significant increase in half-life after nephrectomy provide evidence that in the dog renal excretion is important in the elimination of amphetamine. However, despite the importance of renal excretion, biotransformation appears to play the major role in the elimination of this drug.     

Long-term effect of gluten restriction on bone mineral density of patients with coeliac disease

Aim : To assess the long-term effect of a gluten-free diet on bone mineral density of adults with untreated coeliac disease.
Methods : Bone mineral density was assessed at baseline and after a mean duration of 37 months of treatment in 25 unselected newly diagnosed coeliac patients.
Results : At baseline, osteopenia (>−1 s.d. below normal) was evident in the lumbar spine and total skeleton in 18 (72%) and 21 (84%) patients, respectively. At the end of the study, bone density had increased (mean bone mass Z -score increase: Z-score +1.0 for the lumbar spine and +1.1 for total skeleton) in 22 and 23 patients, respectively. Patients who adhered to strict gluten restriction ( n =15) demonstrated a similar bone remineralization in the spine than those patients with partial compliance ( n =10) (mean Z -score increase: +1.0, in both areas). A greater mean annual change in Z -score in the total skeleton was noted in patients who followed strict gluten restriction (0.4±0.1) respect to those with partial compliance (0.3±0.1); however, this difference was not statistically significant. Pre-menopausal women had significantly greater remineralization that post-menopausals ( P >0.05). Remineralization showed an inverse correlation with the degree of basal osteopenia ( r =−0.525; P <0.002).
Conclusions : Long-term treatment with gluten-free diet produces a significant improvement in bone density in coeliac patients. Remineralization was more pronounced in patients who better comply with gluten-free diet, in pre-menopausal women and in patients with the lowest baseline bone mineral density.     

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose

Aims To investigate the kinetics of the (+)RS- and (−)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.
Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250  mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.
Results A two-compartment model adequately described the disposition of (+)RS-MQ. CL/ F was 6.5±1.8 l  h⁻¹, V _ss/ F 815±165  l, and k 0.0081± 0.0023  h⁻¹. The kinetics of (−)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92±0.25 vs 2.14±0.63 l h⁻¹, 95% CI for the difference 0.86–1.60 l h⁻¹ ) and a longer half-life (345 vs 185  h, 95% CI for the difference 47–291  h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (−)SR-MQ was significantly correlated within subjects ( r =0.69, P <0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (−)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.
Conclusions The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.     

A practical guide to the management of hypertension in renal transplant recipients

Hypertension as well as hypotension can be harmful to a newly transplanted renal allograft. Elevated blood pressure is also a major risk factor for cardiovascular death, which is a frequent occurrence despite successful renal transplantation. Renal artery stenosis, immunosuppressive drugs, chronic rejection, retained native kidneys, and excessive extracellular fluid volume may all contribute to post-transplant hypertension. Antihypertensive agents are widely used in the management of post-transplant hypertension. Careful clinical judgement and knowledge of the pharmacology, pharmacodynamics, pharmacokinetics, adverse drug reaction profiles, potential contraindications, and drug-drug interactions of antihypertensive agents are important when therapy with antihypertensive drugs is initiated in renal transplant recipients. Since blood pressure elevation in any individual is determined by a large number of hormonal and neuronal systems, the effect of antihypertensive agents on the allograft should be considered a critical factor in the management of hypertension in renal transplant recipients. Most renal transplant recipients have other risk factors for premature cardiovascular death such as diabetes mellitus, hypercholesterolemia, insulin resistance, obesity, left ventricular hypertrophy and ischaemic heart disease. Initial antihypertensive therapy should be tailored individually according to the patient's risk factors. A realistic therapeutic goal for blood pressure management in the initial post-operative state is a systolic blood pressure <160 mm Hg and a diastolic blood pressure <90 mm Hg with lower pressure targets becoming applicable late post-transplantation.     

Unrecognized renal insufficiency and chemotherapy-associated adverse effects among breast cancer patients

Several studies have shown that more than half of cancer patients have unrecognized renal insufficiency (RI), which is a reduced glomerular filtration rate (GFR) with normal serum creatinine. The aim of this study was to determine whether unrecognized RI is associated with an increased risk for chemotherapy-associated adverse effects in breast cancer patients treated with combined doxorubicin and cyclophosphamide treatment. GFR was estimated for 95 breast cancer patients from January 2005 to August 2009 using the Cockcroft-Gault formula. Unrecognized RI was defined as GFR less than 75 ml/min/1.73 m and the patients were grouped according to their estimated GFR. Logistic regression models were used to assess the effect of GFR on clinical outcomes. In total, 49 (52%) patients experienced at least one of the following chemotherapy-associated adverse effects during the course of treatment: an episode of neutropenic fever with hospital admission, a delay in chemotherapy treatment for a medical reason, a need for dose adjustment because of toxicity of the chemotherapeutic drugs, and the need for use of granulocyte colony-stimulating factor. The incidence of these adverse effects occurred more frequently in patients with GFR less than 75 compared with patients with GFR at least 75 (64 vs. 42%, odds ratio 5.29, 95% confidence interval 2.10-13.33) and remained statistically significant after adjustment for age, BMI, and initial doses of chemotherapeutic drugs (odds ratio 3.56, 95% confidence interval 1.08-11.67). Neutropenic fever, dose delay, and dose adjustment as separate outcomes occurred more frequently in the GFR less than 75 group but lost statistical significance after adjustment. Our results demonstrate that unrecognized RI is associated with an increased risk for chemotherapy-associated adverse events in this patient population. Further prospective studies are required to determine whether a dose reduction in patients with unrecognized RI reduces adverse effects without adversely affecting the benefit of treatment.