ABCB1基因多态性对肝移植后他克莫司用量的影响

背景:钙神经素抑制剂他克莫司被广泛用于移植后预防排斥反应的发生,但其治疗窗狭窄,且药代动力学个体差异较大.目的:观察ABCB1基因多态性对肝移植患者移植后早期免疫抑制剂他克莫司的用量及C/D比值的影响.方法:选择2008-01/2010-09-31在昆明市第一人民医院暨昆明医学院附属甘美医院肝胆外科接受原位肝移植患者67例,通过检测67例肝移植受者移植后不同时间他克莫司的血药浓度及其用量,并利用DNA直接测序检测受体ABCB1的基因多态性,分析肝移植后免疫抑制剂他克莫司的用量及其血药浓度与ABCB1基因多态性的关系.结果与结论:肝移植后他克莫司的口服需药量在个体间存在很大差异,67例肝移植患者中,ABCB1不同位点的基因多态性分布不同,其中仅ABCB1 3435C>T基因多态性与他克莫司用量有关.提示ABCB1的基因多态性可能是患者肝移植后他克莫司药代动力学显著个体差异的重要因素,ABCB1 3435C>T野生型的患者需要更高剂量的他克莫司便可达到目标血药浓度水平,检测ABCB1的基因多态性可以优化肝移植后免疫抑制剂的个体化治疗方案.     

ABCB1基因多态性对肝移植后他克莫司用量的影响

背景：钙神经素抑制剂他克莫司被广泛用于移植后预防排斥反应的发生,但其治疗窗狭窄,且药代动力学个体差异较大。目的：观察ABCB1基因多态性对肝移植患者移植后早期免疫抑制剂他克莫司的用量及C/D比值的影响。方法：选择2008-01/2010-09-31在昆明市第一人民医院暨昆明医学院附属甘美医院肝胆外科接受原位肝移植患者67例,通过检测67例肝移植受者移植后不同时间他克莫司的血药浓度及其用量,并利用DNA直接测序检测受体ABCB1的基因多态性,分析肝移植后免疫抑制剂他克莫司的用量及其血药浓度与ABCB1基因多态性的关系。结果与结论：肝移植后他克莫司的口服需药量在个体间存在很大差异,67例肝移植患者中,ABCB1不同位点的基因多态性分布不同,其中仅ABCB1 3435C〉T基因多态性与他克莫司用量有关。提示ABCB1的基因多态性可能是患者肝移植后他克莫司药代动力学显著个体差异的重要因素,ABCB1 3435C〉T野生型的患者需要更高剂量的他克莫司便可达到目标血药浓度水平,检测ABCB1的基因多态性可以优化肝移植后免疫抑制剂的个体化治疗方案。     

Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films

A sublingual soluble-film formulation of buprenorphine/naloxone (B/N) has been approved by the US Food and Drug Administration for the treatment of opioid dependency. This preparation provides unit-dose, child-resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has a potentially preferred taste vs. tablets. This study compared the ability of buprenorphine (B) and B/N films to suppress spontaneous withdrawal in opioid-dependent volunteers. Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal. Subjects were randomized to receive either B (16?mg, n = 18) or B/N (16/4?mg, n = 16) soluble films for 5 days. The primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score. Thirty-four subjects completed induction onto soluble films. There was a significant decrease in COWS scores but no significant differences between the groups. The results support the use of B and B/N soluble films as safe and effective delivery methods for opioid induction.     

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.     

脑脊液/血清苯妥英钠浓度比值与ABCB1基因多态性的相关性研究

目的研究ATP结合盒B亚家族成员1转运蛋白(ABCB1)基因的遗传多态性与脑脊液、血苯妥英钠浓度及其比值的关联性。方法依赖高效液相色谱法(HPLC)测定200例癫痫患者的脑脊液、血苯妥英钠浓度以及依靠PCR-RFLR法分析患者的ABCB1 C1236T、ABCB1 C3435T和ABCB1 G2677T/A三个单碱基突变位点。多组间统计数据比较采用单因素方差分析。结果在ABCB1基因三个突变位点的各自基因型中,均未发现血浆苯妥英钠浓度、脑脊液苯妥英钠浓度以及两者比值具有统计学差异(P>0.05)。结论脑脊液、血清苯妥英钠浓度及其比值未发现与ABCB1基因的多态性相关。     

Increased aminoglycoside dosage requirements in hematologic malignancy.

Aminoglycoside pharmacokinetic parameters were studied prospectively in 27 patients with an underlying hematologic malignancy and fever associated with neutropenia and in 18 control patients. Pharmacokinetic parameters and dosages were determined by linear regression analysis of a one-compartment model by the method of Sawchuk et al. (R. J. Sawchuk, D. E. Zaske, R. J. Cippolle, W. A. Wargin, and R. G. Strate, Clin. Pharmacol. Ther. 21:362-369, 1976). Significant differences between the study and control groups were found for aminoglycoside volume of distribution (0.40 +/- 0.1 versus 0.27 +/- 0.05 liter/kg [mean +/- standard deviation], respectively; P less than 0.0001), clearance (116.6 +/- 48.9 versus 68.6 +/- 26.7 ml/min, respectively; P less than 0.0001), half-life (2.27 +/- 0.66 versus 3.5 +/- 1.8 h, respectively; P less than 0.0001), and elimination rate constant (0.33 +/- 0.11 versus 0.24 +/- 0.09 h-1, respectively; P less than 0.001). The percentage of bone marrow blast cells (at the time of diagnosis) in patients with acute leukemia significantly correlated with increased aminoglycoside clearance (R2 = 36.98%; P = 0.0001). Patients with stage IV lymphomas (Hodgkins disease and non-Hodgkins lymphoma) had a significantly increased clearance compared with patients with lower stages of lymphomas (105.1 +/- 18.5 versus 84.1 +/- 14.9 ml/min; P = 0.014). Fever, leukocyte count, or chemotherapy, among other clinical and laboratory parameters that were studied, had no significant correlation or effect on aminoglycoside disposition. The average dose of amikacin required to maintain peak concentrations in serum above 20 micrograms/ml in patients with a hematologic malignancy was 27.5 +/- 8.43 mg/kg per day. Pharmacokinetic parameters and dosages for the control patients were comparable to general literature standards. we conclude that the dosages recommended by the manufacturers or those derived from nomograms underestimate the aminoglycoside volume of distribution and clearance in patients with a hematologic malignancy and result in suboptimal peak aminoglycoside concentrations in serum. We recommend that in febrile neutropenic patients with an underlying hematologic malignancy, amikacin be initiated at 7.5 to 10 mg/kg per dose every 8 h (2 to 2.5 mg/kg per dose every 8 h for gentamicin) and adjusted within 24 h based on individual pharmacokinetic analysis.     

Aminoglycoside pharmacokinetics: dosage requirements and nephrotoxicity in trauma patients

We evaluated prospectively gentamicin and tobramycin pharmacokinetics in 37 patients with multiple system trauma and seven patients with isolated closed head trauma. The mean apparent volume of distribution (Vd) was 0.38 +/- 0.10 and 0.27 +/- 0.04 L/kg actual body weight (ABW) in patients with multiple trauma and closed head trauma, respectively. The difference in Vd between the two groups of patients was significant (p less than .002). Vd was not predictable on the basis of age, sex, weight, trauma score, or hospital day that therapy was initiated. Mean aminoglycoside clearance (Cl) was 123 +/- 46 ml/min. Neither serum creatinine nor estimated creatinine Cl predicted aminoglycoside Cl with sufficient accuracy to be clinically useful (r = .33 and .67, respectively). The mean daily dose was 6.1 +/- 1.6 mg/kg. The mean peak serum level was 5.8 +/- 1.3 micrograms/ml. Only one patient developed clinically significant renal dysfunction. Our data indicate that a loading dose of gentamicin or tobramycin of 3 mg/kg ABW in patients with multiple trauma and 2.5 mg/kg ABW in patients with isolated head trauma will obtain a mean initial peak serum level of 6.6 micrograms/ml. Although adequate maintenance dosing requires individualization based on pharmacokinetic analyses, large aminoglycoside doses can be used safely in patients with blunt trauma if appropriate monitoring is employed.     

ABCB1基因多态性与苯妥英钠治疗癫痫疗效的相关性研究

目的研究ATP结合盒B亚家族成员1转运蛋白(ABCB1)基因的遗传多态性对苯妥英钠治疗癫痫的影响。方法 200例癫痫患者按照患者临床资料分为控制组和耐药组,采集两组患者的外周血6 ml,依赖高效液相色谱法(HPLC)测定苯妥英钠血药浓度以及依靠PCR-RFLR法分析200例患者的ABCB1 C1236T、ABCB1 C3435T和ABCB1 G2677T/A三个单碱基突变位点。用SHEsis软件对ABCB1基因C1236T、C3435T和G2677T/A进行单体型推断,多组间统计数据比较采用单因素方差分析。结果在ABCB1 C1236T中CC基因型在耐药组的百分率为17.5%,显著高于控制组(2.1%),TT基因型在控制组百分率为55.4%,高于耐药组的百分率41.6%(P<0.05);在G2677T/A中GG基因型在耐药组分布达29.6%,高于控制组的9.7%,TT基因型在控制组的百分率为30.4%,高于耐药组(4.6%)(P<0.05);在C3435T位点,徐州地区癫痫患者耐药组和控制组的分布频率没有统计学差异(P=0.349)。单倍体检测发现TTC单体型在控制组中的分布频率较高为24.1%(P<0.05);没有观察到ABCB1基因多态性与苯巴比妥稳定血浆药物浓度存在相关影响。结论 ABCB1基因遗传多态性对苯妥英钠的血药浓度没有影响,但是影响苯妥英钠对癫痫患者的治疗效果。     

Pharmacokinetics and dosage requirements of netilmicin in cystic fibrosis patients.

The pharmacokinetics of netilmicin were determined in 10 patients with cystic fibrosis. Mean (+/- standard error of the mean) values for total body clearance and volume of distribution were 2.62 (+/- 0.18) ml/min per kg of body weight and 0.38 (+/- 0.01) liter/kg, respectively, and were considerably larger than the same parameters reported for patients without cystic fibrosis.     

Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes

Polymorphisms in CYP2C9 and VKORC1 have been shown to be associated with warfarin dose requirements and could be used to predict warfarin dose. We conducted a prospective study in which warfarin dose was prescribed based on CYP2C9 and VKORC1 polymorphisms in 108 Han-Chinese patients without prior warfarin treatments. Using the genotype-based dosing, 83% of patients reached stable, therapeutic international normalized ratio (INR) within 2 weeks of treatment initiation and none of the patients developed clinical bleeding or thromboembolic event. Ten percent (11) of patients with INR > 4 and no clinical bleeding were detected during this study. At 12 weeks, 69% of the patients' maintenance doses matched the prediction. Dosing algorithms incorporating genetic factors, age, and body surface area were developed, which could explain up to 62% of the total variation (R(2) of 0.62). This study demonstrated that pharmacogenetics-based dosing could improve time to stable, therapeutic INR, reduce adverse events, and achieve high sensitivity.     

Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride.

Plasma methadone levels, symptom complaints, and urine tests for illicit opiate use were followed weekly in 17 patients on a methadone maintenance program. There were very large differences between patients in the plasma level established at a given dosage, implying large differences in the rate of methadone metabolism. Despite virtually constant daily dosage, the plasma methadone levels fluctuated greatly from week to week and from day to day in individual patients. With rate exceptions there was no relationship between plasma methadone level and symptom complaints or between weekly chamges in plasma methadone level and changes in symptom complaints. Except possible to identify the ocassional patient with unusually low plasam methadone levels, the determination of methadone levels is not likely to be or practical value in methadone programs.     

Comparison of intravenous buprenorphine and methadone self-administration by recently detoxified heroin-dependent individuals

Although buprenorphine is used worldwide as a safe and effective maintenance medication for opioid dependence, some countries have reported a growing incidence of abuse of this medication. Buprenorphine is considered to have lower abuse potential because of its partial agonist profile, but no studies have directly compared the reinforcing effects of buprenorphine with those of full mu opioid agonists in humans. The present double-blind, placebo-controlled inpatient study compared the reinforcing and subjective effects of intravenously administered buprenorphine (0.5, 2, and 8 mg) and methadone (5, 10, and 20 mg). Participants (n = 6) were detoxified from heroin during the first 1 to 2 weeks after admission. During subsequent weeks, participants received a sample drug dose and $20 on Monday, and they could self-administer either the sampled dose or $20 during one choice session per day on Thursday and Friday. Participants responded under a modified progressive ratio schedule during each choice session. All active doses maintained higher progressive ratio break points (largest completed ratio) than placebo. There were no significant differences in break point values between buprenorphine and methadone or among the different doses of drug. However, several subjective ratings, including "good drug effect", "high", and "liking" dose-dependently increased after administration of buprenorphine and methadone. The peak ratings for these effects did not significantly differ for the two drugs. These results demonstrate that under these experimental conditions, buprenorphine and methadone were equally effective in producing reinforcing and subjective effects.     

The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes

The aim of this study was to search for a possible association between the variant allele of the single nucleotide polymorphisms A118G in the OPRM1 gene and C3435T and G2677T/A in the ABCB1 gene and altered antinociceptive effect and adverse drug reactions of oxycodone. Thirty‐three healthy subjects exposed to experimental pain including electrical stimulation and the cold pressor test were included. A118G: We found that the variant G allele was associated with reduced antinociceptive effect as measured by pain tolerance thresholds to single electrical nerve stimulation (8% increase vs. 25% for the wild‐type carriers, P = 0.007). C3435T: The carriers of the variant T allele generally had less adverse drug reactions on oxycodone than the carriers of the wild‐type genotype. G2677T/A: The carriers of the variant T allele had a better antinociceptive effect of oxycodone than the carriers of the wild‐type genotype in the cold pressor test (25% reduction vs. 15%, P = 0.015 in the discomfort rating and 25% reduction vs. 12%, P = 0.007 in the pain time AUC) and less adverse drug reactions. The combined wild‐type genotype 3435CC‐2677GG was associated with less antinociceptive effect of oxycodone in the discomfort rating of the cold pressor test (13% reduction vs. 23%, P = 0.019) and more severe adverse drug reactions than the carriers of the variant alleles. We found a moderate association between less antinociceptive effect of oxycodone and the variant allele of A118G. There was strong association between less adverse drug reactions of oxycodone and the variant alleles of C3435T and G2677T/A.     

Common leukemia- and lymphoma-associated genetic aberrations in healthy individuals

Leukemia- and lymphoma-associated (LLA) chromosomal rearrangements are critical in the process of tumorigenesis. These genetic alterations are also important biological markers in the diagnosis, prognosis, and treatment of hematopoietic malignant diseases. To detect the presence or absence of these genetic alterations in healthy individuals, sensitive nested RT-PCR analyses were performed on a large number of peripheral blood samples for selected markers including MLL partial tandem duplications (PTDs), BCR-ABL p190, BCR-ABL p210, MLL-AF4, AML1-ETO, PML-RARA, and CBFB-MYH11. Using nested RT-PCR, the presence of all of these selected markers was detected in healthy individuals at various prevalence rates. No correlation was observed between incidence and age except for BCR-ABL p210 fusion, the incidence of which rises with increasing age. In addition, nested RT-PCR was performed on a large cohort of umbilical cord blood samples for MLL PTD, BCR-ABL p190 and BCR-ABL p210. The results demonstrated the presence of these aberrations in cord blood from healthy neonates. To our knowledge, the presence of PML-RARA and CBFB-MYH11 in healthy individuals has not been previously described. The present study provides further evidence for the presence of LLA genetic alterations in healthy individuals and suggests that these mutations are not themselves sufficient for malignant transformation.     

Diazepam and methadone interactions in methadone maintenance

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.