Resistance to imatinib (Glivec): update on clinical mechanisms.

Imatinib mesylate, an orally administered 2-phenylaminopyrimidine derivative that inhibits BCR/ABL tyrosine kinase activity, has shown great promise in the treatment of chronic myelogenous leukemia (CML). This small molecule, tyrosine kinase inhibitor, has also been shown to be effective against metastatic gastrointestinal stromal tumors (GISTs) expressing the stem cell factor (SCF) receptor kit. However, the threat of resistance in patients has prompted investigators to uncover the mechanisms whereby malignant cells develop resistance to imatinib, and has also led to the establishment of strategies designed to over-ride imatinib resistance. Here, we provide a comprehensive overview of the effectiveness of imatinib in the treatment of chronic, accelerated and blast crisis-phase CML, Philadelphia chromosome-positive (Ph+) acute lymphoid leukemia (ALL) and metastatic GIST. Established mechanisms of resistance to imatinib are discussed, as are novel therapeutic approaches to improving drug responsiveness by reversing development of imatinib resistance in patients.     

The effect of imatinib mesylate (Glivec) on human tumor-derived cells

Imatinib mesylate is a specific inhibitor of the Bcr-Abl protein tyrosine kinase that competes with ATP for its specific binding site in the kinase domain. It has activity against platelet-derived growth factor receptor alpha and beta (PDGFR-alpha and -beta), and c-kit, the receptor for stem cell factor. We have used a standardized ATP-tumor chemosensitivity assay and immunohistochemistry to determine the cytotoxicity of imatinib mesylate in tumor-derived cells from cutaneous and uveal melanoma, and ovarian carcinoma. Imatinib mesylate was tested at concentrations ranging from 2.0 to 0.0625 micromol/l alone and in combination with a cytotoxic drug (cisplatin, doxorubicin, paclitaxel or treosulfan). Imatinib mesylate showed low inhibition (IndexSUM>300) across the range of concentrations tested in this study, with few tumors exhibiting increasing inhibition with increased drug concentration. The median IC90 values for cutaneous and uveal melanoma and ovarian carcinoma were 13.2 micromol/l (4.0-294.3 micromol/l), 12.0 micromol/l (2.0-285.4 micromol/l) and 7.71 micromol/l (6.51-11.02 micromol/l), respectively. Imatinib mesylate potentiated the effect of different cytotoxics in 9% (5/54) of cases and had a negative effect in 13% (7/54) of cases, with no effect in the remainder. No correlation of effect was noted with c-kit, platelet-derived growth factor receptor-alpha or platelet-derived growth factor receptor-beta expression, assessed by immunohistochemistry. The signaling pathways mediated by activation of c-kit or platelet-derived growth factor receptor may act as antiapoptotic survival signals in some cancers and inhibition of these pathways may potentiate the activity of some cytotoxic drugs by inhibiting the survival signal. Growth inhibition, however, may reduce the efficacy of cytotoxic drugs, which tend to target proliferating cells preferentially, and clinical effects are therefore difficult to predict.     

Absolute bioavailability and noncompartmental analysis of intravenous and intramuscular Cefotan (cefotetan) in normal volunteers

Cefotetan (1 g) was administered to 12 normal volunteers as a 30 minute intravenous infusion and as an intramuscular injection. The pharmacokinetic parameters were estimated using noncompartmental analysis. The mean +/- SD maximum plasma concentration, terminal half-life, and systemic clearance after intravenous infusion were 158 +/- 21 micrograms/mL, 4.54 +/- 1.05 hours, and 29.1 +/- 3.8 mL/min/1.73 m2, respectively. Renal clearance and nonrenal clearance accounted for 63.1% and 36.9% of the systemic clearance, respectively. The mean +/- SD maximum plasma concentration, time to maximum concentration, terminal half-life, and absolute bioavailability after intramuscular injection were 75.5 +/- 8.7 micrograms/mL, 1.33 +/- 0.48 hours, 4.32 +/- 0.77 hours, and 0.931 +/- 0.193, respectively. Moment analysis gave average +/- SD mean residence times (MRT) of 4.98 +/- 0.75 and 5.86 +/- 0.77 hours after intravenous and intramuscular administration, respectively. The average +/- SD mean absorption time (MAT) after intramuscular injection was 1.11 +/- 0.57 hours. The mean +/- SD steady-state volume of distribution after intravenous infusion was 0.129 +/- 0.024 L/kg. The mean +/- SD cumulative percentage of the dose excreted in the urine in 24 hours were 61.1 +/- 11.4% and 50.4 +/- 13.5% after intravenous and intramuscular dosing, respectively. The maximum urinary cefotetan concentrations occurred during the first 2 hours after dosing by both routes of administration. Cefotetan tautomer was detected in the plasma and urine of all subjects after both routes of administration, but the mean concentrations were only minimal compared to those for cefotetan. In conclusion, intramuscular cefotetan (1 g) is rapidly and almost completely absorbed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absolute bioavailability of glimepiride (Amaryl) after oral administration

Twelve healthy fasting male volunteers received a single 1.0 mg dose of glimepiride either as an intravenous injection over one minute or as a tablet. Blood and urine samples were taken before drug administration and afterwards for up to 24 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). There were no statistically significant differences between mean serum pharmacokinetic parameters for the oral and intravenous formulations either with glimepiride or M1. Mean urinary recovery of M1 plus M2 was 50% of the dose for the glimepiride tablet and 51% for the intravenous injection. The absolute bioavailability of the tablet formulation was 107% (AUDC(glimepiride)), 109% (AUDC(M1)) and 97% (urinary recovery). The tablet formulation of glimepiride is completely bioavailable and was safe and well tolerated in healthy volunteers.     

Absolute bioavailability and pharmacokinetics of treprostinil sodium administered by acute subcutaneous infusion

The objective of this study was to evaluate the absolute bioavailability and acute pharmacokinetics of treprostinil sodium administered by continuous, short-term subcutaneous infusion in normal subjects. Fifteen healthy volunteers received treprostinil via an intravenous infusion at 15 ng/kg/min over 150 minutes, followed by a 5- to 7-day washout and a subcutaneous infusion at the same rate administered over 150 minutes. Serial plasma samples were collected predosing, during dosing, and postdosing, and plasma treprostinil concentration levels were measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Acute administration of treprostinil administered by subcutaneous infusion at a rate of 15 ng/kg/min for 150 minutes achieved a mean Cmax of 1.47 ng/mL. Mean AUC infinity values for intravenous and subcutaneous dosing were 3.52 and 3.97 ng.h/mL, respectively, resulting in a mean apparent absolute bioavailability of 113% for subcutaneous administration. It was possible that the area under of the curve for the intravenous administration was underestimated because most of the terminal elimination phase could not be documented due to the LLOQ of the assay. The mean apparent elimination half-life of treprostinil following subcutaneous administration was 1.38 hours, compared to 0.87 hours following intravenous administration. It was concluded that treprostinil administered by subcutaneous administration is completely absorbed, with a slightly longer half-life compared to intravenously administered treprostinil.     

Absolute bioavailability of moxonidine

In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean +/- standard deviation] 3438 +/- 962 pg.h/ml (AUC(0----Tlast)) and 3674 +/- 1009 pg.h/ml (AUC(0----infinity)) for treatment A; 3855 +/- 1157 pg.h/ml (AUC(0----Tlast)) and 4198 +/- 1205 pg.h/ml (AUC(0----infinity)) for treatment B. Mean peak plasma concentrations of 1495 +/- 646 pg/ml were attained at 0.56 +/- 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 +/- 1342 pg/ml at 0.17 +/- 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h)) in absolute figures and as percentage of the dose administered were 102 +/- 26 micrograms or 51 +/- 13% for the tablet and 122 +/- 33 micrograms or 61 +/- 16% for the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absolute bioavailability of theophylline from a sustained-release formulation using different intravenous reference infusions

Summary The effect of different intravenous infusions on the absolute bioavailability of theophylline from a sustained-release formulation has been investigated. Oral administration of 750 mg theophylline (2 capsules Euphylong 375) was referenced to intravenous aminophylline infusions corresponding to 506 mg theophylline over 8 h (63 mg·h^–1) in Study 1, and to 749 mg theophylline over 14 h in Study 2. A reduction in the infusion rate from 69 to 33 mg·h^–1 was made in Study 2 after 8 h in order to mimic the concentration/time profile of the oral formulation as closely as possible. The absolute bioavailability was 100 (89, 115) % in Study 1 and 88 (73, 105) % in Study 2.The lower clearance values and, as a consequence, the lower bioavailability ratios observed with the higher intravenous dose, although not significant, indicate that the absolute bioavailability of theophylline might appear to depend on the choice of the intravenous reference standard.     

Glivec (STI571, imatinib), a rationally developed,targeted anticancer drug

In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.     

Absolute bioavailability of digoxin tablets

Ten healthy male volunteers each received 0.5 mg digoxin orally and i.v. in a randomised, cross-over sequence with at least two weeks between doses. Plasma concentration and cumulative urinary excretion of digoxin were measured up to 6 and 144 h, respectively, after administration using a radioimmunoassay method. Absolute bioavailability (i.e. the percentage absorption from tablets compared to i.v. injection) was calculated by four methods: by comparing areas under plasma concentration/time curves (AUC) up to 6 h and to infinity, also by comparing cumulative urinary excretion up to 144 h (t max.) and to infinity. The mean of the two extrapolated values for the absolute bioavailability of digoxin (Sandoz) tablets is 78%.     

Absolute bioavailability of chlorthalidone in man: A cross-over study after intravenous and oral administration

Summary Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t_1/2 after i.v. dosing was 36.5 h (±10.5 SD), and the mean plasma t_1/2 after oral doses was 44.1 h (±9.6 SD). The mean red blood cell concentration t_1/2 after i.v. doses was 46.4 h (±9.9 SD), and the mean red blood cell t_1/2 after the oral doses was 52.7 h (±9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (±8.6 SD) % of the intravenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (±8.5 SD) %. Faecal excretion ranged from 1.3–8.5% of dose in the i.v. study to 17.5–31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were — a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F=0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.     

A comparison of the safety, timing and cost-effectiveness of administering antibiotics by intravenous bolus (push) versus intravenous piggyback (slow infusion) in surgical prophylaxis

This study was carried out to evaluate the safety, timing and cost-effectiveness of administering perioperative antimicrobial prophylaxis with cefmetazole via intravenous (IV) bolus, or 'push', compared with the more common method of IV 'piggyback' administration. A total of 60 patients were studied, 30 in each group. No major adverse reactions were noted in either group. Phlebitis did not occur with either method of administration. Loss of patency was noted in 2 patients in the IV bolus group at the time of catheter removal. While no overall difference in timing of antibiotic administration in relation to the surgical procedure was noted, 2 patients in the IV piggyback group did not receive their preoperative dose until after surgery had started. Both pharmacy preparation time and nursing administration time were shorter with the IV push method, resulting in a cost avoidance of $US0.60 per dose. Material cost avoidance, primarily due to elimination of the minibag and IV tubing with bolus administration, was $US3.25 per dose. Extrapolated cost avoidance for our institution, for both prophylaxis and treatment, is $US184 000 per year. Administration of selected antibiotics by IV push is safe, allows optimal timing of administration, minimises preparation and administration time, and is cost-effective. Hospitals and outpatient care facilities should consider this alternative method of antibiotic administration.     

Absolute bioavailability of cefixime in man

In a four-way cross-over study, the absolute bioavailability of cefixime was determined in 16 healthy volunteers. Each subject received a single 200-mg dose as an intravenous (IV) and oral solution, and 200-mg and 400-mg capsule doses of the drug. Blood and urine samples were collected for 24 hours after each dose. Cefixime was well tolerated after IV and oral doses of the drug and no serious drug-related adverse effects were observed. The maximal serum concentration (Cmax) of cefixime following the 200-mg oral solution and 200-mg and 400-mg capsule doses were 3.22, 2.92, and 4.84 micrograms/mL, respectively. Mean area under the serum concentration time curves (AUC) following the IV, 200-mg oral solution, and 200-mg and 400-mg capsule doses were 47.0, 26.0, 23.6, and 39.4 micrograms.hr/mL, respectively. Mean elimination half-life values of the drug were comparable after oral and IV doses, ranging from 3.2 to 3.5 hours. Based on serum AUC values, the absolute bioavailability of cefixime was 52.3%, 47.9%, and 40.2% after the 200-mg oral solution, 200-mg capsule and 400-mg capsule doses, respectively. Respective ratios based on 24-hour urinary recovery data were 44.7%, 41.7%, and 40.5%. Therefore, the results show that the percent of cefixime adsorbed after 200-mg and 400-mg oral doses was similar.     

头孢克肟口崩片在健康人体内的相对生物利用度研究

目的研究头孢克肟口崩片与胶囊在中国健康成年男性志愿者体内的相对生物利用度,评价两者的生物等效性。方法采用随机、开放、双周期交叉试验设计,20名男性健康受试者分别单剂量口服试验制剂头孢克肟口崩片200 mg或参比制剂胶囊200 mg。采用HPLC-UV法测定给药后不同时间采集的血样中头孢克肟的血药浓度。结果受试者单次口服200 mg头孢克肟后,头孢克肟口崩片与胶囊的Cmax分别为（2.922±1.161）、（2.725±1.042）mg.L-1 tmax分别为（3.42±0.94）、（3.50±0.61）h AUC0~t分别为（21.32±9.87）、（19.54±9.51）mg.h.L-1 t1/2分别为（3.68±1.69）、（3.86±1.73）h。方差分析结果表明2种制剂的参数之间没有显著性差异,头孢克肟口崩片与胶囊的相对生物利用度为（110.2%±12.7%）。结论受试制剂头孢克肟口崩片与参比制剂头孢克肟胶囊为生物等效制剂。     

静脉输注纳布啡与瑞芬太尼辅佐硬膜外分娩镇痛的效果比较

目的:比较静脉输注纳布啡与瑞芬太尼辅佐硬膜外阻滞应用于分娩镇痛的临床效果和安全性。方法:选择2020年8月至10月广州医科大学附属第三医院足月初产妇150例,按照简单随机数字表法分为单纯硬膜外镇痛组（C组）、纳布啡辅佐硬膜外镇痛组（N组）和瑞芬太尼辅佐硬膜外镇痛组（R组）,每组50例。3组均待宫口开至3 cm时行硬膜外...     

Absolute bioavailability and stereoselective pharmacokinetics of doxepin

1. Commercial doxepin contains geometric isomers in the proportions Z:E = 15:85. Z-doxepin and its metabolite Z-N-desmethyldoxepin are both active antidepressants, whereas the corresponding E-isomers are less active therapeutically. 2. The present pharmacokinetic study was a balanced, randomized, two-treatment, two-period, two-sequence crossover design in which 12 healthy male volunteers were given single doses of commercial doxepin intravenously and orally on two occasions separated by a washout period. 3. A two-compartment model with no lag time and first-order elimination fitted the plasma concentration-time curves after intravenous dosing. Pharmacokinetic parameters estimated from the model were comparable with those estimated by non-compartmental methods. 4. All pharmacokinetic parameters displayed a wide between-subject variability. Both isomers of doxepin showed large volumes of distribution and relatively short half-lives in plasma, suggestive of extensive distribution and/or tissue binding. The mean fraction absorbed after oral administration was 0.29 for each isomer. Renal clearances of each isomer were very low after either oral or intravenous dosing, although all four analytes were quantifiable in the urine for prolonged periods. 5. After oral dosing, plasma concentrations of the doxepin isomers remained roughly in the ratio Z:E = 15:85, whereas those of N-desmethyldoxepin were closer to 1:1 in all but two outliers, who had high levels E-N-desmethyldoxepin.     

红景天苷在比格犬体内绝对生物利用度研究

目的建立比格犬血浆中的红景天苷的HPLC-MS/MS测定方法,研究红景天苷在比格犬体内的绝对生物利用度。方法以天麻素为内标,血浆样品经蛋白沉淀后,经Symmetry RP18(100 mm×4.6 mm,3.5μm)柱分离,使用体积分数0.1%甲酸溶液(A)-含0.1%甲酸和20%乙腈的甲醇溶液(B)作为流动相,进行等度洗脱(35%B),流速为0.4 ml/min,柱温40℃,进样量2μl;通过电喷雾电离源(ESI),以多反应监测(MRM)模式进行负离子检测,红景天苷、天麻素的MRM离子对分别为m/z 299.1→118.9、m/z 285.1→122.9。比格犬分别以口服和静注两种给药方式给予红景天苷原料药,在不同时间点取血,样品采用HPLC-MS/MS法测定,研究红景天苷的药动学及绝对生物利用度。结果红景天苷的质量浓度在10~10000 ng/ml内线性关系良好(r>0.9986),最低定量浓度为10.0 ng/ml。方法回收率为89.5%~91.8%,日内精密度(RSD)<9.7%,日间精密度(RSD)<7.3%。单剂量口服15 mg/kg或静注1.5 mg/kg红景天苷原料药后,cmax分别为(9680±3725)和(9310±1645)ng/ml;tmax分别为(1.25±0.67)和(0.011±0.017)h,AUC0?t分别为(20535.4±5200.0)和(4646.7±720.5)ng·h/ml,AUC0-∞分别为(20607.9±5266.2)和(4691.6±715.2)ng·h/ml;t1/2分别为(1.31±0.63)和(0.98±0.13)h。结论该方法简便快速、灵敏可靠,可用于红景天苷体内过程研究。红景天苷在比格犬体内的绝对生物利用度为(43.9±11.2)%。     

Absolute bioavailability and stereoselective pharmacokinetics of doxepin

1. Commercial doxepin contains geometric isomers in the proportions Z : E = 15:85. Z -doxepin and its metabolite Z - N -desmethyldoxepin are both active antidepressants, whereas the corresponding E -isomers are less active therapeutically. 2. The present pharmacokinetic study was a balanced, randomized, two-treatment, two-period, two-sequence crossover design in which 12 healthy male volunteers were given single doses of commercial doxepin intravenously and orally on two occasions separated by a washout period. 3. A two-compartment model with no lag time and first-order elimination fitted the plasma concentration-time curves after intravenous dosing. Pharmacokinetic parameters estimated from the model were comparable with those estimated by non-compartmental methods. 4. All pharmacokinetic parameters displayed a wide between-subject variability. Both isomers of doxepin showed large volumes of distribution and relatively short half-lives in plasma, suggestive of extensive distribution and/or tissue binding. The mean fraction absorbed after oral administration was 0.29 for each isomer. Renal clearances of each isomer were very low after either oral or intravenous dosing, although all four analytes were quantifiable in the urine for prolonged periods. 5. After oral dosing, plasma concentrations of the doxepin isomers remained roughly in the ratio Z : E = 15:85, whereas those of N -desmethyldoxepin were closer to 1:1 in all but two outliers, who had high levels E - N -desmethyldoxepin.