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1.
Summary Twenty-six patients with various solid tumors entered a Phase I trial with 4 -Deoxydoxorubicin (Esorubicin, IMI-58), a new doxorubicin analogue. The drug was administered weekly i.v. for 3–4 weeks. Leukopenia proved to be dose limiting. The maximum tolerated dose (MTD) was reached at 20 mg/m 2 weekly for 3 weeks. For Phase II trials, a weekly dose of 15 and 17.5 mg/m 2 can be proposed for poor and good risk patients respectively. Non-hematologic toxicity was minimal. Phase II trials with this new anthracycline are warranted. 相似文献
2.
The subchronic toxicity of Hematide ?, a synthetic PEGylated peptidic erythropoiesis-stimulating agent (ESA), was evaluated in CD-1 mice at intravenous doses of 0, 1, 5, 25, and 125?mg/kg administered once every 3 weeks for 3 months. Hematide displayed sustained plasma levels with reduced clearance and prolonged half-lives up to 59.4 hours that translated into sustained, pronounced polycythemia, bone marrow hyperplasia, and splenic and liver extramedullary hematopoiesis. Toxicological findings were considered to be secondary to exaggerated pharmacology, rather than a direct drug effect, and included mortality at ≥25?mg/kg/dose. The no-observed-adverse-effect-level was determined to be 5?mg/kg. 相似文献
3.
Summary
Introduction: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different
toxicity profile. In preclinical trials it has shown synergy with chemotherapy.
Patients and methods: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin when combined
with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with pathologically
proven solid tumors, ≤2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function were enrolled.
Dose limiting toxicities (DLT) were defined as ≥ grade 3 non-hematological, or grade 4 hematological toxicity. No growth factors
were used during cycle 1.
Results: Three of four patients treated at dose level 1, docetaxel 60 mg/m 2 and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg orally daily on Days 1–14 of a 21 day cycle experienced DLT (grade
3 electrolyte changes in two patients, and grade 4 neutropenia in one patient). Ten patients were treated at dose level −1,
docetaxel 60 mg/m 2 and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally daily on Days 1–14 of a 21 day cycle with one DLT (Grade 4 neutropenia).
There were no treatment-related deaths or irreversible toxicities. Of the 14 response-evaluable patients, five achieved a
partial response (5 out of 9 patients with non-small cell lung cancer.
Conclusions: Docetaxel 60 mg/m 2 and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1–14 days of a 21 day cycle is the maximum tolerated
dose without the use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial
is warranted.
Revlimid? is a registered trademark of Celgene Corporation. 相似文献
4.
Summary Current chemotherapy regimens have failed to demonstrate a significant impact on the overall survival of patients with recurrent head and neck cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Alpha-interferon potentiates the activity in vitro of both agents of one of the most active regimens currently available, cisplatin and 5-fluorouracil. The purpose of the current study was to evaluate the feasibility and efficacy in patients with recurrent head and neck cancer of adding -interferon to cisplatin 14 mg/m 2 daily and 5-fluorouracil 700 mg/m 2 daily for 5 days. No significant toxicity occurred with -interferon at dose level 0,1 × 10 6 units/m 2 daily for five days. Of four patients treated at dose level +1, -interferon 3 × 10 6 units/m 2, two developed prolonged grade III neutropenic following the fourth course. One of three patients developed grade IV thrombocytopenia and 6 of 13 courses at this dose level resulted in grade III neutropenia. A phase II study was performed in 19 patients with cisplatin 17 mg/m 2/ day, 5-fluoruracil 700 mg/m 2/day and a-interferon 3 × 10 6 units/m 2/day. During the phase II study grade III neutropenia occurred in 6 patients and grade IV neutropenia in another patient during at least one course. Grade III and IV thrombocytopenia occurred in one patient each during the phase II study. Overall, major responses occurred in 7 or 23 patients (30%): 5 in phase I and 2 in phase II.In conclusion, the addition of -interferon to cisplatin and 5-fluorouracil is feasible, but does not appear to increase response rates in recurrent head and neck cancer. 相似文献
5.
Background: Overexpression of Bcl-2 is associated with worse prognosis for a number of cancer types. The present study was designed
to determine the maximum tolerated dose (MTD) of oblimersen (antisense Bcl-2) and gemcitabine when administered to patients
with refractory malignancies. Materials and methods: Sixteen patients with advanced solid tumors refractory to standard therapies were treated with escalating doses of oblimersen
continuous, 120-h intravenous infusion given every 14 days, with a fixed-dose-rate intravenous infusion of gemcitabine administered
on day 5 of each cycle. Serial plasma samples were collected to calculate the pharmacokinetics of oblimersen and gemcitabine,
and also to measure the effect of oblimersen on Bcl-2 expression. Results: 7 women and 9 men, median age 55 years (range 35–74 years), received a 5-day infusion of oblimersen at dose levels of 5 mg/kg/day
( n = 4) or 7 mg/kg/day ( n = 12). On the 5th day of the infusion, gemcitabine was given at 10 mg/m 2/h for a total dose of 1,000 mg/m 2 ( n = 7; cohorts I and II), 1,200 mg/m 2 ( n = 3; cohort III), or 1,500 mg/m 2 ( n = 6; cohort IV). Edema was the dose-limiting toxicity (DLT), necessitating expansion of cohort IV. No subsequent DLTs were
noted. Thus, the maximum planned doses were well tolerated, and a formal MTD was not determined. Most hematologic toxicities
were grade 1 or 2. There was low-grade fatigue, nausea/vomiting, and myalgias/arthralgias. Oblimersen C ss and AUC increased in relation to the dose escalation, but gemcitabine triphosphate levels did not correlate well with dose.
There were no objective responses, though 5 patients had stable disease. A >75% reduction in Bcl-2 expression in peripheral blood mononuclear leucocytes was seen more frequently in patients who achieved stable disease than
in progressing patients. Conclusions: The maximal planned dose levels of oblimersen and gemcitabine in combination were well tolerated. Only one DLT (edema) occurred.
There was a correlation between Bcl-2 reduction and stable disease. The recommended doses of the drugs for future studies are 7 mg/kg/day of oblimersen on days
1–5, and gemcitabine 1,500 mg/m 2 on day 5, every two weeks. 相似文献
6.
Summary The plasma concentrations of free -methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following -methyldopa (1 g) orally. Five of these patients subsequently received -methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of -methyldopa intravenously. After oral administration a large amount of total plasma -methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated -methyldopa in plasma (ratio at 4 hours ranged from 3.73 – 0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous -methyldopa than -methyldopate. The plasma concentration of -methyldopa (free and esterified) 60 minutes after i.v. -methyldopate was 1.7±0.3 µg/ml wile at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 µg/ml. Although small amounts of sulphate conjugate were detected after i.v. -methyldopate, insignificant quantities of conjugate were found after i.v. -methyldopa. The average fall in mean arterial pressure was 27 mm Hg following i.v. -methyldopa but only 2.7 mm Hg following -methyldopate. These results suggest that sulphate conjugation of -methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of -methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free -methyldopa have been demonstrated. 相似文献
8.
Summary To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of -methyldigoxin 0.3 mg. After oral or intravenous administration of -methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.Supported by the Deutsche Forschungsgemeinschaft 相似文献
9.
AimTo determine the absolute oral bioavailability ( Fp.o.) of saxagliptin and dapagliflozin using simultaneous intravenous 14C‐microdose/therapeutic oral dosing (i.v.micro + oraltherap). MethodsThe Fp.o. values of saxagliptin and dapagliflozin were determined in healthy subjects ( n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography‐tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively. ResultsThe geometric mean point estimates (90% confidence interval) Fp.o. values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap. ConclusionsSimultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability. 相似文献
10.
Summary 4-Deoxydoxorubicin (dxDx), a new doxorubicin analogue, was administered intravenously on a 3-week schedule to 73 patients affected by advanced malignant neoplasms. Sixty-five patients, treated with eight dose levels ranging from 10 to 45 mg/m 2, were evaluable. The dose-limiting toxicity was myelosuppression, mainly leukopenia. About one third of the patients complained of vomiting which was almost always mild. Minimal hair loss was also documented in about 40% of patients. No hepatic or renal toxicity was observed. Transient and aspecific electrocardiographic changes were recorded in 6% of patients after 1 h and in 3% after 24 h from drug injection. Left ventricular ejection fraction was decreased in two patients after a cumulative dose of 90 mg/m 2. One patient died with cardiorespiratory insufficiency and his initial cardiovascular disease might have been aggravated by dxDx. No changes in myocardial function parameters were documented in 18 patients who reached higher cumulative doses, i.e. 100 mg/m 2 and 200 mg/m 2. The highest total dose administered in this study was 340 mg/m 2. Therapeutic activity was observed with doses ranging from 25 to 45 mg/m 2. Partial response was documented in pancreatic, colon, anal and breast carcinomas as well as in non-Hodgkin's lymphoma. Minor response was observed in prostatic, thyroid, and renal carcinomas as well as in chronic lymphocytic leukemia. The maximum tolerated dose was assessed to be between 40 and 45 mg/m 2. A Phase II trial is ongoing utilizing the dose of 35 mg/m 2 every 3 weeks. 相似文献
11.
Twenty-nine chemotherapy-naive patients with primary hepatocellular carcinoma were treated with oral -all trans-retinoic acid (retinoic acid, TRA 50 mg/m2 tid) on a 3-week on/one week off schedule until progression or grade 3 or 4 toxicity. Eligibility requirements allowed abnormal liver function tests as long as the creatinine and bilirubin levels were normal. No responses were seen and the median survival was four months. Grade 3 side effects occurred in 11 patients and grade 4 in four and included a wide range of toxicities. The results indicate that oral TRA is ineffective against primary hepatocellular carcinoma and suggest that dose-modification of this retinoid may be required in patients with significant malignant hepatic involvement. 相似文献
12.
African green monkeys (vervets) have been proposed as an alternate species that might allow improved access and provide high-quality pharmacokinetic results comparable with other primates. However, no oral data are available in vervets to evaluate cross-species predictive performance. Therefore, this study was conducted to evaluate the use of the vervet to predict human oral pharmacokinetics and drug interactions. Oral pharmacokinetic studies were conducted in the vervet for eight compounds: phenytoin, moxifloxacin, erythromycin, lidocaine, propranolol, ciprofloxacin, metroprolol, and prednisolone. To assess drug–drug interactions, co-administration experiments were conducted with ketoconazole and either propranolol or erythromycin. In general, the vervet provided similar predictivity for human oral exposure as cynomolgus or rhesus monkeys. In all non-human primates, human exposure to phenytoin would be over-predicted, and erythromycin, lidocaine, and propranolol under-predicted, with good predictivity for the other compounds studied. Furthermore, in the vervet, ketoconazole co-administration resulted in a six-fold increase in exposure to erythromycin, demonstrating proof of concept for drug–drug interaction screening. These data support further exploration of the vervet as an alternate primate species for use in preclinical pharmacokinetic screening. 相似文献
13.
Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies. 相似文献
14.
Summary
Purpose To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics
of irofulven combined with capecitabine in advanced solid tumor patients.
Experimental design Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15.
Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m 2/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000.
Results Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients
in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3
thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of
14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade
3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1,
DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease
stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization
and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug–drug
interactions.
Conclusions Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose
is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m 2/day.
Work previously presented in part at the Annual Conference of the American Society for Clinical Oncology, Chicago, IL, 2003. 相似文献
15.
Identifiability is an important component of pharmacokinetic–pharmacodynamic (PKPD) model development. Structural identifiability is concerned with the uniqueness of the model parameters for a set of perfect input–output data and deterministic identifiability with the precision of parameter estimation given imperfect input–output data. We introduce two subcategories of deterministic identifiability, external and internal, and consider factors that distinguish between these forms. We define external deterministic identifiability as a function of externally controllable variables, i.e., the design, and internal deterministic identifiability as a function of the model and its parameter values. The concepts are explored using three common PK and PKPD models, and verified for their precision for the selected set of parameter values under optimal design. 相似文献
16.
Summary Five healthy adults were administered zimelidine orally (150 mg) and by intravenous infusion (20 mg) in a crossover design. Blood and urine samples were collected for a period of 28 hours after dosing and the concentrations of zimelidine and norzimelidine determined. There was no significant difference in terminal phase half-life of zimelidine after oral (4.7 h±1.3 SD) or intravenous dosing (5.1 h±0.7 SD). An average of 50% of the ingested oral dose reached the systemic circulation. Excretion of unchanged zimelidine in urine was on average 1.26% of the intravenous dose. In appears that zimelidine is completely absorbed from the gastrointestinal tract and first-pass metabolism in the liver reduces the bioavailability to 50%. The mean plasma half-life for norzimelidine was 22.8 h. The area under the plasma concentration time curve for norzimelidine after oral administration was 92% of that after intravenous administration. The plasma concentration of both zimelidine and norzimelidine are predicted to approach steady-state within 3–5 days. 相似文献
17.
AimThe aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7. MethodsNon-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously. ResultsTwenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%. ConclusionsThe population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy. 相似文献
18.
In vitro and preclinical in vivo data have shown a synergistic antitumor activity between -interferon and some antiproliferative agents. A phase I study of the concurrent administration of interferon- 2 and mito-xantrone was initiated, to determine the maximum tolerated dose of mitoxantrone given i.v. every 3 weeks in escalating doses combined with a fixed dose of s.c. interferon 2 (6 × 10 6 IU three times per week 3), in patients with advanced solid tumors resistant to conventional chemotherapy. At least three evaluable patients were entered in each dose level of mitoxantrone starting at 4 mg/m 2, with no escalations allowed in the same patient. Twenty-seven patients received a total of 101 cycles and five dose-levels were explored (4-6-8-10-12 mg/m 2 of mitoxantrone). The dose-limiting toxicities were leukopenia and granulocytopenia at 12 mg/m 2 of mitoxantrone, at which dose hematological toxicity occurred in > 50% of cases, with one patient presenting grade 4 leuko-granulocytopenia. No severe thrombocytopenia occurred. In the majority of patients transient hepatic enzyme elevations and a flu-like syndrome due to interferon a 2 were observed in all dose-levels explored. These observations suggest that the hepatotoxic effects of interferon a 2 do not emphasize mitoxantrone side-effects if given simultaneously. When mitoxantrone is administered with 6 × 10 6 IU of interferon 2, the recommended dose for future phase II studies is 10 mg/m 2/weeks 3 with escalation up to 12 mg/m 2 in selected patients if such a combination is well tolerated in terms of myelosuppression. Regarding therapeutic activity, four out of 25 (16%) cases evaluable for response achieved a partial response. In conclusion the concomitant administration of recombinant interferon 2 and mitoxantrone allows the possibility to give a therapeutic dosage of both agents. Because the combination of the two agents was fairly well tolerated and antitumor activity was observed, phase II trials are warranted. 相似文献
19.
Xiao-xu-ming decoction (XXMD) is a traditional Chinese medicine that has been widely used to treat theoplegia and its sequelae. This paper reports the development of three separate assays based on reversed phase high-performance liquid chromatography–mass spectrometry (HPLC–MS) and HPLC–MS/MS for the determination of seven active constituents of XXMD viz oroxylin A-7- O-glucuronide, wogonoside, liquiritigenin, cimifugin, 5- O-methylvisammiol, glycyrrhizic acid and glycyrrhetinic acid in rat plasma. All calibration curves were linear ( r >0.99) with lower limits of quantitation (LLOQs)<12.4 ng/mL. Intra- and inter-day precisions (as relative standard deviation) were all <10.7% with recoveries in the range of 88.7–113%. In addition, the seven analytes were shown to be stable in rat plasma samples under relevant storage conditions. The validated methods were successfully applied to a pharmacokinetic study in rat after oral administration of XXMD. 相似文献
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