A phase II trial of interferon alpha-2A plus fluorouracil in advanced renal cell carcinoma

Summary In vitro studies have documented the synergistic activity of interferon (IFN) and fluorouracil (5-FU) in human cancer cell lines, and recent clinical trials have demonstrated the efficacy of this combination in metastatic colon cancer. The current study was undertaken to evaluate the combination of IFN alpha-2a plus 5-FU in previously untreated patients with metastatic renal cell carcinoma. From May 1990 through August 1990, 14 patients with metastatic renal cell carcinoma were treated with 5-FU 750 mg/m² day continuous infusion IV days 1–5, followed by weekly IV infusions of 5-FU 750 mg/m² beginning on day 12. Patients concurrently received IFN alpha-2a 9×10⁶ IU subcutaneously 3 times per week beginning on day 1. The median age of patients treated was 57 (range 38–80) with a median Karnofsky performance status of 90 (range 60–100). Sites of metastases included lung only in 6 patients, liver only in 1 patient, 1 patient had bilateral disease at presentation, and the remaining patients had multiple sites of metastases. The median duration of therapy was 2 months. The predominant toxicities seen were stomatitis, nausea, flu-like symptoms and neurotoxicity. The only grade IV toxicity observed was severe vomiting in 1 patient, though 5 patients discontinued therapy within 2 months because of poor subjective response. With a minimum follow-up of 13 months no objective responses were seen. Thirteen of the 14 patients have had progressive disease and 11 have died. The median time to progression was 2 months (range 0.5–6 months) and the median survival was 5 months (range 2–14.5+months). We conclude that at this dose and schedule, IFN alpha-2a plus 5-FU is ineffective in the treatment of advanced renal cell carcinoma.From the Hoosier Oncology Group, the Walter Cancer Institute, Indianapolis, Indiana and the Department of Medicine, Indiana University, Indianapolis, USA.     

Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion

Summary The limiting toxicity of low dose continuous infusion 5-fluorouracil (200–300 mg/m²/day) is often palmarplantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42% –82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at a dose of 200 mg/m²/day until toxicity or progressive disease forced discontinuation.The first signs of the syndrome developed at a median of 2 months following infusion initiation and, unless treatment was interrupted, became progressively worse. The incidence of moderate to severe PPE was 71% in the 14 previously untreated patients (exact 95% confidence intervals of 42–92%). Seventy-eight percent of the responders in the no prior treatment group developed PPE. The incidence of moderate to severe PPE was only 27% in the 11 previously treated patients (exact 95% confidence intervals of 6–61%). The higher incidence of PPE in the previously untreated patients probably resulted from a longer total infusion time (median = 7.3 months) than the previously treated (median = 4.5 months). The longer infusion time in turn was a result of the higher response rates (64 vs 18%) in the previously untreated versus treated groups.Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.The five previously untreated patients who received pyridoxine for PPE continued 5-FU for a median of 6 months after development of the syndrome. The six previously untreated patients who did not receive pyridoxine when they developed PPE were able to continue 5-FU for a median of only 2.5 months after development of the syndrome. A similar number of clinical responders to 5-FU were present in both groups.Considering the high incidence of PPE and response in previously untreated colon cancer patients who receive protracted continuous 5-FU, prophylactic pyridoxine in conjunction with this treatment modality might be useful.     

Raltitrexed (tomudex) administration in patients failing multiple prior chemotherapy regimens in advanced colorectal cancer: a pilot study

Purpose: To evaluate efficacy of Raltitrexed, a specificthymidilate synthase inhibitor, in patients with advancedcolorectal cancer (ACC) failing multiple prior chemotherapyregimens (e.g. 5-FU+LV, CPT-11, etc). Methods: 20 patients with ACC; 13 males/7 females,median age 64 (range: 53–69), median Karnovsky PS: 80 (70–90), and sites of metastases; liver: 16, lung: 6, lymph nodes:9, peritoneal: 8 and a life expectancy of at least 3 months,were entered in the present pilot study of Raltitrexedadministration. All patients had progressed after priorchemotherapy with 5-FU+LV and subsequently CPT-11, and somehad received further infusional 5-FU. Raltitrexed wasadministered at a dose of 3 mg/m² i.v. every 21 days. Results: 3 patients obtained stable disease (SID), 15%,with tumor marker decline (CEA, CA-19.9). Time-to-progressionwas 4.8 months (2.2–7) and survival 7.4 months (6.0–7.8).Toxicity was in general not severe and consisted mainly ofmyelosuppression; neutropenia (WHO) grade 2: 45% and grade 3:22%, and anemia grade 1–2: 40%. Conclusion: Response to treatment with Raltitrexed islimited in patients with ACC failing multiple priorchemotherapy regimens, however, a limited percentage ofpatients with SD derived clinical benefit.     

Weekly irinotecan plus UFT and leucovorin as first-line chemotherapy of patients with advanced colorectal cancer

Summary We evaluated the antitumoral efficacy and safety of CPT-11 125 mg/m² (weekly 90 min i.v. infusion; days 1, 8 and 15) combined with UFT (oral combination of tegafur and uracil) 200 mg/m²/day plus leucovorin (LV) 45 mg/m²/day (both divided into three separate oral doses every 8 h, days 1–21) every 4 weeks as first-line chemotherapy of metastatic colorectal cancer (CRC). Fifty-three patients 18 years old with histologically confirmed diagnosis of advanced CRC and bidimensionally measurable disease were enrolled. Three patients (6%) showed CR and 8 patients (15%) showed PR (ORR = 21% (95% CI, 10–32). Stable disease was reported in 19 patients (36%) [tumor control rate = 57% (95% CI, 43–70)]. The median time to progression and overall survival were 7.9 and 18.2 months, respectively (1-year rate = 74%; 2-years rate = 26%). CPT-11/UFT/LV treatment was well tolerated: the most reported grade 3/4 toxicities were neutropenia (11% of patients) and delayed diarrhea (28% of patients). No significant differences in response rate, survival or toxicity were found between younger (65 years) and older patients (> 65 years). Weekly CPT-11 plus UFT/LV was found effective and safe as first-line chemotherapy for metastatic CRC. The addition of CPT-11 to UFT/LV doubled the response rate compared to the results previously reported with UFT/LV, while myelosuppression remained low.     

Does leucovorin alter the intratumoral pharmacokinetics of 5-fluorouracil (5-FU)? A Southwest Oncology Group study

Purpose and design: We previouslydocumented that there was an associationbetween the intra-tumoral pharmacokinetics(TPK) of 5-FU and response to therapy with5-FU and leucovorin (p < .0001). Since wehave shown that other modulators of 5-FU,such as methotrexate, interferon andneutrexin alter its TPK, it was of interestto determine if the modulating effect ofleucovorin would also alter the tumoral PKof 5-FU. In order to determine the effectof leucovorin on intratumoral 5-FUpharmacokinetics, 23 patients (21evaluable) underwent ¹⁹F magneticresonance spectroscopy ¹⁹F-MRS)twice. The first ¹⁹F-MRS was following5-FU 600 mg/m² alone, and the second¹⁹F-MRS was following by leucovorin500 mg/m² and then 5-FU 600 mg/m². Results: A comparison of theintratumoral 5-FU pharmacokineticsindicated that there was no general effectof leucovorin on the intratumoral half-lifeof 5-FU. In only two of these 21 patientswas the half-life of 5-FU altered, and inboth cases it was decreased by more than20%. Partial responses to 5-FU plusleucovorin therapy were seen only inpatients with a long intratumoral half-life(trapping) of 5-FU (3 PR in 11 patientswith T_1/2 20 minutes, comparedto 0 PR in 11 patients with T_1/2 <20 minutes). There was a statisticallysignificant correlation between tumorresponse and the intratumoral T_1/2 of5-FU, consistent with our prior results ina larger number of patients. However, therewas no statistically significantcorrelation of time-to-progression orsurvival with classification of thepatients into trappers or non-trappers,probably due to the small sample size inthis current study. Conclusion: The data reported hereare compatible with the hypothesis thatleucovorin enhancement of 5-fluorouracilantitumor responses is not mediated by thelevels of 5-FU in tumors, but rather, isdue to the modulation by leucovorin ofcellular metabolic processes that followthe uptake of free 5-FU into the tumorcell. The MRS technique may be useful inselected instances for elucidating thepossible metabolic interactions of drugsin vivo.     

5-Fluorouracil vs. epirubicin vs. 5-fluorouracil plus epirubicin in advanced gastric carcinoma

From January, 1985, through January, 1987, 165 patients with advanced gastric cancer were randomized to receive epirubicin (E) alone (90 mg/m² day 1), 5-Fluorouracil (5-FU) alone (500 mg/m² days 1–5), or the combination of E (90 mg/m² day 1) and 5-FU (400 mg/m² days 1–5). Courses were repeated every four weeks. Patients were stratified by extent (locally advanced vs. metastatic), evaluability (measurable vs. non-measurable) and by history of prior radiotherapy (yes vs. no). Randomization to single arm epirubicin was stopped after 26 patients were enrolled. Objective responses occurred in only 1/16 (6%) of the patients treated with E alone, 1/40 (5%) with 5-FU alone and 4/33 (12%) with both 5-FU and E. There were no significant differences in all eligible patients with respect to time to progression or overall survival in the three treatment arms. Toxicity was primarily hematologic and more pronounced in the combination arm. Neither 5-FU alone, epirubicin alone, or the combination have a major impact in the treatment of gastric carcinoma.     

Trimetrexate in advanced carcinoma of the esophagus

Summary Twenty-four patients with advanced epidermoid carcinoma of the esophagus were treated with trimetrexate (TMTX), a lipid soluble non-classical antifol. Patients were given TMTX 8 mg/m² intravenously day 1–5 every 28 days. In nine of these patients the dose was escalated to 12 mg/m² day 1–5 every 28 days. Three patients had a partial response (95% confidence limit 3–32%) with a median response duration of 14 weeks. No hematologic toxicity was documented. Two patients developed moderate stomatitis and only 3 patients experienced any nausea or vomiting. The median survival of all patients is 12 weeks. It is concluded that a higher dose of TMTX should be studied in patients with esophageal cancer in order to assess the true therapeutic value of the agent at a dose closer to the median tolerated dose. A phase II ECOG study using TMTX 12 mg/m² intravenously day 1–5 every 21 days is currently being conducted.     

Using zebrafish to assess the effect of chronic,early developmental exposure to environmentally relevant concentrations of 5-fluorouracil and leucovorin

Environmental contaminants can deleteriously affect aquatic animals. One such contaminant is 5-fluorouracil (5-FU), a long-prescribed chemotherapeutic drug. Leucovorin (LV) is co-administered with 5-FU, potentiating its effects. Zebrafish (Danio rerio) larvae were reared in ng/L treatments of either 5-FU, LV, or a combined 5-FU/LV mixture for 8 dy. Survival was measured daily and swimming behavior assessed every other day. After 8 dy, larval length was measured, and densitometry of p53-labeled cryostat sections determined the extent of apoptosis. No significant differences in survival or apoptosis were found; larvae in the highest concentrations were largest. Changes in behavior of 5-FU-treated larvae were based on exposure duration; changes in LV-treated larvae were affected by drug concentration and duration. Larvae co-exposed to 5-FU/LV had responses like 5-FU-treated larvae. Overall, early developmental exposure of zebrafish larvae to environmentally-relevant concentrations of 5-FU and LV did not adversely affect survival, growth, and behavior suggesting realistic concentrations are sublethal and non-toxic.     

A Phase II trial of weekly infusional 5-fluorouracil in combination with lowdose leucovorin in patients with advanced colorectal cancer

Exogenous leucovorin is a source of reduced folate which enhances the inhibition of thymidylate synthase that results from 5-fluorouracil (5-FU) administration. Extracellular reduced folate concentrations of 1 M have been reported to yield maximal enzyme inhibition in several cell lines treated with 5-FUin vitro. Clinical studies indicate that low doses of leucovorin have equivalent efficacy to higher doses in successfully modulating 5-FU in the treatment of colorectal cancer. Based on pharmacokinetics at higher doses, steadystate total plasma reduced folate concentrations of 1 M would be expected from the administration of leucovorin 50 mg/m² by 24 h infusion. This dose was admixed with 5-FU 2300 mg/m² and administered by 24 h infusion weekly to 38 patients with advanced colorectal cancer, of whom 32 are evaluable for response. Disease sites included liver (33 patients), lung (12 patients), and bone (4 patients). Toxicity was mild to moderate, except for grade 3 diarrhea in 5 patients, and chest pain in 2 patients. Among the 32 evaluable patients, there were 14 partial remissions for a total response rate of 44% (95% confidence interval 27–61%). The median duration of response was seven (range 1 to 20+) months, and median duration of survival 16 months. These results support the use of low doses of leucovorin to modulate weekly infusional 5-FU in colorectal cancer, and provide a basis for the integration of this regimen with other modulators of 5-FU.     

Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer

Purpose. To investigate thehypothesis that a systemic agent designedto inhibit dihydropyrimidine dehydrogenase(DPD), the first enzyme in thefluoropyrimidine degradative pathway, couldimprove the effective amount of5-fluorouracil (5-FU) delivered to a tumorresulting in enhanced response. Patients and methods. Eligibility includedcytologically or pathologically verifieddiagnosis of colorectal cancer thatrecurred during or within 12 months ofcompletion of adjuvant therapy,representing patients generally consideredresistant to fluorinated pyrimidinetherapy. Stratification was into twocohorts: recurrence while receivingadjuvant therapy, and relapse within 12months of completing adjuvant therapy.Treatment consisted of 28 days of oraltherapy every five weeks with eniluraciland 5-FU administered in a 10:1 ratio. Thedaily dose of eniluracil was 10 mg/m²with 5-FU 1 mg/m², divided into twodoses. Results. Twenty-five patientsare evaluable for response: 9 relapsedduring therapy and 16 relapsed within oneyear of adjuvant therapy. In the firstgroup, there was one partial response (9%;95% CI 0–41%); in the second cohort therewas one confirmed complete response (5%;95% CI 0–23%) and one unconfirmed partialresponse, for an overall response rate of10%. Conclusions. This regimen lackssignificant activity in this targetpopulation. Pre-treatment intratumoral DPDexpression was not assessed, therefore themechanism of fluorinated pyrimidineresistance cannot be specificallyattributed to elevated DPD levels.Attempting restoration of chemotherapysensitivity through blockade of enzymes orsignal transduction molecules responsiblefor resistance is rational, provided thattumor target expression is the basis fortrial entry.     

Role of cytochrome P4502D6 in the metabolism of brofaromine

Summary The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period.The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t_1/2, t_max and C_max were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml^–1 versus 223 ng · ml^–1. This, together with a significantly longer t_1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA.In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime.It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.     

Phase II trial of PALA and 6-methylmercaptopurine riboside (MMPR) in combination with 5-fluorouracil in advanced pancreatic cancer

Summary The biochemical modulators PALA, an inhibitor of aspartate transcarbamylase which depletes uridine nucleotide pools, and 6-methylmercaptopurine riboside (MMPR) which inhibits purine metabolism, selectively potentiate the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Based on a phase I trial of this combination, we performed a phase II trial in patients with advanced pancreatic cancer. PALA 250 mg/m² was administered i.v. on day 1, followed 24h later by MMPR 150 mg/m² as a bolus i.v. injection, and 5-FU 2300 mg/m² by 24h infusion. Treatments were repeated weekly. Seventeen patients, all previously untreated with chemotherapy, were entered, of whom 14 are evaluable for response. Toxicity grade 2 included nausea (6/17), vomiting (4/17), diarrhea (3/17), stomatitis (5/17), and neurotoxicity (2/17). Among 14 evaluable patients there were no partial responses, and two patients with stable disease. Pretreatment with PALA and MMPR is insufficient to enhance the activity of 5-FU in pancreatic cancer.     

Development of nanoliposomal irinotecan (nal-IRI,MM-398, PEP02) in the management of metastatic pancreatic cancer

Introduction: Systemic chemotherapy remains the standard of care for patients with advanced pancreatic ductal adenocarcinoma (PDAC). The introductions of FOLFIRINOX and nab-paclitaxel/gemcitabine combinations have improved the first-line treatment outcomes of patients with metastatic PDAC; while second-line therapy options are limited. Based on the results of pivotal NAPOLI-1 study, nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) became the first US Food and Drug Administration (FDA) approved regimen for patients with metastatic PDAC with previous gemcitabine-based chemotherapy in November 2015.

Areas covered: We reviewed and summarized the rationale, pharmacokinetics, therapeutic efficacy and adverse events of nal-IRI alone or combined with 5-FU/LV for metastatic PDAC with previous gemcitabine-based chemotherapy.

Expert opinion: In the NAPOLI study, nal-IRI plus 5-FU/LV significantly improved the overall survival, progression-free survival and objective response rate compared to 5-FU/LV alone. The nal-IRI plus 5-FU/LV treatment was associated with a manageable toxicity profile and comparable outcomes in patients with negative demographic characteristics. The relatively sparse of neurotoxicity makes nal-IRI plus 5-FU/LV as a more favorable option than oxaliplatin-containing regimens and the current recommended standard treatment for patients with metastatic PDAC after frontline nab-paclitaxel/gemcitabine treatment. The front-line therapeutic role of nal-IRI is currently under investigation.     

Comparison of the Pharmacokinetics of S-1, an Oral Anticancer Agent, in Western and Japanese Patients

Objective: S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western and Japanese patients. Methods: A single dose (25–45 mg/m²) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24hr. Using NONMEM, oteracil and CDHP were analyzed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations, and finally we compared the exposures in Western and Japanese patients using simulations. Results: A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes.     

Pharmacokinetics and dialysability of isradipine in chronic haemodialysis patients

Summary The pharmacokinetics of isradipine, a calcium-channel blocker, have been studied in eight patients on chronic haemodialysis. A single oral dose of 5 mg was administered on both a non-haemodialysis and a haemodialysis day and the plasma concentrations of isradipine were analyzed.The mean c_max, t_max, AUC, and t_1/2 in plasma on the non-haemodialysis day were 5.2 ng·ml^–1, 1.4 h, 23.8 ng·h·ml^–1, and 3.1 h, respectively. The dialysis clearance of isradipine was negligible (5.0 ml·min^–1).The t_1/2 values during haemodialysis were not significantly different from those observed during the same period post dose on the non-haemodialysis day. The study demonstrates that supplemental doses of isradipine are not necessary in these patients since isradipine is not significantly removed by haemodialysis.     

A randomised phase II study of OSI-7904L versus 5-fluorouracil (FU)/leucovorin (LV) as first-line treatment in patients with advanced biliary cancers

Summary The prognosis of advanced biliary tract carcinoma is poor with chemotherapy limited to a palliative role. This randomised study was designed to evaluate the effectiveness of a new liposomal thymidylate synthase inhibitor (TSI), OSI-7904L, in parallel with a modified de Gramont regimen of 5-FU/LV in patients with advanced biliary cancer. Patients with previously untreated advanced or metastatic carcinoma of the biliary tract were randomised to receive either OSI-7904L 12 mg/m² intravenously every 21 days or a modified de Gramont schedule of 5-FU/LV (intravenous l-LV 200 mg/m², bolus 5-FU 400 mg/m² and a 46-h infusion of 5-FU 2,400 mg/m²) every 14 days. Twenty-two patients were randomised, 11 to each group. No patients responded in the OSI-7904L arm, while one patient achieved a partial response in the 5-FU/LV arm. The rates of disease stabilisation were 4/11 (OSI-7904L) and 10/11 (5-FU/LV). Both treatment arms were generally well tolerated. These results show that the activity of OSI-7904L is below a level of clinical relevance in advanced biliary tract cancer, providing only a small degree of disease stabilisation. A simplified de Gramont schedule appears to have marginally more activity. Both treatments were well tolerated. Research funding and OSI-7904L provided by OSI Pharmaceuticals Inc.     

The pharmacokinetics and pharmacodynamics of 12 weeks of glyburide therapy in obese diabetics

Summary We have studied the pharmacokinetics and pharmacodynamics of glyburide during long-term therapy in 20 patients with type II diabetes mellitus. The patients were divided according to body mass index (BMI) into an obese group [n=12, age 55(13) y, BMI 36.2(9.2) kg·m^–2, total body weight (TBW) 100(23) kg], and a non-obese group [n=8, age 61(13) y, BMI 24.5(2.1) kg·m^–2, TBW 73(7) kg].The dosages of glyburide were titrated to achieve specified therapeutic goals based upon serum glucose concentrations or to a maximum dosage of 20 mg per day. The pharmacokinetics of glyburide were determined at week 12 of treatment. On the study day, the patients took a 2.5 mg liquid test dose of glyburide with a Sustacal meal challenge. The elimination rate constant (_z), clearance (CL), and apparent volume of distribution (V_z) were 0.08 h^–1, 3.3 l·h^–1, and 47.0 l in the obese group, and 0.07 h^–1, 3.1 l·h^–1, and 56.8 l in the non-obese group. These values were not statistically significantly different. However, there were differences between the groups when the volume and clearance were corrected by TBW or BMI but not by ideal body weight (IBW) or fat-free mass (FFM).Regression analysis between the pharmacokinetic variables and body weight status revealed statistically significant correlations between volume or clearance and body weight. However, due to large inter-patient variability, these relations were relatively weak and were considered to be non-predictive.In regard to the pharmacodynamic effects of glyburide, there were greater C-peptide and insulin responses at baseline and after 12 weeks of therapy in the obese than in the non-obese patients. However, there were no significant differences in glucose responses between the two groups. More non-obese patients needed the maximum dose (20 mg) of glyburide (7/8) compared with obese patients (6/12).These findings suggest that obese patients may be more sensitive to the effects of glyburide. Alternatively, our obese patients may have had less serious disease than our non-obese patients.     

奥沙利铂联合亚叶酸钙和氟尿嘧啶持续滴注治疗晚期大肠癌的临床观察

OBJECTIVE To evaluate the efficacy and toxicity of oxaliplatin(L-OHP) in combination with Leucovorin(LV) fluorouracil(5-FU) in the treatmet of advanced colorectal cancer.METHODS 35 patients with advanced colorectal cancer enrolled.All patients received mo     

Pharmacokinetics and tolerance of a new penem antibiotic,FCE 22101, in healthy volunteers after a single intravenous dose

Summary The clinical tolerance and pharmacokinetics of FCE 22101 (sodium (5R, 6S)-6-[(1R)-hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate), a new penem antibiotic, have been studied after giving a single i.v. dose of 4 mg·kg^–1 to ten healthy male volunteers. The pharmacokinetics was estimated according to a two-compartment open model. The peak plasma concentration (C_max) was 15.5 (1.08) µg·ml^–1, mean (SEM). FCE 22101 was rapidly cleared from the systemic circulation [ =44.2 (4.2) min; CL=7.21 (0.47) ml·kg^–1·min^–1]. The mean apparent volume of distribution at steady-state was 246 (16.9) ml·kg^–1. The mean residence time relative to the 10 min infusion was 39.4 (1.5)min. Urinary recovery of FCE 22101 showed wide inter-subject variation, ranging from 10.2 to 53.6% of the dose. No subject complained of adverse effects.