Continuous Intravenous Infusion In Patients Research Articles

Comparison emergence of sedation, using dexmedetomidine and remimazolam, in spinal anaesthesia - double blinded randomized controlled trial.

Background: Continuous intravenous infusion of remimazolam may be suitable for sedation in patients undergoing regional anaesthesia. However, there have been no studies comparing remimazolam and dexmedetomidine for this purpose. This study compared emergence from sedation between dexmedetomidine and remimazolam following continuous intravenous infusion in patients undergoing spinal anaesthesia. Methods: This double-blinded, randomised controlled trial assessed the sedative effects of dexmedetomidine and remimazolam. Following spinal anaesthesia, patients were sedated using continuous intravenous infusion of either dexmedetomidine (D group) or remimazolam (R group).The D group received dexmedetomidine administered at 6 mL/kg/h (6 µg/kg/h) for 10 minutes, followed by 1 mL/kg/h (1 µg/kg/h). The R group received remimazolam administered at 6 mL/kg/h (6 mg/kg/h) for 10 minutes, followed by 1 mL/kg/h (1 mg/kg/h). Sedation levels were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The time to reach MOAA/S ≤ 3 from the start of drug infusion and the time to reach MOAA/S = 5 from the end of infusion were recorded. Hemodynamic parameters and respiratory rate were also monitored. Results: The R group reached MOAA/S ≤ 3 significantly faster than the D group during induction of sedation (4 ± 1 minutes and 11 ± 3 minutes, respectively, p < 0.001). The R group also reached MOAA/S = 5 significantly faster than the D group during emergence from sedation (11 ± 3 minutes and 16 ± 5 minutes, respectively, p < 0.001). Both groups maintained stable hemodynamic parameters and respiratory rate without any significant differences, although the mean heart rate was significantly lower in the D group than in the R group after the start of infusion. Conclusion: Remimazolam demonstrated significantly faster induction of and emergence from sedation compared to dexmedetomidine, with no significant differences in haemodynamics or respiratory depression.

Corrigendum to “Safety, Tolerability, Pharmacokinetics, and Efficacy of Terlipressin Delivered by Continuous Intravenous Infusion in Patients with Cirrhosis and Refractory Ascites”

Corrigendum to “Safety, Tolerability, Pharmacokinetics, and Efficacy of Terlipressin Delivered by Continuous Intravenous Infusion in Patients with Cirrhosis and Refractory Ascites”

Safety, Tolerability, Pharmacokinetics, and Efficacy of Terlipressin Delivered by Continuous Intravenous Infusion in Patients with Cirrhosis and Refractory Ascites

Background. Terlipressin is a long acting synthetic analogue of vasopressin, which is used to manage variceal bleeding and hepatorenal syndrome. Terlipressin is being developed to treat refractory ascites in cirrhotic patients who are no longer responsive to diuretic drugs and require repeated paracentesis. This study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of a continuous intravenous (IV) infusion of terlipressin as an outpatient treatment for refractory ascites in patients with advanced liver cirrhosis. Methods. This was an open-label Phase 2a trial. Patients received a continuous IV infusion of terlipressin 2 mg/day escalating to 4 mg/d during an initial 7-day inpatient period, followed by 21 days as outpatients. The PK, safety/tolerability, and effects on the need for and volume of paracentesis were evaluated. Results. Four of 6 patients experienced ≥50% increase in the interval between large volume paracenteses (LVP) with terlipressin. The volume of ascites removed by LVP in the 28-day treatment period was reduced in all patients by ≥30% compared with pretreatment. Terlipressin was rapidly eliminated with a mean half-life of 42.3 minutes, mean clearance of 5.6 mL/min/kg, and volume of distribution of 0.33 L/kg. Average steady state plasma concentrations ranged from 1.69 to 5.55 ng/mL and increased proportionally with increasing dose. Three (50.0%) patients reported treatment-related adverse events, but none were serious. Conclusion. Continuous terlipressin IV infusion improved control of refractory ascites with an acceptable safety and predictable PK profile. Further evaluation of terlipressin is warranted in a randomized controlled trial for treating refractory ascites and related complications of cirrhosis.

Safety, tolerability, pharmacokinetics and pharmacodynamic activity of terlipressin delivered by continuous intravenous infusion in patients with cirrhosis and refractory ascites: a phase 2a open-label trial

Safety, tolerability, pharmacokinetics and pharmacodynamic activity of terlipressin delivered by continuous intravenous infusion in patients with cirrhosis and refractory ascites: a phase 2a open-label trial

Safety and efficiency of the port-catheter for intensive intravenous chemotherapy in patients with multi-drug resistant tuberculosis and extensively drug-resistant tuberculosis

PURPOSE. To study the efficacy and tolerability of the port catheter for continuous intravenous infusion in patients with MDR-TB and XDR-TB.&#x0D; MATERIALS AND METHODS. In a controlled study examined the effectiveness of the port catheter during an intensive 7-component anti-TB treatment with intravenous application of 3 anti-TB drugs (moxifloxacin, PAS, linezolid) in 16 patients with MDR-TB and XDR-TB. In the comparison group, which is formed by a pair of matching according to the drug resistance profile of MTB, the same intensive chemotherapy regimens in which the infusion of these drugs was carried out by daily injections of veins. In each group dominated patients with retreatment cases – 14 (87.5 %) patients. The planned duration of intravenous therapy was 2–4 months.&#x0D; RESULTS. Port-catheter for continuous infusion of combination of anti-tuberculosis drugs in comparison to their administration in the usual way ensures high efficiency and safety. In any case, was not observed phlebitis, no complaints of pain at the injection site, only 12.5 % cases were hematoma after setting the port in comparison to 100.0 % of patients with daily venous injections. In the study group was not a single case of interruption of intravenous infusion. In the control group, 56.2 % of patients discontinued intravenous treatment due to inability to penetrate the vein, patient’s complaints pain or phlebitis. At the end of the intensive phase of chemotherapy sputum conversion and disappearance of clinical symptoms were observed in 15 (3.7 %) patients of the study group, that was 26.7 % higher, than in control group (p&gt;0,05). We found significant difference in terms of sputum conversion, which occurred in the study group through (2,2±0,1) months vs (3,7±0,3) months (&lt;0,05) in control group.&#x0D; CONCLUSIONS. Port-catheter for long-term daily infusions of combination of anti-TB drugs compared with their usual daily injections is safe and effective method of intravenous therapy. It is not accompanied by subjective complaints of patients and the development of phlebitis, which leads to early sputum conversion. With daily injections of veins 56.2 % of patients prematurely discontinued treatment through intensive local complications or phlebitis. Application of intensive treatment with the introduction of anti-TB drugs allows for faster time to achieve sputum conversion.

Safety and efficiency of the port-catheter for intensive intravenous chemotherapy in patients with multi-drug resistant tuberculosis and extensively drug-resistant tuberculosis

PURPOSE. To study the efficacy and tolerability of the port catheter for continuous intravenous infusion in patients with MDR-TB and XDR-TB.&#x0D; MATERIALS AND METHODS. In a controlled study examined the effectiveness of the port catheter during an intensive 7-component anti-TB treatment with intravenous application of 3 anti-TB drugs (moxifloxacin, PAS, linezolid) in 16 patients with MDR-TB and XDR-TB. In the comparison group, which is formed by a pair of matching according to the drug resistance profile of MTB, the same intensive chemotherapy regimens in which the infusion of these drugs was carried out by daily injections of veins. In each group dominated patients with retreatment cases — 14 (87.5 %) patients. The planned duration of intravenous therapy was 2—4 months.&#x0D; RESULTS. Port-catheter for continuous infusion of combination of anti-tuberculosis drugs in comparison to their administration in the usual way ensures high efficiency and safety. In any case, was not observed phlebitis, no complaints of pain at the injection site, only 12.5 % cases were hematoma after setting the port in comparison to 100.0 % of patients with daily venous injections. In the study group was not a single case of interruption of intravenous infusion. In the control group, 56.2 % of patients discontinued intravenous treatment due to inability to penetrate the vein, patient’s complaints pain or phlebitis. At the end of the intensive phase of chemotherapy sputum conversion and disappearance of clinical symptoms were observed in 15 (3.7 %) patients of the study group, that was 26.7 % higher, than in control group (p&gt;0,05). We found significant difference in terms of sputum conversion, which occurred in the study group through (2,2±0,1) months vs (3,7±0,3) months (&lt;0,05) in control group.&#x0D; CONCLUSIONS. Port-catheter for long-term daily infusions of combination of anti-TB drugs compared with their usual daily injections is safe and effective method of intravenous therapy. It is not accompanied by subjective complaints of patients and the development of phlebitis, which leads to early sputum conversion. With daily injections of veins 56.2 % of patients prematurely discontinued treatment through intensive local complications or phlebitis. Application of intensive treatment with the introduction of anti-TB drugs allows for faster time to achieve sputum conversion.

Analgesic efficacy, adverse effects, and safety of oxycodone administered as continuous intravenous infusion in patients after total hip arthroplasty.

BackgroundTotal hip arthroplasty (THA) causes extensive tissue damage and severe pain. This study aimed to assess the analgesic efficacy, adverse effects (AEs), and safety of continuous intravenous (iv) oxycodone infusion with ketoprofen (injected into the iv line) in patients after THA, and to assay serum oxycodone levels.Patients and methodsFourteen patients, aged 59‒82 years with American Society of Anesthesiologists (ASA) classification I or III, underwent THA with intrathecal analgesia and sedation induced by iv propofol. After the surgery, oxycodone (continuous iv infusion) at a dose of 1 mg/h (five patients) or 2 mg/h (nine patients) with 100 mg ketoprofen (injected into the iv line) was administered to each patient every 12 h. Pain was assessed using a numerical rating scale (NRS: 0 – no pain, 10 – the most severe pain) at rest and during movement. AEs, including hemodynamic unsteadiness, nausea, vomiting, pruritus, cognitive impairment, and respiratory depression, were registered during the first 24 h after surgery.ResultsOxycodone (continuous iv infusion) at a dose of 2 mg/h with ketoprofen (100 mg) administered every 12 h provided satisfactory analgesia in all nine patients without the need of rescue analgesics within the first 24 h after THA. In three out of five patients, oxycodone at 1 mg/h was effective. Oxycodone did not induce drowsiness, vomiting, pruritus, respiratory depression, or changes in blood pressure. Bradycardia appeared in two patients, and nausea was observed in one patient.ConclusionOxycodone infusion with ketoprofen administered by iv is effective in patients after THA. Intravenous infusion of oxycodone is a predictable, stable, and safe method of drug administration.

Phase I Trial of AEG35156 Administered as a 7-Day and 3-Day Continuous Intravenous Infusion in Patients With Advanced Refractory Cancer

To establish the maximum-tolerated dose and evaluate tolerability, pharmacokinetics, pharmacodynamic effects, and antitumor activity of AEG35156, a second-generation antisense to X-linked inhibitor of apoptosis (XIAP) protein, in patients with advanced refractory malignant tumors. This was a first-in-man, open-label, phase I dose-escalation study. AEG35156 was administered by continuous intravenous infusion over 7 days (7DI) or 3 days (3DI) of a 21-day treatment cycle. Dose escalation started at 48 mg/m(2)/d and continued until consistent dose-limiting toxicity (DLT) was observed. Thirty-eight patients were entered in seven cohorts. Grade 3 to 4 adverse events were uncommon and were predominantly abnormal laboratory values: elevated ALT, thrombocytopenia, and lymphopenia. DLTs comprised elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia. The maximum-tolerated doses were defined as 125 mg/m(2)/d for the 7DI regimen and < or = 213 mg/m(2)/d for the 3DI schedule. AEG35156 area under the plasma concentration curve and peak plasma concentration increased proportionally with dose. Suppression of XIAP mRNA levels was maximal at 72 hours (mean suppression, 21%), and this coincided with a dramatic decrease in circulating tumor cells in a patient with non-Hodgkin's lymphoma. Two further patients had unconfirmed partial responses. Circulating biomarkers of cell death and apoptosis altered in association with drug infusion and toxicity. In this first-in-man study, AEG35156 was well tolerated, with predictable toxicities, pharmacokinetic properties, and clinical evidence of antitumor activity in patients with refractory lymphoma, melanoma, and breast cancer. Phase I/II trials of AEG35156 chemotherapy combinations are ongoing in patients with pancreatic, breast, non-small-cell lung cancer, acute myeloid leukemia, lymphoma, and solid tumors for which docetaxel is indicated.

A phase I trial of AEG35156 (XIAP antisense) administered as a continuous intravenous infusion in patients with advanced tumors

3059 Background: The X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein. AEG35156 is a synthetic 2nd generation antisense oligonucleotide to human XIAP that enhances cancer cell apoptosis preclinically as a single agent and in combination with chemotherapeutics. Methods: The primary objective was to establish the maximum tolerated dose (MTD) of AEG35156 given as a 7-day continuous infusion every 3 weeks. Other objectives were to determine AEG35156 pharmacokinetics, XIAP inhibition in peripheral blood mononuclear cells and in tumour cells where feasible and document anti-tumour activity. Results: Sixteen adult patients have completed at least one 7-day infusion. Two dose-limiting toxicities (DLT) were observed in five patients treated at 160 mg/m2/day: grade 3 thrombocytopenia for more than 7 days and grade 3 ALT and AST elevation. Seven patients have been treated at 125 mg/m2/day with one DLT of grade 3 transaminase elevation. An approximately 50% decrease in XIAP mRNA was seen in peripheral blood leucocytes three days after the start of infusions at 160mg/m2/day. One patient with small lymphocytic non-Hodgkin’s lymphoma had marked but short lived decreases in peripheral lymphoblasts during AEG35156 administration closely associated with XIAP mRNA knockdown. One patient with breast cancer had an unconfirmed partial response. The trial has now been amended to also determine the MTD of a 3-day continuous infusion every 3 weeks. Three patients have been treated with 3-day infusions at 160mg/m2/day every 3 weeks with no significant toxicities observed and patients are currently being accrued at 213mg/m2/day. Conclusions: AEG35156 can be safely delivered by continuous infusion and preliminary evidence of XIAP mRNA knockdown and antitumour activity has been observed. [Table: see text]

Continuous intravenous infusion (CIVI) topotecan may be safely combined with tipifarnib

2064 Background: Dose limiting (DL) myelosuppression occurred when topotecan 1.0 mg/m2/d × 5d was combined with tipifarnib (Proc ASCO, 2001, abst 321). We now report on a 3+3 cohort design to determine the safety and pharmacokinetics (PK) of this combination with topotecan given as CIVI in patients (pts) with refractory solid tumors. Methods: Pts were treated with escalating dose levels of topotecan (0.2–0.4 mg/m2/d) given as 21-day infusion in combination with tipifarnib 200 mg PO bid for 21 d every 28 d. Blood was drawn for topotecan PK and intracellular (PBMC) toposisomerase I on d 1 (baseline) and d 5 (tipifarnib omitted d1, cycle 1), and weekly × 8 for ras-farnesylation (membrane bound fraction). Plasma levels of the closed form of topotecan were determined by SPE and HPLC with fluorometric detection. Topoisomerase I in PBMCs was detected by Western blot. Results: 14 patients were accrued at 3 dose levels: topotecan 0.2 mg/m2/d (3 pts), 0.3 mg/m2/d (3), and 0.4 mg/m2/d (8), combined with tipifarnib. Median age was 50 years (33–62). 32 cycles (median 2) were given. Grade 1–3 fatigue, nausea, thrombocytopenia, neutropenia and anemia were common, and at dose level 3, two heavily-pretreated patients had DL myelosuppression. Six others had no significant toxicity over prolonged times. Of nine evaluable for response, a mucinous peritoneal cancer had a minor response for 5 m, an ovarian granulosa cell tumor had a mixed response in lung metastases for 15 m, and a PNET of bone had a minor response for 17 m; six had progression. Mean steady state (± SD) levels of topotecan for dose levels I, II and III were, respectively, 0.48 ± 08 (N = 3), 1.26 ± 0.32 (N = 3) and 1.47 ± 0.1 (N = 5) ng/ml, and were linear with respect to topotecan dose (r = 0.95). By the end of the 21 d infusion, 90% of baseline topoisomerase I signal was depleted in PBMCs. Conclusions: In contrast with bolus topotecan, CIVI topotecan may be combined at known effective doses with tipifarnib. Recommended phase II doses are 0.4 mg/m2/d × 21 days and 200 mg bid daily for those with limited prior therapy. Phase II studies in gynecologic and breast tumors are planned. Supported by UO1- 76642; CA 16087. [Table: see text]

Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer

Phenoxodiol is a multi-pathway initiator of apoptosis with broad anti-tumor activity and high specificity for tumor cells. Its biochemical effects are particularly suited to reversal of chemo-resistance, and the drug is being developed as a chemo-sensitizer of standard chemotherapeutics in solid cancers. This phase I, single-center trial was conducted to test a continuous intravenous dosing regimen of phenoxodiol in patients with late-stage, solid tumors to determine toxicity, pharmacokinetics, and preliminary efficacy. Phenoxodiol given by intravenous infusion continuously for 7 days on 14-day cycles was dose-escalated on an inter-patient basis at dosages of 0.65,1.3, 3.3, 20.0, and 27.0 mg/kg/day (three to four patients per stratum). Treatment cycles continued until disease progression. Toxicity was based on standard criteria; efficacy was based on changes in tumor burden (WHO); pharmacokinetic analysis was conducted on plasma samples at specified time points during treatment cycles. Nineteen heavily-pre-treated patients with solid tumors received a median of three cycles of treatment (range 1-13); two patients received >or= 12 cycles. No dose-limiting toxicities were encountered, with emesis and fatigue (one patient) and rash (one patient) the only significant toxicities. Stabilized disease was the best efficacy outcome, with one patient showing stable disease at 24 weeks. Pharmacokinetics suggested a linear relationship between dosage and mean steady-state plasma concentrations of phenoxodiol. A 7-day continuous infusion of phenoxodiol given every 2 weeks is well tolerated up to a dose of 27.0 mg/kg/day.

A Phase I Trial of Gemcitabine Administered as a 96-h Continuous Intravenous Infusion in Patients with Advanced Carcinoma and Lymphoma

Preclinical data suggest gemcitabine may have schedule-dependent activity favoring prolonged infusion. We sought to determine the recommended phase II dose (RPTD) and toxicity of gemcitabine when given as a continuous intravenous (CIVI) over 96 h. Gemcitabine was initially given at 1 mg/m(2)/d for 48, then 72, and finally 96 h. The dose was then increased to 2, 4, 6, 10, 15, 20, and 25 mg/m(2)/d. Dose levels of 7, 8, 9 mg/m(2)/d as 96-h infusion were added later after a protocol modification. After identifying the RPTD using an every 3-wk schedule, we then evaluated the feasibility of repeating the infusion every 2 wk, and then weekly for 3 of 4 wk. Thirty-four patients with a variety of tumor types received a total of 126 cycles of therapy (median of 2 cycles, range 1-10 cycles). The RPTD was 8 mg/m(2)/d every 3 wk, and 6 mg/m(2)/d every 2 wk. The most common grade 2 or higher toxicities at all dose levels (>or= grade 2) included fever (n = 14), dyspnea (n = 7), mucositis (n = 6), hypotension (n = 6), nausea/vomiting (n = 6), and fatigue (n = 5). Neutropenia and/or thrombocytopenia were uncommon. Administration of gemcitabine as a 96-h infusion results in a markedly different toxicity profile and RPTD than when given by a conventional 30-min infusion. The RPTD was 8 mg/m(2)/d (32 mg/m(2)/course) when given every 3 wk, or 6 mg/m(2)/d (24 mg/m(2)/course) when given every 2 wk.

Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 administered as a weekly 24 h continuous intravenous infusion in patients with advanced solid tumors

BMS-214662 is a novel farnesyltransferase (FT) inhibitor that has shown promising suggestions of single agent activity in patients with advanced solid tumors when administered as a 1 h intravenous (i.v.) infusion every 3 weeks. The degree of FT inhibition in peripheral blood mononuclear cells (PBMCs) was greatest at the end of the infusion and rapidly reversed as the concentration of the drug in the plasma decayed. A second phase I trial of BMS-214662 administered as a weekly 24 h i.v. infusion was initiated to determine if the duration of maximum FT inhibition could be significantly extended by prolonging the infusion time and increasing the frequency of administration. Infusion of BMS-214662 was prolonged from 2, 4, 8, 16, 24 h in single patient cohorts and repeated weekly for 3 out of 4 weeks. The initial dose was 56 mg/m(2). When the infusion duration reached 24 h, the dose was escalated at a constant multiples of 1.4 in single patient cohorts until the occurrence of toxicity greater than grade 1, upon which groups of at least three patients were evaluated at each dose level. The plasma pharmacokinetics and FT inhibition in PBMCs were measured in all patients at the prospective maximum tolerated dose. Nineteen patients participated in the study (11 males/8 females) and the weekly dose was increased to a maximum of 300 mg/m(2) given as a 24 h i.v. infusion. Drug-related toxicity greater than grade 1 first occurred at 300 mg/m(2), with two patients experiencing dose-limiting toxicity. One patient developed a grade 3 hyponatremia and another developed reversible grade 3 diarrhea, grade 2 renal toxicity, and grade 3 transaminitis. A 275 mg/m(2) dose was then evaluated, where one of the three patients treated experienced reversible grade 4 renal toxicity and grade 3 diarrhea. In view of the identical renal toxicity at 275 mg/m(2) in another study and limited drug availability, there was no further accrual to this dose level and the study was closed. No evidence of antitumor activity was observed. The plasma pharmacokinetics of BMS-214662 was linear with high interpatient variability. In the three patients evaluated at the 275 mg/m(2) dose level, the maximum inhibition of FT activity in PBMCs was 47+/-23% of the baseline. Administering BMS-214662 as a weekly 24 h continuous i.v. infusion permitted a considerably greater dose intensity to be delivered as compared to a single 1 h infusion given once every 3 weeks. The more prolonged infusion schedule resulted in a much lower degree of maximum FT inhibition in PBMCs than achieved with the 1 h infusion, although the duration of enzyme inhibition was longer, consistent with the lower peak plasma concentration of the drug provided by comparably tolerated doses when given as a 24 h infusion. Similarly, delivering the drug with increased dose intensity permitted by this weekly administration schedule did not appear to enhance its therapeutic benefit, at least in this phase I trial. Continued development of BMS-214662 may depend upon the potential for using it in combination with other anticancer drugs.

A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors

Background:: This study of GTI-2040, a 20-mer phosphorothioate oligonucleotide complementary to the messenger ribonucleic acid (mRNA) of the R2 subunit of ribonucleotide reductase (RNR), was conducted to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of the agent in patients with advanced solid tumors or lymphoma. Plasma pharmacokinetics of GTI-2040 and suppression of RNR expression in peripheral blood mononuclear cells were also studied.Patients and methods:: GTI-2040 was administered as a continuous intravenous infusion for 21 days every 4 weeks. Dose escalation was performed using an accelerated, dose-doubling schedule until any drug related toxicity≥grade 2 was observed; subsequent dose escalation followed a more conservative dose escalation scheme with three patients/cohort.Results:: A total of 49 cycles of therapy were administered to 36 patients at GTI-2040 doses ranging from 18.5mg/m2/day to 222mg/m2/day. GTI-2040 was generally well tolerated. At the highest dose level examined, two patients experienced dose limiting reversible hepatic toxicity. Constitutional toxicities consisting of fatigue and anorexia were the most common toxicities.Conclusions:: The recommended dose of GTI-2040 given on this infusion schedule is 185mg/m2/day. GTI-2040 appears to have a manageable toxicity profile and is generally well tolerated as a single agent.

Steady‐State Serum Concentrations of Progesterone Following Continuous Intravenous Infusion in Patients With Acute Moderate to Severe Traumatic Brain Injury

Progesterone (PG) has been shown to provide substantial neuroprotection after traumatic brain injury (TBI) in multiple animal models. As a first step in assessing applicability to humans, the authors examined the effects of acute TBI and extracranial trauma on the pharmacokinetics of PG given by intravenous infusion. Multiple blood samples were obtained from 11 female and 21 male trauma patients receiving PG and 1 female and 3 male patients receiving placebo infusions for 72 hours. Values for C(SS), CL, t(1/2), and Vd were obtained using AUC((0-72)) and postinfusion blood samples. C(SS) values were 337 +/- 135 ng/mL, which were significantly lower than the target concentration of 450 +/- 100 ng/mL. The lower C(SS) is attributed to the CL, which was higher than anticipated. In addition, t(1/2) was longer and V(d) was higher than anticipated. These results demonstrate that stable PG concentrations can be rapidly achieved following TBI.

APOPTOSIS AND CHEMOTHERAPY FOR BLADDER CANCER

We discuss the role of apoptosis, that is gene directed self-destruction of a cell, in the response of bladder transitional cell carcinoma cells to chemotherapy. A directed MEDLINE literature search of apoptosis, bladder cancer and chemotherapy was performed to extract relevant information for review. The characteristics of apoptotic cells were defined and the methods in common use to detect these traits is described. The role of the key mediators of the apoptotic process in bladder cancer is discussed in the context of chemosensitivity and disease stage. The importance of the apoptosis induction after chemotherapy is highlighted. On stimulus by appropriate external or internal signals a cell may alter the expression of genes encoding for proteins associated with the apoptotic process. The development of apoptosis depends on the balance between pro-apoptotic and anti-apoptotic proteins. Key alterations in genes and proteins related to apoptosis within bladder cancer result in a shift away from the default state of apoptosis toward a cell with increased survival properties that is chemoresistant. Much current research in bladder cancer is aimed at restoring chemosensitivity by shifting the cell toward a pro-apoptotic phenotype. Successful translation of this work into clinical practice may improve survival in patients in whom prognosis is currently poor.

A Phase I trial of h-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma

Abnormal expression of Ras proteins frequently is found with oncogenic transformation making ras a promising therapeutic target. ISIS 2503 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in patients with advanced cancer. A continuous intravenous infusion of ISIS 2503 was administered for 14 days every 3 weeks to 23 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 2503 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 10.0 mg/kg/day of body weight was reached. Toxicity was scored by the National Cancer Institute's Common Toxicity Criteria, and tumor response was monitored after every two treatment cycles. Pharmacokinetic studies were performed in some of the patients up to, and including, the final dose of 10 mg/kg/day/day of body weight. Levels of H-ras mRNA expression also were determined in the circulating lymphocytes of some patients by quantitative reverse transcriptase-polymerase chain reaction. A total of 23 patients received 63 cycles of ISIS 2503 at escalating doses to 10.0 mg/kg/day without dose-limiting toxicity and only minimal side effects. Four patients had stabilization of their disease for 6-10 cycles. No consistent decreases in H-ras mRNA levels were observed in peripheral blood lymphocytes. ISIS 2503, an antisense oligonucleotide against H-ras, was well tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day continuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and future trials of ISIS 2503 in combination with chemotherapy should be considered.

A phase I study of rhizoxin (NSC 332598) by 72-hour continuous intravenous infusion in patients with advanced solid tumors

Rhizoxin (NSC 332598) is a novel macrolide antitumor antibiotic that inhibits microtubule assembly and also depolymerizes preformed microtubules. In preclinical evaluations, rhizoxin demonstrated broad antitumor activity in vitro and in vivo including both vincristine- and vindesine-resistant human lung cancers. Prolonged exposure schedules in xenograft models demonstrated optimal efficacy indicating schedule-dependent antitumor activity. The early phase I and II evaluations a five-minute bolus infusion schedule was studied, however, only modest anti-tumor activity was noted, possibly due to rapid systemic clearance. To overcome these limitations and to exploit the potential for schedule-dependent behavior of rhizoxin, the feasibility of administering rhizoxin as a 72-hour continuous intravenous (i.v.) infusion was evaluated. Patients with advanced solid malignancies were entered into this phase I study, in which both the infusion duration and dose of rhizoxin were increased. The starting dose was 0.2 mg/m2 over 12 hours administered every 3 weeks. In each successive dose level, the dose and infusion duration were incrementally increased in a stepwise fashion. Once a 72-hour i.v. infusion duration was reached, rhizoxin dose-escalations alone continued until a maximum tolerated dose (MTD) was determined. Nineteen patients were entered into the study. Rhizoxin was administered at doses ranging from 0.2 mg/m2 i.v. over 12 hours to 2.4 mg/m2 i.v. over 72 hours every 3 weeks. The principal dose-limiting toxicities (DLT) were severe neutropenia and mucositis, and the incidence of DLT was unacceptably high at rhizoxin doses above 1.2 mg/m2, which was determined to be the MTD and dose recommended for phase II studies. At these dose levels, rhizoxin could not be detected in the plasma by a previously validated and sensitive high-performance liquid chromatography assay with a lower limit of detection of 1 ng/ml. No antitumor responses were observed. Rhizoxin can be safely administered using a 72-hour i.v. infusion schedule. The toxicity profile is similar to that observed previously using brief infusion schedules. Using this protracted i.v. infusion schedule the maximum tolerated dose is 1.2 mg/m2/72 hours.

917 - Phase II trial of topotecan (T) as a continuous intravenous infusion in patients (PTS) with high grade gliomas

917 - Phase II trial of topotecan (T) as a continuous intravenous infusion in patients (PTS) with high grade gliomas

Effect of bolus injection versus continuous infusion of furosemide on diuresis and neurohormonal activation in patients with severe congestive heart failure

Previous studies have demonstrated that continuous infusion of furosemide results in increased diuresis and natriuresis compared with bolus administration of the drug in patients with severe heart failure. We reasoned that continuous infusion of furosemide caused less activation of neurohumoral mechanisms, since other studies have shown that bolus administration of furosemide may activate this system. We therefore tested the hypothesis that continuous administration of furosemide would increase water and sodium excretion due to less activation of neurohormones. Eight patients with severe heart failure were studied during continuous infusion over 24 h and bolus injections of furosemide twice daily in a randomized cross-over study. Bolus administration of furosemide increased diuresis and natriuresis significantly in the first 4 h after administration compared with continuous administration, but this was later reversed, resulting in similar 24 h total output. The neurohormones measured at baseline were all markedly elevated. Neither regimens of furosemide caused any further significant changes in neurohumoral response except that pro-ANF decreased more during the first 8 h after bolus administration compared to continuous infusion. This study has demonstrated that bolus administration of furosemide in conventional doses is equally effective as continuous intravenous infusion in patients with severe heart failure. This may be due to maximal neurohormonal activation in severe heart failure (NYHA III-IV) which could not be further activated by bolus administration.