Prolonged Intravenous Infusion Research Articles

Prolonged intravenous eptifibatide infusion for prevention of coronary stent thrombosis

Coronary bare-metal stent thrombosis usually occurs within a week of angioplasty, and may result in myocardial infarction and death. Thrombosis is effectively prevented by antiplatelet therapy with aspirin and clopidogrel. We describe a patient who was unable to ingest oral medication after angioplasty due to gastrointestinal surgery, and was therefore at risk for stent thrombosis. Intravenous eptifibatide was infused for 8 days in order to achieve parentreal platelet inhibition. We suggest a role for long-term intravenous administration of glycoprotein IIb/IIIa inhibitors for prevention of stent thrombosis in patients unable to take oral antiplatelet therapy.

Making sense of antisense

The specific and rational targeting of key genes, identified to be vital to driving cancer growth, has recently led to the successful development of several small molecule and antibody therapeutics. However, despite considerable efforts, antisense oligonucleotides (ASO) have yet to prove their worth as targeted therapies. However, many important genes cannot be readily targeted by antibodies or small molecules, and could be blocked by ASOs. Moreover, the latest generation of ASOs is safe, well tolerated and able to modulate target protein expression both in surrogate and tumour tissue in the clinic. This review will describe the experience acquired with these agents to date and will raise critical issues relevant to the further optimal development of these agents. Future clinical studies need to evaluate combinations of several different ASO targeting multiple key targets, including strategies that reverse functional redundancy of the key target ( e.g., targeting several Bcl family members including Bcl-2 and Bcl-x). Approaches to maximise the duration of target blockade yet avert the need for prolonged intravenous infusions, with the consequent risk of line infection and thrombosis, are also needed. These may include slow-release depot subcutaneous formulations. Short interfering (Si) RNA therapeutics, which are now being evaluated in early clinical trials, are also envisioned to impact the future utility of this class of therapeutics. The high manufacture cost of these agents, when compared with small chemical molecules, could however, limit their success unless cost-effective manufacturing processes are developed.

Radiochemotherapy with Vinblastine, Methotrexate, and Bleomycin in the treatment of verrucous carcinoma of the head and neck

To explore whether the combined radiochemotherapy with Vinblastine, Methotrexate, and Bleomycin could be an effective alternative treatment to surgery in verrucous carcinoma (VC) of the head and neck. Combined radiochemotherapy was used in 12 patients with previously untreated VC. They were irradiated to equivalent tumor dose of 44-70 Gy (median, 56 Gy) and had > or = 2 courses of concomitant chemotherapy. Chemotherapy regimen consisted of prolonged intravenous infusions of Vinblastine 2 mg (day 1); Methotrexate 50 mg (day 2); Bleomycin 15 mg (days 2 and 3), and repetition at 2-3 week intervals. Eleven of 12 patients were cured of VC, and one died of purulent meningitis associated with intracranial extension of VC from the oral cavity. Of 11 patients cured of VC, eight had advanced tumors. The median follow-up of cured patients was 3.6 years (range, 1.4-13.6 years). All the patients developed mucositis of grade > or = 3, whereas no serious late side-effects were recorded. Combined radiochemotherapy with Vinblastine, Methotrexate, and Bleomycine is highly effective in the treatment of VC of the head and neck. It could be successfully used in the patients with inoperable VC or as an alternative to surgery.

Spotlight

Cheng et al., pp.345–353 Prolonged exposure to estrogens can induce tumors in laboratory animals and has been associated with breast and uterine cancers in humans. The proliferative effect of estrogen on breast epithelium is part of the mechanism. In addition, recently surfaced evidence demonstrated that estrogen metabolites can cause DNA damage and mutations, an important step in tumor initiation. Oxidation of two catechol estrogen (CE) metabolites, 4-hydroxyestradiol and 4-hydroxyestrone, generates quinone intermediates. They can react with purine bases to form DNA adducts that generate highly mutagenic apurinic sites; CEs can also generate oxygen radicals and DNA double strand breaks (DSB). Cheng et al. examined whether breast tumorigenesis is linked to inherited variants in five genes that are involved in detoxifying pathways of estrogen metabolites. Women harboring a greater number of high-risk genotypes of CE-metabolizing genes faced an increased risk of breast cancer. This trend was more pronounced in women who had never been pregnant or older at their first full-term pregnancy and therefore at greater risk for breast cancer. Cheng also examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes. They found that a joint effect was significantly associated with breast cancer development. This study supports the hypotheses that increased estrogen exposure confers a higher risk of breast cancer, in part caused by DSB in DNA. Brennetot et al., pp.446–450 High-frequency microsatellite instability (MSI-H) is due to either insertion or deletion of repetitive sequences during DNA replication and failure of the mismatch repair system (MMR) to correct these errors. As a consequence, MMR-deficient tumors accumulate thousands of small mutations genome-wide. Almost all tumors from patients with human non-polyposis colorectal cancer (HNPCC) are MMR deficient, as are 10–15% of sporadic colorectal, gastric and endometrial cancers.2 Allelic profiles of BAT-26 and BAT-25 obtained by independent fluorescent PCR of these markers. MSI-H tumors differ from microsatellite-stable (MSS) tumors in molecular and in clinicopathological attributes. Generally, patients with MSI-H tumors are reported to have a better clinical outcome than patients with MMR-proficient tumors. Hence, screening of all human tumors where the MSI phenotype is frequent would not only allow the treatment to be custom-tailored but also assist in the diagnosis of ambiguous HNPCC cases. The present study demonstrates that together the markers BAT-25 and BAT-26, two mononucleotide repeats widely used as part of a larger set of markers, are sensitive enough to establish the MSI status of human tumors. Furthermore, they can detect instability when the tumor cell content of a sample is as low as 5–10%. This observation is very important in the context of proposed regular MSI screening for all colorectal, gastric and endometrial cancers. Not only might fewer markers than the routinely suggested panel of five suffice to reliably establish the microsatellite status of tumors, the labor-intensive and time-consuming process of enriching tumor cells in contaminated samples may only be required in a small subset of biopsies. Merchan et al., pp.490–498 Most angiogenesis inhibitors were developed intentionally to interrupt new blood vessel formation. In an unexpected twist, the antiangiogenic activity of several cytotoxic agents was discovered accidentally, among them the widely used chemotherapeutic paclitaxel. In addition to its well-known microtubule-interfering effect, paclitaxel inhibits endothelial cell (EC) migration, invasion, capillary tube formation and proliferation at low concentrations in vitro. In vivo, it significantly reduces microvessel density and decreases vascular endothelial growth factor (VEGF) production. While paclitaxel's effects on ECs are well studied and clinical trials investigating its antiangiogenic potential are underway, the underlying mechanism has not yet been elucidated. Based on the latest results by Merchan et al. it appears that an approximately fivefold increased ability of human ECs to accumulate the drug when compared to other cell types is responsible for the enhanced sensitivity of ECs. However, at the same time low concentrations of paclitaxel upregulate the expression of Cox-2, an enzyme also known for its angiogenesis-stimulating activity. Combined treatment with the specific Cox-2 inhibitor celecoxib resolved the undesirable dichotomy and resulted in more pronounced antiendothelial effects than applying either compound alone. These findings could be extended to a clinical setting, where four patients with prostate cancer or malignant melanoma were treated with prolonged intravenous infusions of paclitaxel and celecoxib. The potent antiangiogenic activity observed in plasma specimens suggests that a combination treatment may be an attractive strategy to capitalize on the intrinsic antiangiogenic and cytotoxic effects of each agent alone.

Oxaliplatin: Is It a New Standard Weapon for Colorectal Cancer?

Oxaliplatin: Is It a New Standard Weapon for Colorectal Cancer?

Antisense Oligonucleotides in the Treatment of Non–Small-Cell Lung Cancer

Antisense oligonucleotides (ASONs) are one of the new classes of molecularly targeted agents that have transitioned from the laboratory into clinical trials. Rational drug design has resulted in agents directed against a number of important cellular targets, including the mRNA of bcl-2, protein kinase (PK) C–α, PKA-I, H-ras, c-raf, R1 and R2 subunit of ribonucleotide reductase, and transforming growth factor β2. These drugs are well tolerated with favorable toxicity profiles, and preliminary studies have demonstrated that they can be feasibly combined with chemotherapy. Plasma half-life is short, generally necessitating continuous prolonged intravenous infusion. Shorter administration schedules are being investigated. Efficacy has been demonstrated in early-phase studies in non–small-cell lung cancer (NSCLC), non-Hodgkin's lymphoma, ovarian cancer, melanoma, and prostate cancer. Molecular correlative studies with peripheral blood mononuclear cells and tumor tissue have demonstrated suppression of target proteins, suggesting that these drugs are indeed reaching the target. Here we discuss the current status of development of ASONs, focusing on LY900003 (formerly ISIS 3521), an agent directed against PKC-α currently under study in NSCLC. Phase III studies will determine the ultimate role these agents will play in the treatment of cancer. Future areas of study include combination with radiation and other molecularly targeted agents, alternative dosing schedules, liposomal administration, and the development of new antisense agents directed against additional molecular targets.

Antiinflammatory Activity of IVIG Mediated through the Inhibitory FC Receptor

Purpose of the Study. High-dose intravenous gamma globulin (IVIG) has proven effective for the treatment of autoimmune diseases such as immune thrombocytopenia (ITP), but the mechanism for its beneficial effects have not been clearly defined. In this study, the molecular basis for the antiinflammatory property of IVIG was investigated in a murine model of ITP.Methods. ITP was induced in mice through the injection of an antiplatelet monoclonal antibody (mAb), and pretreatment with either IVIG or Fc antibody fragments (which bind to Fcγ receptors on cells, but cannot bind antigens) could prevent the resulting thrombocytopenia. Through the use of specific blocking antibodies and transgenic mice, the authors tested whether IgG receptors (FcγRIIB, FcγRIII) were involved in the protective effects of IVIG.Results. The FcγRIIB receptor was required for protection, as demonstrated by genetic deletion or blocking with mAb. In addition, protection by IVIG was associated with the induction of FcγRIIB, which inhibits macrophage activation, and presumably also inhibits the phagocytosis of platelets in the spleen.Conclusions. The authors concluded that IVIG inhibits autoantibody-mediated thrombocytopenia by inducing inhibitory FcγRIIB receptors on macrophages. The balance of inhibitory (FcγRIIB) and activating (FcγRIII) Fc receptors is likely to be a critical factor in the regulation of macrophage phagocytosis. These results suggest that autoantibody-triggered inflammatory diseases could be treated by new medications that inhibit macrophage phagocytosis.Reviewer’s Comments. IVIG is an effective treatment for many diseases caused by autoantibodies, but its utility is limited by high cost, administration by prolonged intravenous infusion, and the occasional occurrence of side effects such as aseptic meningitis and renal insufficiency. This work suggests that new approaches could be developed that would utilize the same protective mechanism as IVIG, but be more easily administered and potentially have fewer side effects. This research also suggests that defects in the FcγRIIB inhibitory mechanism could underlie antibody-mediated autoimmunity. Although additional work is needed to determine whether the findings in this mouse model apply to human disease, these results are cause for optimism.

Nonstationary disposition of valproic acid during prolonged intravenous infusion: contributions of unbound clearance and protein binding.

Circadian variations in disposition have been observed for a variety of agents, including anticonvulsants. Valproic acid (VPA), an anticonvulsant used to control generalized and partial seizures, has exhibited diurnal oscillations in steady-state concentrations during long-term administration to humans and non-human primates. The present study was conducted to assess potential diurnal changes in the disposition of VPA during prolonged i.v. infusion in rats. Animals, maintained on a strict 12-h per day light cycle, were equipped with venous cannulae and an arterial microdialysis probe. VPA was administered as a 50-mg/kg loading dose followed by a 42 mg/kg/h infusion for 70 h. Blood and microdialysate samples were obtained at timed intervals after establishment of steady-state throughout two complete light/dark cycles; and total (serum) and unbound (microdialysate) VPA was determined by gas chromatography. Modest oscillations (6-7 h period) in total and unbound VPA were observed; clearance and binding parameters were not different between light and dark periods. However, unbound clearance increased, and unbound fraction decreased, with time over the course of the infusion. These results suggest that time-dependent changes in VPA disposition occur in rats, although oscillations in steady-state concentrations do not appear to be diurnal in nature.

The immunomodulatory effects of prolonged intravenous infusion of propofol versus midazolam in critically ill surgical patients

Both propofol and midazolam are known to inhibit immune function. The aim of this study was to investigate cytokine production in critically ill surgical patients as early markers of immune response to prolonged infusion of propofol and midazolam. The study enrolled 40 elective patients who were to receive long-term sedation for more than 2 days. Patients were randomly allocated to one of two equally sized groups. Central venous blood samples for measurement of interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were drawn prior to the start and after 48 h of infusion. After 48 h, propofol caused significant increases in IL-1beta (24%), IL-6 (23%) and TNF-alpha (4.8 times) levels, while midazolam caused significant decreases in IL-1beta (21%), IL-6 (21%) and TNF-alpha (19%). Both agents caused significant decreases in IL-8 levels (propofol: 30%, midazolam: 48%, p < 0.05). Propofol caused significant decreases in IL-2 levels (68%, p < 0.001) but increases in IFN-gamma (30%, p < 0.05), whereas there was no significant change with midazolam compared with the pre-infusion level. In conclusion, during 48 h of continuous infusion, propofol stimulated, while midazolam suppressed, the production of the pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha, and both caused suppression of IL-8 production. Propofol inhibited IL-2 production and stimulated IFN-gamma production, whereas midazolam failed to do so. Therefore, sedative agents may have clinical implications in high-risk and immunocompromised patients.

Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia.

Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia.

Kynurenergic manipulations influence excitatory synaptic function and excitotoxic vulnerability in the rat hippocampus in vivo

Competing enzymatic mechanisms degrade the tryptophan metabolite l-kynurenine to kynurenate, an inhibitory and neuroprotective compound, and to the neurotoxins 3-hydroxykynurenine and quinolinate. Kynurenine 3-hydroxylase inhibitors such as PNU 156561 shift metabolism towards enhanced kynurenate production, and this effect may underlie the recently discovered anticonvulsant and neuroprotective efficacy of these drugs. Using electrophysiological and neurotoxicological endpoints, we now used PNU 156561 as a tool to examine the functional interplay of kynurenate, 3-hydroxykynurenine and quinolinate in the rat hippocampus in vivo. First, population spike amplitude in area CA1 and the extent of quinolinate-induced excitotoxic neurodegeneration were studied in animals receiving acute or prolonged intravenous infusions of l-kynurenine, PNU 156561, ( l-kynurenine+PNU 156561) or kynurenate. Only the latter two treatments, but not l-kynurenine or PNU 156561 alone, caused substantial inhibition of evoked responses in area CA1, and only prolonged (3 h) infusion of ( l-kynurenine+PNU 156561) or kynurenate was neuroprotective. Biochemical analyses in separate animals revealed that the levels of kynurenate attained in both blood and brain (hippocampus) were essentially identical in rats receiving extended infusions of l-kynurenine alone or ( l-kynurenine+PNU 156561) (4 and 7 μM, respectively, after an infusion of 90 or 180 min). However, addition of the kynurenine 3-hydroxylase inhibitor resulted in a significant decrement in the formation of 3-hydroxykynurenine and quinolinate in both blood and brain. These data suggest that the ratio between kynurenate and 3-hydroxykynurenine and/or quinolinate in the brain is a critical determinant of neuronal excitability and viability. The anticonvulsant and neuroprotective potency of kynurenine 3-hydroxylase inhibitors may therefore be due to the drugs' dual action on both branches of the kynurenine pathway of tryptophan degradation.

Prolonged Central Intravenous Ketorolac Continuous Infusion in a Cancer Patient with Intractable Bone Pain

To report the case of a prolonged intravenous ketorolac continuous infusion given via a central line in a cancer patient with intractable bone pain. A 56-year-old Hispanic man with stage IV non-small-cell lung cancer and multiple bone metastases was admitted to the hospital for intractable pain inadequately controlled at home by conventional therapy. He was treated with an intravenous continuous infusion of ketorolac 120 mg in 250 mL of NaCl 0.9% infused over 24 hours. The ketorolac was given via a central line for 14 days in addition to fentanyl patient-controlled analgesia. Over this time period the patient reported his pain to be well controlled. His requests for bolus doses of fentanyl decreased dramatically and the dose of the continuous intravenous fentanyl was reduced by 22%. In addition, the total daily dose of ketorolac was reduced following a change from intermittent bolus dosing to a continuous infusion. The management of cancer pain secondary to bone metastasis is a difficult and challenging problem frequently encountered by the healthcare team. The use of nonsteroidal antiinflammatory drugs (NSAIDs) as adjuvant therapy is a common practice. However, many terminally ill patients are unable to take oral medications, thus limiting NSAID treatment options. Ketorolac tromethamine is approved by the Food and Drug Administration (FDA) as a parenteral NSAID. As with other NSAIDs, the risk of adverse drug reactions must be considered when using this class of medication. The FDA has approved ketorolac for the short-term (< or = 5 d) management of moderately severe acute pain that requires analgesia at the opioid level, usually in the postoperative setting. However, certain patients may benefit from long-term use exceeding the FDA-recommended guidelines of 5 days of maximum therapy. A prolonged central intravenous ketorolac continuous infusion was successful in treating a cancer patient with intractable bone pain secondary to widely metastatic non-small-cell lung cancer.

Perioperative management with prolonged intravenous insulin infusion versus subcutaneous insulin in children with type I diabetes mellitus

Our objective was to retrospectively evaluate glycemic excursion and insulin dosage in the perioperative period in children and adolescents with type I diabetes mellitus receiving a prolonged intravenous insulin infusion for 2–3 days compared to conventional subcutaneous insulin treatment. A retrospective review of surgical admissions at the Children's Hospital of Los Angeles in patients with type I diabetes mellitus was conducted for the 3-year period from July 1989 to June 1992, to evaluate two treatment protocols used during that period. For the nine admissions in group 1, patients received 0.06–0.1 units regular insulin/kg/h beginning 2 h prior to surgery and lasting for 2–3 days postoperatively; while, for the ten admissions in group 2, subjects were given subcutaneous regular and intermediate-acting insulin as 2–4 injections daily, with the regular insulin dose prior to surgery decreased to 66–75% of usual. Blood glucose levels were determined at the bedside at hourly intervals and insulin dose adjustment done with the aim of achieving blood glucose levels between 5.5 and 8.3 mmol/L (100–150 mg/dL). The mean bedside blood glucose levels for group 2 were significantly higher 1 h prior to surgery and during the intraoperative period ( p < 0.05). In the postoperative period, group 2 blood glucose levels were significantly higher at multiple times for up to 3 days with multiple levels greater than 11.1 mmol/L (200 mg/dL), which was not seen in group 1. The mean insulin dosage (units/kg) prior to admission was not different for the two groups. On the day of surgery and during postoperative days 1 and 2, patients in group 1 received a greater insulin dosage than group 2 subjects ( p < 0.025). In group 1, insulin dosage was increased 23% and 15% over baseline for postoperative days 1 and 2, respectively, then, by day 3, was decreased back toward the baseline. In group 2 subjects, a 13.8% increase occurred on the day of surgery due to extra insulin given immediately following the procedures, followed by a 5.4, 44.2, and 66.6% increase over baseline for postoperative days 1 through 3, respectively. In conclusion, meticulous glycemic control was readily achieved in the perioperative period with a constant intravenous insulin infusion for up to 3 days in children and adolescents with type I diabetes. To achieve glycemic control, insulin dosage needs to be increased on the day of surgery and for approximately 2 postoperative days.

Teicoplanin or vancomycin in the treatment of gram-positive infections?

The glycopeptide antibiotics vancomycin and teicoplanin have similar mechanisms of action on bacterial cell wall synthesis. Their spectra of activity are limited to Gram-positive bacteria, with the degree of bactericidal activity depending on the species of micro-organism. Staphylococcus aureus, Staphylococcus epidermis, enterococci and Clostridium difficile are generally sensitive, including methicillin-resistant strains of S. aureus and S. epidermidis. Glycopeptide resistance has recently emerged in staphylococci and enterococci. Vancomycin has a shorter half-life than teicoplanin and requires multiple dosing to maintain adequate serum levels. It can only be given by prolonged intravenous infusion over 1 h. In contrast, the pharmacokinetics of teicoplanin allow for once-daily dosing, either by rapid intravenous infusion or by the intramuscular route. The latter offers reliable absorption for patients with limited venous access and is also of benefit for out-patient therapy. Teicoplanin is a safer drug than vancomycin. It is associated with a lower incidence of nephrotoxicity or ototoxicity. Compared to vancomycin, the availability of the intramuscular route and the absence of a requirement for routine serum monitoring, together with the reduced need to treat drug-related side-effects make teicoplanin more cost-effective. It is as effective as vancomycin for most indications, is safe, easy to administer and an important agent for treating Gram-positive infections. Its role in hospitals is likely to increase if the price of drug acquisition is kept low.

Insulin secretion and clearance during low-dose graded glucose infusion.

The present study was undertaken in normal volunteers to define the alterations in beta-cell responsiveness to glucose associated with different physiological states, including fasting and refeeding, and after prolonged intravenous glucose infusion. A low-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels using a two-compartment model utilizing individual kinetic parameters. From 5 to 9 mmol/l glucose, the relationship between glucose and ISR was linear. After a 42-h glucose infusion at a rate of 4 mg.kg-1.min-1, the ISR increased by 53% over the same glucose concentration range (P < 0.002), resulting in a shift of the dose-response curve to the left. Insulin clearance rates decreased 27% after the 42-h glucose infusion (P < 0.001). After a 72-h fast, ISR decreased by 32% from baseline over the 5-8 mmol/l glucose range (P = 0.056), resulting in a shift of the dose-response curve to the right. This shift was reversed by a 42-h period of refeeding, after which ISR was increased by 77% compared with the fasting study (P < 0.02). Refeeding enhanced the beta-cell responsiveness, and ISR increased by 31% after refeeding compared with the baseline study (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Paclitaxel administered by 1-hour infusion. Preliminary results of a phase 1/11 trial comparing two schedules

Paclitaxel currently is administered by prolonged intravenous infusion because of the occurrence of severe hypersensitivity reactions in patients in early clinical trials. However, intensive premedication probably is more important in eliminating allergic reactions than is the length of infusion. The authors evaluated the feasibility of two paclitaxel schedules using a 1-hour, outpatient infusion. Fifty-six patients with advanced, refractory malignancies were randomized to receive one of two paclitaxel schedules: 135 mg/m2 administered as a single dose over 1 hour, or 135 mg/m2 administered in divided daily doses for 3 days, each over 1 hour. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. No serious hypersensitivity reactions occurred with either schedule of paclitaxel. In addition, other adverse effects were usually mild and easily tolerated. Other than alopecia, which occurred in all patients, myelosuppression was the most common severe toxicity. However, grade 3 leukopenia occurred in only 19% of treatment courses, and grade 4 leukopenia (nadir < 1000/microL) occurred in only 2%. Nine patients required hospitalization for treatment of infection associated with neutropenia. No significant differences in toxicity were observed when the two paclitaxel regimens were compared. Although it is too early to assess the results adequately, preliminary findings showed that thus far 11 of 56 patients (20%) had a partial or complete response to therapy. Responses were observed in patients with breast, ovarian, and lung cancer. Paclitaxel can be safely administered in a 1-hour infusion in an outpatient setting, either as a single dose or in divided doses for three days. Severe hypersensitivity reactions did not occur in 162 treatment courses, and neutropenia was mild in most patients. Incorporation of this dose and these schedules of paclitaxel into combination chemotherapy regimens should be feasible. An investigation of higher paclitaxel doses given in a 1-hour infusion is currently in progress.

Kinetics of cell labelling and thymidine replacement after continuous infusion of halogenated pyrimidines in vivo

Purpose :Iododeoxyuridine (IdUrd) is a halogenated pyrimidine which has been recognized as a clinical radiosensitizer. It is generally agreed that the extent of radiosensitization correlates with the degree of thymidine substitution in DNA. Controversy exists regarding the optimal administration schedule to achieve maximum radiosensitization. To obtain more information relating to this problem, we present experiments on an in vivo human tumor xenograft continuously exposed to a fixed serum concentration of halogenated pyrimidines so as to study the kinetics of cell labeling and thymidine replacement. Methods and Materials : Human colon tumor (HCT-116) cells were injected subcutaneously into nude mice. After 10 days, most animals (> 90%) developed measurable tumor nodules with a volume doubling time of 5 ± 1 days. Once the tumors reached a cross-sectional area of 0.25–0.30 cm 2, miniosmotic pumps were implanted to deliver a dose of 100 mg/kg/day of IdUrd by continuous infusion. After an IdUrd exposure time of 1–7 days, blood and tumor tissue were collected. Results : The steady state serum IdUrd concentration was 0.95 ± 0.1 μM, which is a clinically relevant concentration for a prolonged continuous intravenous infusion. The tumor cell potential doubling time (T pot) was 25 ± 2 h. The percent IdUrd thymidine replacement and the fraction of cells labeled, followed exponential saturation kinetics with a halflife of 33 ± 9 and 27 ± 2 h, respectively. After 5 days of exposure (∼- 5 × T pot, the thymidine replacement in tumor cells was 2.0 ± 0.2% and the fraction of tumor cells labeled was 94 ± 1%. Immunohistochemical staining of IdUrd labeled tumor tissues showed an exposure dependent gradient of cellular labeling that was initially highest in regions close to blood vessels. After 4 days of exposure at 100 mg/kg/day, there was an increase in the fraction of cells in Go + G, and a decrease in the S phase population, suggesting a block between G, and S phase. Conclusion : We conclude that the in vivo kinetics of IdUrd thymidine replacement and fraction of cells labeled after continuous exposure followed exponential saturation kinetics with a halflife of approximately the potential doubling time of the tumor cell population. Simple modeling suggests that some form of prolonged, or briefly interrupted, continuous infusion should be considered for clinical administration because such schedules would leave fewer cells unsensitized than shorter infusions would. Even 10% of unlabeled clonogenic cells could explain the lack of dramatic clinical successes with IdUrd or BrdUrd sensitization.

Effects on Thrombin Generation of Single Injections of Hirulog™ in Patients with Calf Vein Thrombosis

To determine whether single injections of Hirulog, a direct thrombin inhibitor, can inhibit thrombin generation in patients with calf vein thrombosis and, if so, if the inhibition is sustained. Phase II open label cohort study. Tertiary-care referral centres, university affiliated hospitals. 10 patients with venographically-demonstrated calf vein thrombosis. Patients received a single injection of Hirulog, either 1.0 mg/kg subcutaneously or 0.6 mg/kg as a 15 min intravenous infusion. Prothrombin fragment (F1++2) levels, as an index of thrombin generation, were measured before as well as 6 h post- and 24 h post-Hirulog administration. Patients were followed with non-invasive tests to detect thrombus extension into the proximal veins. There was a significant reduction in the levels of F1+2 with both regimens, 6 h after Hirulog. The F1+2 levels 24 h post-Hirulog showed a significant increase relative to the 6 h post-Hirulog results. One patient developed thrombus extension into the popliteal vein and was treated with conventional anticoagulants. The single injections of Hirulog used in the study produced incomplete and temporary suppression of F1+2. Complete and permanent inhibition of thrombin generation with Hirulog in patients with calf vein thrombosis may require higher doses, multiple subcutaneous injections and/or prolonged intravenous infusion.

Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors.

The purpose of this phase I trial was to determine the toxicity and maximum-tolerated dose (MTD) of murine monoclonal antibody (Mab) 14G2a (anti-GD2) in cancer patients. Following tracer doses of iodine-131-labeled 14G2a to determine tumor uptake, 18 patients with refractory melanoma, neuroblastoma, or osteosarcoma received unlabeled 14G2a at total concentrations of 50, 100, and 200 mg/m2 administered as daily 24-hour infusions for 5 days. The overall sensitivity of external immunoscintigraphy was 64 of 74 known metastases (86%). Toxicity from prolonged infusion of 14G2a consisted of severe generalized pain, hyponatremia, fever, rash, paresthesias, weakness, and chronic refractory postural hypotension (two patients). Toxicity was less severe in pediatric patients. The MTD of Mab was 100 mg/m2. Sixteen of 18 patients developed human antimouse antibodies (HAMA) to 14G2a. Terminal-phase half-life (T1/2) of unlabeled Mab was 6.6 +/- 1.8 hours for patients receiving 50 mg/m2 and 39.5 +/- 13.3 hours at the 100-mg/m2 level. Tumor biopsies from six melanoma patients were positive for GD2 antigen, but only two of six had trace amounts of 14G2a present. Three mixed responses (two melanoma, one osteosarcoma) and two partial responses (PRs; neuroblastoma) were observed. Mab 14G2a has modest antitumor activity at the expense of significant toxicity. Dose-limiting neurologic sequelae may significantly limit phase II studies other than in pediatric patients with neuroblastoma.

Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa: evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation.

To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-alpha) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-alpha on 5-FU pharmacokinetics. Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-alpha, 5 x 10(6) IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-alpha administration using the paired t test. The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-alpha 2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-alpha was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-alpha on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-alpha administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1). IFN-alpha substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-alpha-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-alpha to enhance the toxic effects of 5-FU.