High-dose Intravenous Bolus Research Articles

Cutaneous reaction to ifosfamide plus mesna treated with desensitization challenge: a case report

BackgroundIfosfamide is an alkylating agent used in the treatment of a wide range of tumours. Because of known side effects it is usually administered in combination with mesna, a thiol agent with uroprotective activity, to reduce them and increase the therapeutic dose. The most frequently administered regimens for ifosfamide are fractionated doses for 3 to 5 days, high-dose intravenous bolus, and continuous infusion over 24 to 72 h. Hypersensitivity reactions to ifosfamide plus mesna are not frequently described in the literature. Moreover, no reports exist concerning desensitization for this chemotherapy combination.Case presentationA 47-year-old man with stage IV renal sarcoma was treated with the combination of ifosfamide and mesna every 3 weeks in a 4-consecutive-day infusion protocol. During the second cycle of chemotherapy, he presented acute cutaneous symptoms. A 12-step desensitization protocol was proposed in view of the lack of knowledge of the possible hypersensitivity reactions to this combination of chemotherapy agents, and the multiple difficulties found during the study of the case.ConclusionsThe 12-step desensitization protocol was well tolerated. Therefore, it is an appropriate and safe option in the case of suspected allergy to ifosfamide plus mesna.

P371 The addition of intravenous, high dose, bolus of methyl-prednisolone increases the early clinical response to oral corticosteroids in moderately active ulcerative colitis. Preliminary results of a prospective, controlled, multicentre, randomised, open-label study

Abstract Background Oral corticosteroids remain the treatment of choice for moderately active flares of ulcerative colitis (UC). In early controlled studies, oral corticosteroids achieved clinical remission rates of, 30–60% at, 30 days. Some small prospective studies observed that the administration of high-dose intravenous bolus of methyl-prednisolone accelerated their therapeutic action and increased the rate of clinical response. We aimed to evaluate if the outpatient administration of intravenous, high-dose, methyl-prednisolone bolus increases the efficacy of a conventional course of oral prednisone in moderately active UC. Methods Prospective, multicentre, controlled, randomized, open-label study comparing the therapeutic efficacy of a standard oral prednisone schedule with the same schedule preceded by a three-day regimen of high-dose intravenous bolus of methyl-prednisolone. Inclusion criteria were: Moderately active, left-sided/extensive UC (total Mayo score, 6–10), with no prior exposure to immunosuppressants or biologics, and no corticosteroid treatment in the last, 6 months. Patients were randomized to oral prednisone, 60mg/day (ORAL group) or the same schedule preceded by intravenous bolus of, 500mg of methyl-prednisolone for three consecutive days (BOLUS group), stratified by the baseline use of oral, 5ASA and UC onset. Early clinical response was defined as the reduction of the baseline partial Mayo Score (pMS) by at least three points with at least a decrease by, 1 point in rectal bleeding and with an absolute value of, 0 or, 1, seven days after starting treatment (EUDRA CT:, 2016-001170-15)(Clinicaltrials.gov: NCT02921555) Results In all, 71 patients (38 ORAL, 33 BOLUS) were included. At baseline, the median pMS was, 6 (IQR, 5–7). In, 21% of the patients, the index flare was the onset of UC and, 68% had never received systemic corticosteroids for UC. There were no differences in baseline clinical and demographic features between the two study groups. At day, 7, the proportion of patients fulfilling early clinical response criteria was similar in both groups (BOLUS, 63% vs. ORAL, 58%; p = 0.6), but a significantly greater reduction in pMS at day, 3 (-3.4. vs -1.7; p <0.0001) and a significantly higher proportion of patients in clinical remission (pMS <2) at day, 7 (57% vs, 29%; p = 0.017) were observed in the BOLUS group. Conclusion The addition of three high-dose intravenous bolus of methyl-prednisolone to a standard schedule of oral corticosteroids achieves a faster and more intense response in the short-term in moderately active flares of UC, but it does not increase the clinical response rate at seven days. The impact of these effects on the medium-term outcomes is still to be assessed.

Skipping the Drip: Intravenous Proton Pump Inhibitor Bolus Therapy Leads to Poor Outcomes in High-Risk Bleeding.

Background and AimThe aim of this study was to evaluate the impact of a change in our institute’s protocol from continuous intravenous (IV) proton pump inhibitor (PPI) therapy to bolus IV PPI therapy for the treatment of peptic ulcer-related bleeding on patient outcomes. Current guidelines recommend PPI therapy through high-dose IV bolus followed by continuous infusion for bleeding ulcers. Conflicting data have been reported regarding the practice shift to intermittent IV PPI therapy.MethodsA retrospective record review was conducted of patients treated at West Virginia University between 2017 and 2018 for peptic ulcer related bleeding who underwent endoscopy and had high-risk stigmata. Relevant variables were identified. Outcomes were compared between groups based on PPI strategy. The primary endpoint was any poor outcome defined as rebleeding, need for embolization or surgery, or mortality during hospital stay.ResultsA total of 130 patients were included, with a mean age of 62.18 years. Continuous PPI infusion was used in 39.23%, whereas bolus IV PPI was used 60.76%. Poor outcome was encountered in 11 (21.57%) patients in the continuous and 33 (41.77%) patients in the bolus group (p = 0.028). On multivariable analyses, bolus PPI strategy was independently linked to poor outcome (Wald’s odds ratio: 2.8; 95% CI: 1.21-6.84; p = 0.019) and an increased need for embolization/surgery (OR: 4.12, 95% CI: 1.14-19.99; p = 0.046).ConclusionsIV bolus therapy showed worse outcomes compared with continuous IV PPI therapy for patients with peptic ulcer bleeding with high-risk features. More robust data are needed before a practice shift to bolus PPI may be appropriate.

The application of high-dose interleukin-2 for metastatic renal cell carcinoma

Renal cell carcinoma (RCC) evokes an immune response, which has occasionally resulted in spontaneous and dramatic remissions [1-3]. In an attempt to reproduce or accentuate this response, various immunotherapeutic strategies have been studied. The most consistent anti-tumor activity has been reported with interferon alfa (IFN-alpha) and interleukin 2 (IL-2). In recent years, randomized trials have suggested that high-dose intravenous bolus IL-2 is superior in terms of response rate and possibly response quality to regimens that involve either low-dose IL-2 and IFN-alpha, intermediate- or low-dose IL-2 alone, or low-dose IFN-alpha alone. As this list of effective therapies for RCC grows, improvements in patient selection will be necessary to ensure that the only therapy capable of producing durable remissions will remain available to the patients who should receive it [4-7].

Phase I Trial of Sequential Low-Dose 5-Aza-2′-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma

The silencing of gene expression through DNA methylation contributes to defects in antigen presentation and apoptosis in melanoma and renal cell cancer. To determine how a hypomethylating agent would modulate the toxicity and antitumor activity of immunotherapy, we initiated a phase I trial of 5-aza-2'-deoxycytidine (decitabine) plus high-dose interleukin 2 (IL-2). Patients received s.c. decitabine daily x 5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg i.v. q8 hours x 14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. The hypomethylating activity of decitabine was assessed during cycle 1 by measuring hemoglobin F levels and changes in DNA methylation in peripheral blood mononuclear cells. Twenty-one patients with melanoma or renal cell cancer were enrolled. Decitabine did not alter the tolerability of IL-2 but caused grade 4 neutropenia in most patients. Grade 4 neutropenia lasting more than 7 days was the only dose-limiting toxicity, with a trend toward a higher incidence with increasing decitabine doses. Infection occurred in only one patient despite the high incidence of neutropenia, and granulocyte colony-stimulating factor use in several patients expedited neutrophil recovery. Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a dose-independent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients. Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.

Acute Conversion of Atrial Fibrillation in Two Dogs by Intravenous Amiodarone Administration

Journal of Veterinary Internal MedicineVolume 20, Issue 5 p. 1224-1227 Open Access Acute Conversion of Atrial Fibrillation in Two Dogs by Intravenous Amiodarone Administration Mark A. Oyama DVM, DACVIM-Cardiology, Mark A. Oyama DVM, DACVIM-Cardiology Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL. Department of Clinical Sciences, MJR-VHUP-Cardiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA. Department of Clinical Sciences, MJR-VHUP-Cardiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; e-mail: [email protected]Search for more papers by this authorRobert Prosek, Robert Prosek Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL. Department of Small Animal Clinical Sciences, Veterinary Medical Center, University of Florida, Gainesville, FL.Search for more papers by this author Mark A. Oyama DVM, DACVIM-Cardiology, Mark A. Oyama DVM, DACVIM-Cardiology Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL. Department of Clinical Sciences, MJR-VHUP-Cardiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA. Department of Clinical Sciences, MJR-VHUP-Cardiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; e-mail: [email protected]Search for more papers by this authorRobert Prosek, Robert Prosek Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL. Department of Small Animal Clinical Sciences, Veterinary Medical Center, University of Florida, Gainesville, FL.Search for more papers by this author First published: 05 February 2008 https://doi.org/10.1111/j.1939-1676.2006.tb00727.xCitations: 15 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Fuster V., Ryden LE, Asinger RW, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) Developed in Collaboration with the North American Society of Pacing and Electrophysiology. Circulation 2001; 104: 2118– 2150. 2 Nattel S., Shiroshita-Takeshita A., Brundel BJ, et al. Mechanisms of atrial fibrillation: Lessons from animal models. Prog Cardiovasc Dis 2005; 48: 9– 28. 3 Auer J., Weber T., Berent R., et al. Risk factors of postoperative atrial fibrillation after cardiac surgery. J Card Surg 2005; 20: 425– 431. 4 Martinez EA, Bass EB, Zimetbaum P. Pharmacologic control of rhythm: American College of Chest Physicians guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest 2005; 128: 48S– 55S. 5 Slavik RS, Zed PJ. Intravenous amiodarone for conversion of atrial fibrillation: Misled by meta-analysis Pharmacotherapy 2004; 24: 792– 798. 6 Tuseth V., Jaatun HJ, Dickstein K. Amiodarone infusion in the treatment of acute atrial fibrillation or flutter: High versus low dose treatment. Heart 2005; 91: 964– 965. 7 Hofmann R., Steinwender C., Kammler J., et al. Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate. Int J Cardiol 2006; 110: 27– 32. In press. 8 Samuels LE, Holmes EC, Samuels FL. Selective use of amiodarone and early cardioversion for postoperative atrial fibrillation. Ann Thorac Surg 2005: 79:I 13– 116. 9 Somberg JC, Cvetanovic I., Ranade V., et al. Comparative effects of rapid bolus administration of aqueous amiodarone versus 10-minute cordarone I.V. infusion on mean arterial blood pressure in conscious dogs. Cardiovasc Drugs Ther 2004; 18: 345– 351. 10 Somberg JC, Timar S., Bailin SJ, et al. Lack of a hypotensive effect with rapid administration of a new aqueous formulation of intravenous amiodarone. Am J Cardiol 2004; 93: 576– 581. 11 Boriani G., Diemberger I., Biffi M., et al. Pharmacological cardioversion of atrial fibrillation: Current management and treatment options. Drugs 2004; 64: 2741– 2762. 12 Fransi S., Briedis J. Anaphylaxis to intravenous amiodarone. Anaesth Intens Care 2004; 32: 578– 579. 13 Stroke Prevention in Atrial Fibrillation Study, Final results. Circulation 1991; 84: 527– 539. 14 Stellbrink C., Schimpf T. Anticoagulation during cardioversion in patients with atrial fibrillation: Current clinical practice. Am J Cardiovasc Drugs 2005; 5: 155– 162. Citing Literature Volume20, Issue5September 2006Pages 1224-1227 ReferencesRelatedInformation

Effects of a High Dose Intravenous Bolus Amiodarone in Patients with Atrial Fibrillation and a Rapid Ventricular Rate

Abstract Background Amiodarone, given as intravenous bolus has not yet been studied in patients with atrial fibrillation and a high ventricular rate. Methods One hundred consecutive patients with atrial fibrillation and a ventricular rate above 135 bpm were randomized to receive either 450 mg amiodarone or 0.6 mg digoxin given as a single bolus through a peripheral venous access. If the ventricular rate exceeded 100 bpm after 30 min, another 300 mg amiodarone or 0.4 mg digoxin were added. Primary endpoints of the study were the ventricular rate and the occurrence of sinus rhythm after 30 and 60 min. Secondary endpoints were blood pressure during the first hour after drug administration, and safety regarding drug induced hypotension, and phlebitis at the infusion site. Results Baseline heart rate was 144±19 in the amiodarone group and 145±15 in the digoxin group ( p =0.72). Following amiodarone, heart rate was 104±25 after 30 min compared to 116±23 in the digoxin group ( p =0.02) and 94±22 versus 105±22 after 60 min ( p =0.03). After 30 min, sinus rhythm was documented in 14 (28%) patients following amiodarone compared to 3 (6%) patients in the digoxin group ( p =0.003), and after 60 min in 21 (42%) versus 9 (18%) patients ( p =0.012). Asymptomatic hypotension was observed in 4 amiodarone treated patients, and superficial phlebitis in 1 patient. Conclusions Amiodarone, given as an intravenous bolus is relatively safe and more effective than digoxin for heart rate control and conversion to sinus rhythm in patients with atrial fibrillation and a rapid ventricular rate.

Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate

Background Amiodarone, given as intravenous bolus has not yet been studied in patients with atrial fibrillation and a high ventricular rate. Methods One hundred consecutive patients with atrial fibrillation and a ventricular rate above 135 bpm were randomized to receive either 450 mg amiodarone or 0.6 mg digoxin given as a single bolus through a peripheral venous access. If the ventricular rate exceeded 100 bpm after 30 min, another 300 mg amiodarone or 0.4 mg digoxin were added. Primary endpoints of the study were the ventricular rate and the occurrence of sinus rhythm after 30 and 60 min. Secondary endpoints were blood pressure during the first hour after drug administration, and safety regarding drug induced hypotension, and phlebitis at the infusion site. Results Baseline heart rate was 144 ± 19 in the amiodarone group and 145 ± 15 in the digoxin group ( p = 0.72). Following amiodarone, heart rate was 104 ± 25 after 30 min compared to 116 ± 23 in the digoxin group ( p = 0.02) and 94 ± 22 versus 105 ± 22 after 60 min ( p = 0.03). After 30 min, sinus rhythm was documented in 14 (28%) patients following amiodarone compared to 3 (6%) patients in the digoxin group ( p = 0.003), and after 60 min in 21 (42%) versus 9 (18%) patients ( p = 0.012). Asymptomatic hypotension was observed in 4 amiodarone treated patients, and superficial phlebitis in 1 patient. Conclusions Amiodarone, given as an intravenous bolus is relatively safe and more effective than digoxin for heart rate control and conversion to sinus rhythm in patients with atrial fibrillation and a rapid ventricular rate.

Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma.

The present study attempted to identify characteristics that correlated with clinical response to interleukin (IL)-2 therapy in patients with metastatic melanoma. We retrospectively evaluated laboratory and clinical characteristics of 374 consecutive patients with metastatic melanoma treated with high-dose intravenous bolus IL-2 (720,000 IU/kg) from July 1, 1988, to December 31, 1999, at the Surgery Branch of the National Cancer Institute. The overall objective response rate was 15.5%. Pretreatment parameters such as patient demographics, laboratory values, and prior therapy did not correlate with response; however, 53.6% of patients with only subcutaneous and/or cutaneous metastases responded, compared with 12.4% of patients with disease at other sites (P2 =.000001). During therapy, patients who were responders tended to have received more doses during course 1 (16.2 +/- 0.3 doses v 14.5 +/- 0.2 doses; P2 =.0095); however, when limited to patients who were able to complete both cycles of course 1, there was no statistically significant difference (P2 =.27). Responders had a higher maximum lymphocyte count immediately after therapy compared with nonresponders (P2 =.0026). The development of abnormal thyroid function tests and vitiligo after therapy was associated with response (thyroid-stimulating hormone, P2 =.01; free T4, P2 =.0049; vitiligo, P2 < 10(-6)), although thyroid dysfunction may have been related more to the length of IL-2 therapy than to response. The presence of metastases only to subcutaneous and/or cutaneous sites, lymphocytosis immediately after treatment, and long-term immunologic side effects, especially vitiligo, were associated with antitumor response to IL-2 therapy.

Immunotherapy for renal carcinoma: theoretical basis and current standard of care.

Carcinoma of the kidney (a.k.a. ‘hypernephroma’ or renal cell cancer) accounts for 2–3% of all adult cancers, and over 4000 new cases are reported in the UK every year [1]. It occurs more commonly in men, and has a peak incidence around 60–70 years, although can occur at any age. The incidence is increasing [2]. If confined to the kidney, surgical resection is the treatment of choice, and cure can result. However, most patients with metastatic disease survive less than 1 year [3], and chemotherapeutic or hormonal approaches are generally ineffective. The natural history of renal cancer characteristically manifests an indolent course, with long periods of stable disease. In addition, the ‘spontaneous regression’ of metastases has often been reported in the literature, and Evenson & Cole [4] made the observation that renal cancer appeared to have the highest incidence of this controversial and intriguing phenomenon. The actual frequency of spontaneous regression in renal tumours is not known, but estimates put it at around 0.3% [5]. A higher frequency has been reported following nephrect-omy in patients with established metastatic disease [6]. The existence of spontaneous regression has been put forward as evidence that a form of innate ‘host factor’ or immunological response may be involved in its pathogen-esis. Such a hypothesis is supported by the increase in renal cancer cases observed in patients receiving long-term immunosuppressive therapy for organ transplantation [7].

Interleukin-2 in Cancer Therapy

Recombinant interleukin-2 (rIL-2) produces remissions in several human tumours, including metastatic renal cell cancer (RCC) and malignant melanoma. High-dose intravenous bolus rIL-2 is approved in the US in these 2 indications, based on evidence of rIL-2-induced durable remissions in a significant minority of patients. Due to the toxicity associated with high-dose rIL-2, alternative regimens were investigated in RCC, including low-dose intravenous bolus, subcutaneous outpatient regimens and continuous intravenous infusion, yielding similar response rates. A prospective randomised trial comparing different doses and routes of administration is underway. Because response rates to single agent rIL-2 are inadequate, combination therapies were studied. In RCC patients, a combination of rIL-2 and IFNalpha resulted in better response rates than either cytokine alone, with no apparent survival advantage. Combination with chemotherapy increased toxicity and had no proven benefit. Results of adoptive immunotherapy studies combining rIL-2 with either lymphokine-activated killer cells or tumour infiltrating lymphocytes were comparable to those of rIL-2 alone. In malignant melanoma, combination therapy of rIL-2 with chemotherapy was explored. Results of single-institution phase II combination studies of variable chemotherapy and rIL-2 and IFNalpha regimens were promising and randomised trials are underway. rIL-2 is being is evaluated in haematological malignancies. The rationale is based on pre-clinical evidence that a variety of leukaemic blasts are sensitive to cytolysis or growth inhibition mediated by rIL-2-activated immune effector cells. New immunotherapeutic strategies may ultimately improve the anti-tumour efficacy of rIL-2-based therapy. Early trials using rIL-2 as adjuvant therapy to vaccines or dendritic cell-based therapy have yielded promising results. rIL-2 therapy initiates a cytokine-mediated pro-inflammatory process leading to an adverse effect profile that is quite different from traditional chemotherapeutic agents. Dose-limiting toxicities are primarily cardiovascular and pulmonary and are dose-dependent in frequency and severity. Patients receiving high-dose regimens may require intensive care unit support, limiting its use to those with excellent performance status and adequate organ function. Patients receiving less intensive dose regimens may require less rigorous screening and monitoring. It has been postulated that rIL-2 related toxicity is mediated through the release of secondary cytokines, including TNF, IFNgamma, IL-6 and IL-1. With the increasing understanding of the pathophysiological mechanisms of the effects of rIL-2, it is possible that concurrent administration of selective cytokine antagonists may reduce the toxicity associated with rIL-2 without interfering with its anti-neoplastic activity.

High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993.

To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma. Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996. The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis. High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.

High Dose Bolus Heparin as Initial Therapy Before Primary Angioplasty for Acute Myocardial Infarction: Results of the Heparin in Early Patency (HEAP) Pilot Study

Objectives. We sought to determine the effect of high dose intravenous bolus heparin on early coronary patency before primary angioplasty.Background. Early coronary angiography after thrombolysis for acute myocardial infarction has shown better patency when intravenous heparin is used as an adjunct. The present study explores whether heparin alone can induce reperfusion.Methods. In the Heparin in Early Patency (HEAP) pilot study, 108 patients with signs and symptoms of acute myocardial infarction <6 h eligible for primary angioplasty received a single intravenous bolus of 300 U/kg of heparin together with aspirin (160 mg chewed) in the emergency room. The median dose of bolus heparin given was 27,000 U. Patency of the infarct-related artery (IRA) was assessed by coronary angiography at a median of 85 min after the heparin bolus.Results. In 55 patients (51%, 95% confidence interval 38% to 64%), Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 was observed at 90 min: TIMI flow grade 3 in 33 patients (31%); TIMI flow grade 2 in 22 (20%). Thirty-two (64%) of 50 patients with symptoms ≤2 h had TIMI flow grade 2 or 3 versus 23 (40%) of 58 patients with symptoms >2 h (p = 0.02). No significant bleeding was seen. Two patients (2%) died in the hospital. The patency results obtained in patients treated with the high dose bolus heparin were compared with those in 108 patients from a large primary angioplasty database, who were treated with standard therapy, including aspirin but not intravenous heparin, and were matched for clinical and angiographic characteristics with the HEAP pilot study patients. They showed an 18% patency rate (p < 0.001) of the IRA (TIMI flow grade 3 in 9%, TIMI flow grade 2 in 9%) before primary angioplasty.Conclusions. Early therapy with high dose heparin is associated with full coronary reperfusion in a considerable number of patients with acute myocardial infarction, especially in those treated early (<2 h). This simple, inexpensive, probably safe and easily antagonizable treatment may be an attractive first treatment of acute myocardial infarction both before and during the hospital stay in conjunction with primary angioplasty.

Effects of total parental nutrition (TPN) during high-dose interleukin-2 treatment for metastatic cancer.

Patients treated with high doses of interleukin-2 (IL-2) develop profound anorexia, malaise, loss of energy, mucositis, nausea, and vomiting, which may contribute to poor nutrition. We hypothesized that total parenteral nutrition (TPN) administration would ameliorate these changes and could improve fluid and electrolyte balance. A retrospective analysis of protein and energy intake was performed in 21 sequential patients who received a normal diet (controls) and 16 subsequent patients who received TPN during IL-2 treatment. The effect of TPN on laboratory abnormalities induced by IL-2 was also evaluated. Within 24 h of starting IL-2, mean energy intake declined to 2.5-2.8 kcal/kg in controls in contrast to the energy intake of 25-29 kcal/kg in patients receiving TPN. Protein nutrition was affected in a similar fashion, with a markedly lower protein intake in controls (0.08-0.12 g/kg) than in the TPN group (1.02-1.10 g/kg). TPN improved serum calcium and potassium concentrations, particularly during spontaneous diuresis after completion of IL-2 treatment. Unexpectedly, TPN decreased the frequency and severity of cholestatic jaundice caused by IL-2. Patients receiving TPN had an increased propensity for hyperglycemia and hypophosphatemia. High-dose intravenous bolus IL-2 therapy resulted in a markedly negative nutritional balance in control patients. A brief period of TPN during IL-2 treatment was well tolerated and corrected calorie and protein malnutrition. TPN administration also improved control of serum electrolytes. TPN did not adversely affect tumor progression or patient survival.

Cardiopulmonary toxicity of treatment with high dose interleukin-2 in 199 consecutive patients with metastatic melanoma or renal cell carcinoma

Administration of recombinant interleukin-2 (rIL-2) can mediate tumor regression in patients with metastatic melanoma and renal cell carcinoma. In response to recent FDA approval of high dose rIL-2 for use in renal cell carcinoma, the authors recent experience with the cardiopulmonary toxicity associated with high dose IL-2 therapy is reviewed. The treatment courses of all patients receiving high dose intravenous bolus rIL-2 from January, 1988, until December, 1992, were evaluated for cardiopulmonary toxicity. One hundred ninety-nine patients received 310 courses of treatment. There were no treatment-related deaths. Respiratory distress occurred in 3.2% of the courses, requiring intubation in one patient. Three obtunded patients were endotracheally intubated for airway control. Arrhythmias occurred in 6% of the courses (18 patients) with hypotension developing in two of the 199 patients as a result. Eleven of these patients were retreated and recurrent atrial fibrillation developed in two. One episode of significant ventricular tachycardia was noted. Hypotension occurred in 53% of courses; no patients developed hypotension unresponsive to vasopressors. There were no myocardial infarctions; however, 2.5% of patients experienced elevated creatine phosphokinase levels associated with elevated MB isoenzymes attributed to cardiac toxicity. Only one of these patients developed symptoms. Response rates of 19.6% and 15.7% were noted in patients with renal cell carcinoma and melanoma, respectively. Hypotension requiring vasopressors was associated with a significantly improved rate of response in patients with melanoma compared with patients not requiring vasopressors (23.2% vs. 6.5%, P2 = 0.037). Although high dose intravenous rIL-2 therapy can be associated with cardiopulmonary toxicity, toxic side effects generally are not severe and are rapidly reversible.

Treatment of Patients With Metastatic Melanoma With Autologous Tumor-Infiltrating Lymphocytes and Interleukin 2

Studies of human tumor-infiltrating lymphocytes (TILs) derived from patients with a variety of histologic types of cancer have demonstrated that cellular immune reactions against established malignancy exist in humans. We report the results of using autologous TILs plus high-dose bolus interleukin 2 (IL-2), with or without the concomitant administration of cyclophosphamide, in the treatment of 86 consecutive patients with metastatic melanoma. From May 1987 through December 1992, 86 patients (38 female and 48 male) with metastatic melanoma were treated (145 courses) with autologous TILs plus high-dose intravenous bolus IL-2 (720,000 IU/kg every 8 hours). TILs plus IL-2 were administered in two cycles separated by approximately 2 weeks. Two treatment cycles constituted one treatment course. Patients received a maximum of 15 doses of IL-2 per cycle given every 8 hours until grade 3 or 4 toxicity was reached that could not easily be reversed by standard supportive measures. All patients received concomitant medications to abrogate some of the side effects of IL-2 administration: acetaminophen (650 mg every 4 hours), indomethacin (50 mg every 8 hours), and ranitidine (150 mg every 12 hours). Fifty-seven of the 86 patients received a single intravenous dose of 25 mg/kg cyclophosphamide approximately 36 hours before receiving the first intravenous infusion of TILs plus IL-2. Six weeks after treatment, all known sites of disease were evaluated. The overall objective response rate in these patients was 34% and was similar in patients receiving TILs and IL-2 alone (31%) or in conjunction with cyclophosphamide (35%). There was no significant difference in the objective response rate in patients whose therapy with high-dose IL-2 had failed (32%) compared with patients not previously treated with IL-2 (34%). The frequency of response to treatment was greater in those patients who were treated with TILs from younger cultures (P = .0001), TILs with shorter doubling times (P = .03), and TILs that exhibited higher lysis against autologous tumor targets (P = .0008). Patients who received TILs generated from subcutaneous tumor deposits had higher response rates (49%) compared with those receiving TILs from lymph nodes (17%; P = .006). There was one treatment-related death due to respiratory insufficiency. Treatment with TILs and IL-2 with or without cyclophosphamide can result in objective responses in about one third of patients with metastatic melanoma. The side effects of treatment are transient in most patients, and this treatment can be safely administered. These results illustrate the potential value of immune lymphocytes for the treatment of patients with melanoma.

Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report.

A randomized prospective study was performed to compare the efficacy and toxicity of high-dose intravenous bolus interleukin-2 (IL-2) and a lower-dose intravenous bolus regimen for the treatment of metastatic renal cell carcinoma (RCC). Between March 1991 and April 1993, 125 patients with metastatic RCC were randomized to receive IL-2 by intravenous bolus every 8 hours at either 720,000 IU/kg (high-dose) or 72,000 IU/kg (low-dose) to the maximum-tolerated number of doses (or a maximum of 15 doses). After approximately 7 to 10 days, both treatment groups were re-treated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5 to 6 weeks later went on to receive re-treatment with another course (two cycles) of therapy. Response rates and toxicity were determined for the two treatment arms. One hundred twenty-five patients received a total of 208 courses of therapy. Sixty patients were randomized to receive low-dose, and 65 to receive high-dose IL-2. There were no treatment-related deaths in either arm. There was a greater incidence of grade III or IV thrombocytopenia, malaise, and hypotension in patients who received high-dose IL-2, while patients who received low-dose IL-2 had significantly more infections. Three percent of treatment courses with low-dose IL-2 required vasopressor support, compared with 52% of courses with high-dose IL-2. Patients who received low-dose IL-2 had a 7% complete response (CR) and an 8% partial response (PR) rate, and patients who received high-dose IL-2 had a 3% CR and a 17% PR rate. Low-dose intravenous bolus IL-2 represents an effective regimen for the treatment of metastatic RCC, with preliminary results comparable to those observed with high-dose IL-2. Low-dose IL-2 can be administered with significantly fewer complications, reduced use of vasopressor support, and fewer admissions to an intensive care unit (ICU).

Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2

Interleukin-2 (IL-2) is a hormone of the immune system responsible for control of the proliferation and cytotoxicity of T lymphocytes and natural killer cells as well as the proliferation of B lymphocytes. Recombinant IL-2 has been only minimally to modestly successfully to date in the treatment of cancer and infectious diseases, largely because the drug is associated with toxicity and a narrow therapeutic index. Quantitative measurement of IL-2 can be quickly done by enzyme immunoassay. IL-2 bioassay provides an index of biologically active cytokine. IL-2 action and pharmacokinetics can be understood in the context of the effect IL-2 on high (alpha, beta, gamma trimer) vs intermediate (alpha, beta) vs low (beta only or alpha only) affinity IL-2 receptors on various cells of the immune system. IL-2 undergoes rapid renal elimination. The route of administration is important to determine the provision of sustained drug concentrations adequate to support the proliferation and cytotoxicity of immune cells. When IL-2 is given intravenously it has rapid elimination pharmacokinetics with an initial elimination half-life and terminal elimination half-life (t1/2 beta) of 6 to 12 minutes and 40 to 80 minutes, respectively. Subcutaneous or intramuscular administration of IL-2 results in sustained systemic absorption and approximately 30% of the injected dose is absorbed. Because IL-2 is less rapidly cleared from the site of intracavitary injection, when the drug is given by these less traditional routes (e.g. intraperitoneal, intrapleural, intrathecal, intraventricular, intravesicular, and inhalational administration) sustained local IL-2 activity can result. In some cases this has resulted in an improved therapeutic index compared with that resulting after administration of the drug by high dose intravenous bolus or continuous infusion. Depot IL-2 preparations may offer more convenient administration (e.g. t1/2 beta of polyethylene glycolated IL-2 is approximately 10-fold higher than that of recombinant IL-2) or more favourable biodistribution (e.g. IL-2 liposomes are more potent against lung metastases) compared with IL-2 administered by more conventional routes. An understanding of IL-2 clinical pharmacokinetics in relation to immunobiology of this central cytokine should lead to less toxicity and more effective clinical use.

Toxicité cardiaque de la bupivacaïne et diazépam. Etude expérimentale chez le chien anesthésié

The use of diazepam has been suggested for the treatment of convulsions resulting from accidental high plasma levels of local anaesthetics. However, it has been reported that this drug may increase the cardiac effects of bupivacaine in dogs. The present study aimed to assess the effects of diazepam on the electrophysiological signs of a high-dose intravenous bolus of bupivacaine in fourteen dogs, divided into two groups, and anaesthetized with thiopentone and ventilated. All the animals were given a bolus dose of 4 mg · kg −1 bupivacaine. Immediately afterwards, group I (n = 7) received 0.8 ml · kg −1 normal saline solution and group II (n = 7) was given 4 mg · kg −1 diazepam over 1 min. The parameters measured on lead II of the electrocardiogram were : cycle length (R-R interval), QRS length (QRS) and QT interval corrected for heart rate (cQT). Intranodal (AH) and His-Purkinje (HV) conduction times were measured with recording bipolar stimulation electrodes (USCI 6F). Mean aortic pressure (P̄ao) was measured via a femoral arterial line. In the two groups, the parameters were recorded before and 2, 5, 10 and 15 min after the bupivacaine bolus. Arterial blood samples for measurement of bupivacaine and diazepam serum levels were obtained before and 3, 15 and 30 min after the bupivacaine bolus. There was no significant difference between the two groups in the electrophysiological or haemodynamic parameters at any time. However, the increase in HV and QRS length was a little higher in group I than in group II. The administration of diazepam after bupivacaine resulted in lower serum levels of local anaesthetic : 5.1 ± 0,5 vs 7.6 ± 1.4 μg · ml −1 (p < 0.01) at the 3rd min, and 2.14 ± 0.03 vs 3.0 ± 0.4 μg · ml −1 (p < 0.02) at the 5th min. No pharmacokinetic explanation could be found to explain these results that do not confirm previous studies. It was concluded that high doses of diazepam did not increase cardiac electrophysiological or haemodynamic effects of high plasma levels of bupivacaine.

Prostacyclin inhibits gastric emptying and small-intestinal transit in rats and dogs

Prostacyclin (PGI2) antagonizes 16,16-dimethyl prostaglandin E2-induced diarrhea in rats, presumably by inhibiting the fluid accumulation of “enteropooling” in the small intestine. The effect of PGI2 on gastric emptying, small intestinal transit, and colonic transit was examined in rats and dogs to determine if interference with propulsion might also contribute to the antidiarrheal properties of this compound. Rats implanted with chronic duodenal cannulas were given subcutaneous PGI2 (0.1–1000 μg/kg) followed 10 min later by intragastric 51Cr and a visually detectable duodenal transit marker. Forty-five minutes later, the animals were killed. Small-intestinal transit was expressed as the percentage of small intestinal length traveled by the visually detected marker. Gastric emptying was expressed as the percentage of the total 51Cr found in the small intestine. Subcutaneous PGI2 inhibited gastric emptying maximally at 10 μg/kg. Small-intestinal transit was significantly decreased at 50 μg/kg and almost completely suppressed at 1.0 mg/kg. Subcutaneous naloxone (0.5 mg/kg) given 10 min before and 20 min after subcutaneous PGI2 administration did not block PGI2's effects. Intravenous or oral PGI2 in doses as high as 0.2 or 10 mg/kg, respectively, had none of these effects. However, a high-dose intravenous bolus (1.0 mg/kg) or infusion (1.0 mg/kg · 45 min) both inhibited gastric emptying. Small intestinal transit was only decreased by PGI2 infusion, suggesting that this parameter was more sensitive to a sustained blood level than gastric emptying. Hourly injections of subcutaneous PGI2 (0.5 mg/kg) had no effect on rat colonic transit measured over a 3-h period after deposition of the transit marker through a colonic cannula in a manner similar to that described for small-intestinal transit above. Small-intestinal transit was also measured in dogs given a barium suspension through a chronic duodenal cannula. The animals simultaneously received subcutaneous PGI2 (10 μg/kg) and were given an additional treatment and an abdominal x-ray every 30 min thereafter. In vehicle-treated dogs, barium reached the cecal area in an average of 2.8 h after instillation. In PGI2-treated dogs, barium never reached the cecum in the 5-h examination period. Thus, PGI2 inhibits gastric emptying in rat and small-intestinal transit in rat and dog but has no effect on rat colonic transit. These properties could contribute to PGI2's antidiarrheal activity.