Phase I clinical study with pharmacokinetic analysis of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193) administered as a five-day infusion.

A Phase I trial of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193, tiazofurin) was conducted using a 5-day continuous infusion schedule. Twenty-four patients with advanced cancer were entered on this trial. Dose levels ranged from 360 to 2350 mg/sq m/day for 5 days. Neurotoxicity was dose limiting and occurred in six patients. Neurotoxicity was expressed as confusion, lethargy, or obtundation and was associated with focal neurological deficits in four of six patients: hemiparesis, three; cortical blindness and bilateral upper extremity weakness, one. Neurotoxicity was not clearly dose related, occurring at 900 mg/sq m/day for 5 days (two patients), 1100 mg/sq m/day for 5 days (two patients), 1850 mg/sq m/day for 5 days, and 2350 mg/sq m/day for 5 days (one patient each). Other toxicities seen were myelosuppression, desquamation of palms and soles, malar erythema, and hyperpigmentation, stomatitis, chest pain, drug fever, and increased serum creatine phosphokinase. Administered drug [71.5 +/- 11.2% (SE)] was recovered intact in the urine within 24 h of administration. Terminal-phase mean harmonic half-life was 8.0 h. The unpredictable neurotoxicity seen following continuous infusion therapy with tiazofurin suggests that Phase II trials of this schedule are not indicated until better understanding of the biochemical effects of tiazofurin is achieved.

A phase I clinical and pharmacokinetic trial of hepsulfam.

Hepsulfam (1,7-heptanediol-bis-sulfamate) is one of a series of bis-sulfamate acid esters that was synthesized in an attempt to improve the antitumor efficacy of busulfan. Hepsulfam has shown broad antineoplastic activity in preclinical studies. This Phase I trial evaluated hepsulfam given as a single i.v. dose every 21-35 days. Twenty-nine patients with refractory solid tumors participated in this study. Twenty-six of these patients had had either prior chemotherapy or radiation therapy. Fifty-two courses of treatment were given at doses ranging from 30 to 360 mg/m2/day. The dose limiting toxicity was prolonged thrombocytopenia and granulocytopenia. This toxicity was cumulative with Grade 3 or 4 thrombocytopenia occurring in 3 of 15, 4 of 9, and 2 of 2 patients in the first, second, and third courses of greater than or equal to 210 mg/m2, respectively. This toxicity was noted in patients with less than or equal to 1 prior chemotherapeutic regimen, as well as in patients with greater than 1 prior chemotherapeutic regimens. Nonhematological toxicities included Grade 1 or 2 nausea and vomiting and fatigue. There was no evidence of pulmonary toxicity. Plasma levels of hepsulfam were quantified by gas chromatography in 12 patients. The plasma and blood half-lives were 15.9 +/- 4.6 and 90 +/- 13 h, respectively. No objective tumor responses were seen. We conclude that the maximally tolerated dose when hepsulfam is given as a single dose every 35 days is 210 mg/m2, but that there is significant risk of cumulative hematological toxicity at this level.

Phase I clinical trial of a combination of dipyridamole and acivicin based upon inhibition of nucleoside salvage.

A Phase I clinical trial of simultaneous 72-h infusions of dipyridamole and acivicin was carried out in patients with advanced malignancies. The objective of this trial was to determine the maximum tolerated dose of dipyridamole when administered as a 72-h infusion in combination with acivicin. The development of this combination is of interest because of in vitro observations which demonstrate that dipyridamole potentiates the cytotoxic action of acivicin by blocking nucleoside salvage. Patients were treated with concomitant i.v. infusions of dipyridamole and acivicin for 72 h. The acivicin dose infused remained constant during the trial at 60 mg/m2/72 h. The maximum tolerated dose (MTD) of dipyridamole was 23.1 mg/kg/72 h. Limiting toxicities at the MTD of dipyridamole with acivicin were severe gastrointestinal and constitutional symptoms which appeared to be caused by the high doses of dipyridamole administered. Escalation of dipyridamole did not potentiate the mild myelosuppression or the neurotoxicity which occurs with acivicin alone. At a dose of dipyridamole which was well below the MTD, one patient experienced symptomatic orthostatic hypotension, and another patient with coronary artery disease developed dizziness and transient electrocardiogram abnormalities. However, no other hypotensive or cardiovascular events occurred as dipyridamole was escalated to the MTD. Phlebitis occurred at the site of infusion when the dose of dipyridamole exceeded 13.5 mg/kg/72 h. Because of this local toxicity, it was necessary to administer dipyridamole through a central venous catheter to achieve maximum plasma levels. At the MTD of dipyridamole, steady-state total and free plasma levels of 11.9 microM and 27.8 nM, respectively, were attained by 24 h. These are free dipyridamole levels which in vitro were sufficient to block cytidine salvage and to potentiate the biochemical and cytotoxic effects of acivicin against human colon cancer cells (P.H. Fischer et al., Cancer Res., 44:3355-3359, 1984).

Phase I clinical trial of carbetimer.

Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1-2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m2. The dose-limiting toxicity was hypercalcemia (serum calcium greater than 12.5 mg/dl) noted in two of three patients at a dose of 8500 mg/m2. Serum calcium levels between 10.5 and 12.5 mg/dl were noted in an additional three patients treated at doses greater than or equal to 1600 mg/m2. Calcium balance studies in three patients treated at 6500 mg/m2 revealed an increase in urinary cyclic AMP and phosphate excretion after treatment accompanied by a mild elevation of serum parathyroid hormone. Immunological studies in these patients revealed a statistically significant increase in the percentage of peripheral T-helper cells. An increase in the T-helper/suppressor cell ratio was observed in two of the three patients studied. Interleukin 2 production by phytohemagglutinin-stimulated peripheral mononuclear cells was increased in two of three patients. One patient with a renal cell carcinoma showed a mixed response. The recommended dose for phase II trials as assessed from this study is 6500 mg/m2 as a single dose every 28 days.

Procedure costs and outcomes associated with pharmacologic management of peripheral arterial disease in the Department of Defense.

This study was undertaken to determine if differences existed between pharmacologic treatments of peripheral arterial disease (PAD) with respect to PAD-related costs and health care outcomes in the United States Department of Defense health care system. We performed a retrospective review of hospital and prescription data to explore the effects of at least 90 days of aspirin, pentoxifylline, papaverine, or dipyridamole on 4 PAD-related outcomes: number of PAD-related invasive procedures (INV), number of PAD-related examination procedures (EXM), number of PAD-related hospitalization days (HDAYS), and cost of PAD-related procedures (COST) during 5 years. A covariate representing the number of PAD-related hospitalizations before the study period was used to attempt to control for severity of disease state. General linear models were used in the analyses. A statistically significant difference was seen between treatment groups for a linear combination of INV, EXM, HDAYS, and COST when controlling for past PAD-related hospitalizations (P < 0.014). A statistically significant relationship existed between treatment groups and INV (P < 0.041). The pentoxifylline treatment group had a statistically significant higher covariate-adjusted mean INV compared with the aspirin treatment group (P < 0.043). Also, PAD-related past hospitalizations were significantly related to EXM (P < 0.006). Our results appear to support the use of aspirin as a preventive treatment in PAD compared with pentoxifylline or dipyridamole.

Clinical guidelines for the treatment of cancer-related anemia.

Defining clinical guidelines for the treatment of cancer-related anemia requires investigation into causes and characteristics of this malady, uses, benefits, and adverse effects of current treatments; and recognition of currently accepted guidelines set forth by the American College of Physicians and the American Association of Blood Banks. Anemia, the most common hematologic abnormality in patients with cancer, originates from a variety of causes, including occult blood loss, hypoproliferation, and hemolysis, and often involves more than one mechanism. Clinical manifestations include fatigue, dyspnea, tachycardia, dizziness, anorexia, and hypersensitivity to cold. Although the majority of cancer-related anemias are hypoproliferative, establishing their pathophysiology in individual patients is critical to effective treatment. Anemia usually, but not always, resolves with successful treatment of underlying disease. Symptomatic relief can be managed in accordance with established treatment guidelines.

Recombinant interleukin-2.

Recombinant interleukin (IL)-2 is a newly approved immunoregulatory protein produced by lymphocytes that exhibits a wide range of immunologic effects. It is a true biologic response modifier in that is has no known direct antitumor activity, but mediates its cytotoxicity through activation of effector cells including T cells, natural killer cells, and lymphokine-activated killer cells. Recombinant IL-2 has demonstrated activity in patients with renal cell carcinoma and melanoma, with objective response rates of approximately 15-20%. The median duration of response in renal cell carcinoma is 23 months. Toxicity experienced with high-dose IL-2 can be significant. The most common dose-limiting toxicities are hypertension, weight gain, oliguria, respiratory insufficiency, and neurotoxicity. These effects are generally manageable and reversible on discontinuation of therapy. Administration of low-dose IL-2 has emerged as a means of substantially reducing toxicity. At least in renal cell carcinoma, it appears that the response rate to low-dose IL-2 is comparable to that with higher dosages.

Economic analysis of carboplatin versus cisplatin in lung and ovarian cancer.

OBJECTIVE: To conduct an economic analysis on the use of carboplatin versus cisplatin over multiple courses in patients with lung [nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC)] or ovarian cancer. DESIGN: This 1-year study was a prospective, multicentre, cost-minimisation evaluation. Direct medical resource utilisation and costs associated with carboplatin and cisplatin administration over 3 to 6 courses of treatment were measured and compared. The perspective of this evaluation was that of the payer. SETTING: A convenience sample of 16 sites representing a mix of cancer centres, outpatient clinics, medical centres and managed-care sites in a general practice oncology setting participated. PATIENTS AND INTERVENTIONS: Patients were included in this study if they were newly diagnosed with NSCLC, SCLC or ovarian cancer, had not received prior chemotherapy, received either carboplatin or cisplatin as their treatment (additional chemotherapy agents were allowed), and received at least 3 courses of carboplatin or cisplatin therapy up to a maximum of 6 courses. Patients receiving more than 6 courses of therapy were included in this study, but data collection on those patients stopped after the sixth course. Individuals involved with data collection at all sites were trained via on-site and/or teleconference training. Site visits were made to assure reliability of at least 0.80. Data were collected and compiled via a fax transmission process that scans directly through optical mark and character recognition into a computer database. Outcome measures included costs of: medications, emergency room visits, physician/clinic/laboratory visits, home healthcare visits, transfusions, special procedures, consultations, hospitalisations and other/miscellaneous costs. MAIN OUTCOME MEASURES AND RESULTS: Of 220 patients, 164 met the study criteria (response rate = 74.2%) with 95 patients in the carboplatin group (NSCLC = 45, SCLC = 18, ovarian = 32) and 69 in the cisplatin group (NSCLC = 36, SCLC = 21, ovarian = 12). The average number of courses were: NSCLC = 4.3 and 4.2, SCLC = 4.3 and 4.8, and ovarian = 4.7 and 5.1, respectively, for carboplatin and cisplatin. The total costs (treatment and toxicity) associated with the use of carboplatin were higher in NSCLC, similar in SCLC but lower in ovarian cancer. CONCLUSIONS: These results indicate that overall treatment costs may vary depending on cancer type, even when the same drugs are used. The total costs (treatment plus toxicity costs) associated with the use of carboplatin were higher than those of cisplatin in patients with NSCLC, similar in SCLC, but lower in ovarian cancer.

Nutritional parameters observed during 28-day infusion of recombinant human tumor necrosis factor-alpha.

In conjunction with a Phase I investigation of the antineoplastic activity of recombinant human tumor necrosis factor-alpha (TNF-alpha), administered as a 28-day continuous infusion, selected nutritional parameters were evaluated to identify any effect that might be attributed to the TNF infusion. Seven clinically stable men with a variety of tumor types were studied. None had clinical or laboratory evidence of significant malnutrition before entry into the study. Five patients received 10 micrograms of recombinant human TNF-alpha per square meter per day and two patients received 25 micrograms/m2 per day. Indirect calorimetry assessment of resting energy expenditure, body weight, serum TNF concentration, and laboratory analysis of common nutritional markers (albumin, prealbumin, and triglycerides) were performed at baseline, day 14, day 28, and 2 weeks (day 42) after completion of the infusion. There were no statistically significant differences by analysis of variance observed in any parameter during the study period compared with baseline values and values on day 42. Also, there were no differences between any parameters when stratified by dose administered, although the number of patients studied was small. Measured serum TNF concentrations ranged from 0.02 to 1.56 ng/mL and did not correlate with study day or dose of TNF infused. No correlation was observed between serum TNF concentrations and resting energy expenditure. Although others have reported significant metabolic changes associated with acute administration of TNF in humans and animals, our experience does not support a hypermetabolic state in patients receiving low daily dose, long-term (28-day) continuous infusion of recombinant human TNF-alpha, a state that may be consistent with many neoplastic conditions.

Fax technology for collecting outcomes data in a computer database.

In this era of cost containment, outcomes research is becoming more prevalent. Therefore, various technologies allowing for flexibility in study design and the capture of specific clinical information need to be examined and used. These technologies include fax data systems, pocket scanners, automated telephone equipment, and hand-held computer devices. Fax data systems convert a fax machine into an automated data-entry system. Data-filled forms are faxed to a computer, the fax is converted, and the data are entered into preset fields in a database. Applications for fax systems include acute care-based and ambulatory care-based drug-use evaluations, drug recall systems, and patient-completed surveys of health status. Pocket scanners are hand-held instruments for rapid data entry and transport. Applications for pocket scanning include patient interview responses, procedure and disease analysis, and procedure coding. Options for automated telephone equipment include surveys with interactive voice-mail responses or keypad data entry, pharmacist-monitored drug information and survey services, fax-back and mail-out services, and patient-generated disease intervention programs. Hand-held computer technology is a source of information on multiple protocols and care pathways. All these technologies improve data collection with respect to accuracy and speed, facilitate data analysis, and promote cost-efficient information sharing. The purpose of this study was to evaluate the use of fax technology in data collection for a prospective, multicenter study of the outcomes and cost-effectiveness of two drugs used in the treatment of cancer. Details for the pharmacoeconomic study can be found elsewhere. Fax technology was selected because of the ease with which those responsible for managing the data collection could be trained to use it, the affordability and efficiency of the technology, the ease with which data could be analyzed, and the accuracy of data collection.

Rational use of antibiotics in the critically ill patient.

Despite the advent of newer broad-spectrum antibiotics, infection in critically ill patients still is associated with significant morbidity and mortality. For these patients, who frequently receive inappropriate and excessive empiric antibiotic therapy, it is important to develop rational drug usage criteria. Current economic forces, including personnel shortages and the effects of diagnosis-related groups, are also a critical factor in this patient population. Criteria for rational antibiotic selection are based on patterns of infection and knowledge of the pharmacokinetic and pharmacodynamic properties of individual antibiotics. The development and use of treatment protocols, or algorithms, will provide quality patient care for the lowest overall cost.

Understanding cancer pain.

The pathogenesis of cancer pain, the incidence of pain associated with specific types of malignant tumors, and the nature of acute and chronic pain are discussed, and alternative delivery systems for pain management are described. More than 80% of cancer patients with advanced metastatic disease suffer moderate to severe pain. Most cancer pain is caused by direct tumor infiltration; approximately 20% of cancer pain may be attributed to the effects of surgery, radio-therapy, or chemotherapy. The incidence of cancer pain is related to tumor type; 70% or more of patients with tumors of the bone, cervix, and ovaries suffer cancer-related pain, while only 5% of patients with leukemia have pain. Pain is defined by the organs involved. Somatic pain is usually dull and well localized; visceral pain is generalized and difficult to describe. Other types of pain, including deafferentation pain and referred pain, are particularly difficult to manage. Cancer pain may be acute or chronic. The latter may cause psychological reactions that make effective treatment more challenging. Opiate analgesic agents, administered by the epidural or intrathecal routes, block pain more selectively and produce fewer adverse reactions than systemic analgesic agents. The duration and onset of analgesia depend on the lipophilicity of the agent used. Because pain is the most common complaint of the patient with cancer, clinicians should be aware of the range of pharmacologic and nonpharmacologic analgesic modalities available to them. Familiarity with newer modalities and delivery routes, such as spinal administration of opiate analgesics, is recommended.

Biologic response modifiers: the interferon alfa experience.

The effects and toxicities of interferon alfa are described, and the role of the pharmacist in making decisions and providing education about biologic response modifiers (BRMs) is discussed. Interferons have both direct antitumor activity and extensive effects on the immune system. Two recombinant interferon alfa products--interferon alfa-2a and interferon alfa-2b are available commercially. Indications in FDA-approved labeling for interferon alfa include the treatment of hairy-cell leukemia, acquired immunodeficiency syndrome-related Kaposi's sarcoma, and genital warts; however, it also is being used successfully against early chronic myelogenous leukemia, low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and previously untreated multiple myeloma. Other malignancies that respond to treatment with interferon alfa are malignant melanoma, ovarian carcinoma, and renal cell carcinoma. The toxic pattern of interferon alfa consists of flu-like symptoms, which are seen at all doses, on all schedules, and in virtually all patients. After repeated dosing, the chronic toxicities of anorexia, weight loss, and malaise and fatigue may develop. Myelosuppression, central nervous system toxicity, increased hepatic enzyme concentrations, nausea and vomiting, and cardiovascular toxicity also are possible. Serum neutralizing antibodies may be formed during therapy; this phenomenon may affect the clinical outcome. Numerous BRMs are being investigated for clinical use, and pharmacists must become conversant in the issues that surround these agents. Areas in which pharmacist involvement and knowledge are important include overall cost, product similarities and differences, dosing and scheduling, drug delivery systems, ways to minimize waste, adverse effects and their management, drug interactions, storage requirements, differences in production and purification techniques among manufacturers, and education of patients and staff.(ABSTRACT TRUNCATED AT 250 WORDS)

Idarubicin: a second-generation anthracycline.

Because of its in vitro activity in leukemic cell lines and Phase I studies of acute leukemia, Phase II and III clinical trials with idarubicin hydrochloride were conducted in patients with acute lymphocytic leukemia or acute nonlymphocytic leukemia. In the Phase III comparative trials between the combinations of idarubicin and cytarabine and daunorubicin hydrochloride and cytarabine, the idarubicin/cytarabine combination resulted in significantly greater complete remission rates and longer overall survival in two of three studies conducted in the US. As a result, the Food and Drug Administration approved intravenous idarubicin with a Class 1A rating in September 1990 for use in combination with other antileukemic drugs (e.g., cytarabine) for the treatment of acute myelogenous leukemia in adults. The recommended dose of idarubicin is 12 mg/m2 daily for three days by slow intravenous injection in combination with cytarabine. Although idarubicin causes myelosuppression similar to that described with daunorubicin, the incidence of cardiotoxicity in animal models is lower. Idarubicin also has the advantage of oral administration, but the oral formulation of the drug remains investigational. The use of idarubicin in pediatric patients also remains to be established.

Phase I trial of PCNU administered by 5-day courses.

PCNU was selected for clinical trials based on high activity in both standard and intracisternally transplanted murine tumors. PCNU was administered of five daily to 24 patients with refractory advanced solid tumors by courses of five daily iv injections every 6 weeks. The total dose ranged from 25 to 125 mg/m2/course. The major dose-limiting toxicity was reversible thrombocytopenia, with the nadi at 28-49 days and recovery by 2 weeks later. At a dose of 125 mg/m2/course, the mean nadir platelet count was 77 X 10(3)/mm3 (range, 16-201 X 10(3)/mm3). Recovery time was prolonged with successive courses in four patients, suggesting cumulative toxicity. The mean nadir of leukopenia at this dose was 2.6 X 10(3) cells/mm3 (range, 1.2-5.0 X 10(3) cells/mm3) and tended to occur with a later median at Day 44. Nausea and vomiting were unusually mild for a nitrosourea. Sporadic transaminasemia and elevated LDH may have been related to the vehicle, N,N'-dimethylacetamide. Other major organ toxic effects were not encountered, and there were no objective responses. PCNU was found to be a base-substitution mutagen in the Salmonella typhimurium assay. A starting dose of 125 mg/m2, divided into five daily doses, is suggested for phase II trails in patients with no significant hematologic compromise from prior chemotherapy or radiation, and a dose of 75 mg/m2 is recommended for all others.