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J M Koeller

Publications and source records attributed to J M Koeller.

14 recordsLinked to original sources
PubMed1991

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.

Aged↗
PubMed1991

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

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.

Humans↗
PubMed1990

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.

Algorithms↗
PubMed1989

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)

Humans↗
PubMed1988

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).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

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.

Adult↗
PubMed1986

Phase I clinical trial and pharmacokinetics of carboplatin (NSC 241240) by single monthly 30-minute infusion.

Carboplatin (diammine [1,1-cyclobutanedicarboxylate(2-)-O,o']platinum) is a second generation platinum coordination complex. It has a spectrum of activity that is similar to that of cisplatin and is less nephrotoxic and emetogenic in experimental animals. Fifty-two 30-minute infusions of carboplatin were given to 20 evaluable patients with a variety of solid tumors. Maximum tolerated dose was 440 mg/m2. Thrombocytopenia (less than 100,000/mm3) occurred in six of seven patients; two patients experienced a leukocyte count less than 2000/mm3. Platelet and leukocyte count nadirs occurred on day 21. No nephrotoxicity was seen. Blood urea nitrogen, serum creatine levels, and creatinine clearances remained normal, and no consistent elevation of urinary beta 2-microglobulin, leucine aminopeptidase, or N-acetyl-beta-glucosaminidase occurred. Nausea and vomiting were mild to moderate. A single patient developed mild peripheral neuropathy. No auditory toxicity was noted. The recommended dose for Phase II studies is 400 mg/m2 every 28 days for good risk patients; heavily pretreated patients should receive 320 mg/m2.

Antineoplastic Agents↗
PubMed1985

Correlations between leukocyte count and absolute granulocyte count in patients receiving cancer chemotherapy.

The absolute granulocyte count (AGC) has been considered the best index for estimating the risk of infection in patients receiving myelosuppressive therapy. However, many investigators and cooperative oncology groups use the leukocyte count and extrapolate concurrent AGC values from an arbitrary conversion scale. Our review of the literature revealed no analysis of the relationship between the leukocyte count and the AGC in patients receiving cancer chemotherapy. It also failed to provide a method for converting toxicity criteria from one scale to the other. To explore the possible relationship of the leukocyte count to the AGC, we have completed a retrospective analysis of leukocyte count and accompanying AGC in patients receiving cancer chemotherapy. The leukocyte count and the AGC are shown to be linearly related over the entire population, enabling predictable cross-indexing from leukocyte count to AGC by the use of the formula: AGC = -0.7 + 0.8 (leukocyte count). This provides a rational basis for the development of guidelines for drug dosing and toxicity. In the patient group with leukocyte count less than or equal to 4500, however, the magnitude of random variability decreased predictive ability. Numerous patients in this group received differing toxicity scale scores when classified according to the Eastern Cooperative Oncology Group (ECOG) scales for AGC and leukocyte count. In some cases, as much as 46% disagreement occurred. New toxicity scales for AGC and leukocyte count, which were developed based upon the linear relationship above, reduced this disagreement substantially. These scales result in a greater agreement of toxicity ratings, and may provide a more accurate method of classifying toxicity and regulating dosages of chemotherapeutic agents.

Antineoplastic Agents↗
PubMed1985

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.

Adult↗
PubMedDate not supplied

Phase I study of vinblastine and verapamil given by concurrent iv infusion.

Overcoming resistance to chemotherapy is an important goal in cancer treatment. In many systems, resistance to anthracyclines and vinca alkaloids correlates with a diminished intracellular content of drug. In P388 leukemia and Ehrlich ascites tumor, an active outward transport of anthracyclines and vinca alkaloids occurs. Calcium channel blockers, such as verapamil, inhibit this active outward transport and increase intracellular content of vinblastine and anthracyclines in cells resistant to vinca alkaloids and anthracyclines, respectively. We report a phase I trial of vinblastine (1.5 mg/m2 daily as iv continuous infusion X 5 days) in 17 patients and concurrent verapamil in escalating doses. Verapamil was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of vinblastine toxicity when vinblastine and verapamil were given concurrently. ECG change was the dose-limiting toxicity. At 0.12 mg/kg/hour, five of nine patients developed first-degree heart block (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 patients. Reversible nonspecific T-wave changes were seen in four of 17 patients. Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 patients had wbc count nadirs less than 2000/mm3, and two of 17 patients had platelet count nadirs less than 100,000/mm3. Four patients experienced neurotoxicity. A mean vinblastine concentration of 2.2 ng/ml (0.55 nM) and a mean verapamil concentration of 290 ng/ml (0.45 microM) were achieved with the concurrent 5-day infusion. The tolerable levels of verapamil obtained appear to be less than those which were reported to inhibit vinblastine efflux in vitro. Additional in vitro experiments at the tolerable doses of vinblastine and verapamil are recommended.

Adult↗