J. M. Koeller

Electrocardiographic and Cardiovascular Effects of the 5-Hydroxytryptamine3 Receptor Antagonists

OBJECTIVE: To review the electrocardiographic (ECG) and cardiovascular effects of 5-hydroxytryptamine3 (5-HT3) receptor antagonists preclinically, in healthy volunteers, and in patients undergoing chemotherapy or surgery. DATA SOURCES: A MEDLINE search was performed of clinical trials and preclinical data published between 1963 and December 2002 assessing the ECG and cardiovascular effects of 5-HT3 receptor antagonists, supplemented with reviews and secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified were evaluated and all information deemed relevant was included in this review. DATA SYNTHESIS: There are no clinically relevant differences in efficacy and safety among the available 5-HT3 receptor antagonists for prevention and treatment of chemotherapy-induced and postoperative nausea and vomiting. As a class, they have well-defined electrophysiologic activity. Changes in ECG parameters (PR, QRS, QT, QTc, JT intervals) are small, reversible, clinically insignificant, and independent of the patient population studied, and patients are asymptomatic during these changes. ECG changes are most prominent 1–2 hours after a dose of dolasetron, ondansetron, and granisetron and return to baseline within 24 hours. Clinically important adverse cardiovascular events associated with these changes are rare. No serious cardiac events (including torsade de pointes) arising from ECG interval changes have been attributed to 5-HT3 receptor antagonist use. CONCLUSIONS: Clinical data demonstrate that ECG interval changes are a class effect of the 5-HT3 receptor antagonists. Theoretical concern regarding cardiovascular adverse events with these agents is not supported by clinical experience. The significant benefits of these agents outweigh the theoretical small risk of meaningful cardiovascular events.

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

Carboplatin (diammine[1,1‐cyclobutanedicarboxylate(2‐)‐O,ó]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 (<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 β2‐microglobulin, leucine aminopeptidase, or N‐acetyl‐β‐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.

A phase I clinical trial of recombinant DNA gamma interferon.

Recombinant gamma interferon (r-GIFN) demonstrates in vitro and in vivo characteristics that contrast with those of alpha and beta interferons. It has relatively weak antiviral properties, yet relatively potent immunomodulatory effects. A phase I trial was performed with r-GIFN (specific activity 2.6 X 10(6) IU/mg protein), administered as a continuous intravenous (IV) infusion over 24 hours for five days (Cl X 5) and repeated every 28 days. This schedule was chosen based on the short half-life of r-GIFN in animal systems and the in vitro augmentation of biologic effects with continuous exposure to interferons. Twenty-one patients with refractory solid tumors received 46 evaluable courses of therapy. The dose-limiting toxicities included fever, flu-like symptoms, cardiovascular toxicity, and neurotoxicity. The cardiovascular toxicity included hypotension and one episode of cardiac ischemia with chest pain. Neurotoxicity consisted of lethargy and confusion. These toxicities were reversible, and although dose-limiting, occurred sporadically throughout all dosage levels. Mild to moderately severe non-dose-limiting toxicities included nausea and vomiting, leukopenia, and liver function abnormalities. Other infrequent toxicities included hypocalcemia, diarrhea, constipation, and alopecia. The maximally tolerated dose of r-GIFN on this schedule is 0.5 X 10(6) IU/m2/d. Partial responses were seen in one patient with metastatic melanoma and in one patient with renal cell carcinoma. Toxicity and antitumor activity were seen at doses where interferon serum levels could not be detected by radioimmunoassay. In addition, the toxicity and antitumor activity seen were at much lower doses than previously described for shorter infusion schedules of other recombinant gamma interferon preparations. Differences in biologic activity of interferon preparations and/or differences in scheduling may account for this variability. Although this study defines a recommended phase II dose of r-GIFN based on the maximally tolerated dose, the optimal therapeutic index may exist at a lower dosage level.

Phase I clinical investigation of amonafide.

Amonafide (benzisoquinolinedione, NSC 308847) is a new synthetic imide antineoplastic agent with DNA intercalative properties that has been evaluated in a phase I clinical trial. The drug was administered as a single intravenous (IV) infusion over 30 to 120 minutes repeated every 28 days. Ninety-five courses of therapy at doses ranging from 18 to 1,104 mg/m2 were administered to 38 patients with refractory solid tumors. Granulocytopenia was dose limiting. Leukopenia was seen in 13 of 31 courses at doses of 690 mg/m2 or greater. Life-threatening granulocytopenia (less than or equal to 250 microliters) was noted in 1/6 patients treated at 800 mg/m2, 1/8 patients treated at 918 mg/m2, and 2/5 patients treated at 1,104 mg/m2. No definite relationship between myelotoxicity and prior treatment status was noted. Rate-of-infusion dependent, nonhematologic toxicities included diaphoresis, flushing, dizziness, and tinnitus, all of which were ameliorated by increasing the duration of drug infusion to 120 minutes. In addition, nausea and vomiting (grades 1 and 2) were seen in 29/56 courses at doses greater than or equal to 519 mg/m2, but were easily controlled by phenothiazine antiemetics. Amonafide plasma and urine concentrations were determined by high-pressure liquid chromatography (HPLC). Plasma concentrations declined biexponetially with a terminal harmonic mean terminal half-life (t 1/2) of 5.5 h. The mean apparent volume of distribution at steady-state and total body clearance were 532 L/m2 and 84 L/h/m2, respectively. Less than 5% of the total dose of amonafide was excreted unchanged in the urine. Antitumor activity has been noted in one patient with non-small-cell lung cancer (one complete response exceeding 29 months duration) and in one patient with prostatic cancer (complete pain relief and improvement in bone scan for 9 months). The recommended dose for phase II trials with this schedule of amonafide is 918 mg/m2 with dose escalation to amonafide is 918 mg/m2 with dose escalation to myelotoxicity.

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.Staphylococcus aureus and Staphylococcus epidermidis are organisms that frequently cause conjunctivitis or blepharoconjunctivitis. We describe a patient with methicillin-resistant S. aureus and S. epidermidis conjunctivitis who was treated successfully using an extemporaneously prepared topical ophthalmic solution of vancomycin hydrochloride 31 mg/mL. Studies describing the preparation, stability, and comfort of this solution, as well as reports pertaining to efficacy, are reviewed. Controlled clinical trials evaluating the safety and efficacy of vancomycin ophthalmic solution have not yet been performed.

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 ⩽ 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.

Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.

The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.

Head and neck cancer: detection and therapeutics.

The stage of disease remains the major prognostic indicator for head and neck cancer. Five-year survival declines as the disease stage progresses. Currently, only stage I and stage II head and neck cancers are curable; thus, early detection is imperative. Treatment for stage III and stage IV disease is only palliative. Pharmacists can promote early detection by educating high-risk populations (patients who drink and smoke) and monitoring their use of nonprescription medications for palliation of symptoms. Patients with risk factors and symptomatology of head and neck cancer should be referred for proper medical evaluation. Thus, through education and communication, pharmacists can play an important role in the early detection and treatment of head and neck cancers.

The impact of compliance to oncology pathways that include G-CSF rules for use on ER visits/hospitalizations in a multistate program.

135 Background: CareFirst BCBS initiated a multistate oncology pathway program in 2008, which reduced chemotherapy and hospitalization expenditures and also increased supportive care drug utilization. This study evaluated the impact of following pathways including supportive care versus not following pathways on ER visits/hospitalizations and associated costs as a result of anemia, neutropenia, and chemotherapy-induced nausea and vomiting (CINV).nnnMETHODSnThe CareFirst claims database was utilized to evaluate data two years after initiation of the pathways program. Frequency of ER visits/hospitalizations for neutropenia, anemia and CINV was the primary outcome measured and was compared between compliant and noncompliant pathway utilization of granulocyte colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), and antiemetics, respectively. Logistic regression analyses were used to control for expenditures of ESAs, CSFs, and antiemetics in the context of compliance and the corresponding visit types. Costs associated with ER visits/hospitalizations were also compared between compliant and noncompliant pathway utilization of supportive care.nnnRESULTSnOverall, 46 sites with 1,586 patients were evaluated. There were a total of 12 ER visits/hospitalizations for anemia, 231 for neutropenia, and 360 for CINV. G-CSF pathway compliance resulted in a relative reduction in ER visits/hospitalizations of 67.2% (from 28.3% to 11.5%, p<0.001). Logistic regression showed consistent results when controlling for costs with a 69.5% relative reduction of ER visits/hospitalizations (p<0.001). A comparison of ER visits/hospitalization costs as a result of neutropenia demonstrated G-CSF pathway compliance producing an average savings of

New anticancer agents.

1,173 per line of therapy (p=0.001). Analogous analyses did not demonstrate a significant relationship between ESA and antiemetic utilizations and their corresponding ER visits/hospitalizations.nnnCONCLUSIONSnAdherence to oncology pathways, including G-CSF use rules, is associated with a significantly lower ER visits/hospitalization rates and costs associated with febrile neutropenia.