Consent documents, reproductive issues, and the inclusion of women in clinical trials.

PURPOSE: To describe language used in consent documents at one academic medical center to inform women participating in studies of potential reproductive and fetal risks. METHOD: The authors reviewed consent document language describing reproductive and fetal risks in 114 approved protocols. Protocols were identified as being of high, low, or unknown risk based upon FDA drug-risk and radiation-risk categories. RESULTS: Although most consent documents advised women against participating for one or more pregnancy-related reasons, specific information about reproductive or fetal risks was included in fewer consent documents: 8 (73%) of the high-risk studies, 12 (40%) of the low-to-moderate-risk studies, and 29 (40%) of the unknown-risk studies. CONCLUSIONS: Investigators often omit fetal risk information from consent documents. Full disclosure of reproductive and fetal risks in consent documents and discussions can be taught and modeled during the research training period. The authors present a template with language that can be used in consent documents and recommend ongoing discussion of reproductive and fetal risks with women subjects throughout the study period.

5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy.

In the mid-1980s it was discovered that serotonin (5-hydroxytryptamine; 5-HT) was at least partially responsible for producing chemotherapy-induced nausea and vomiting. It was therefore realised that serotonin receptor blockade with serotonin 5-HT3 receptor antagonists could inhibit chemotherapy-induced nausea and vomiting. 5-HT3 antagonists have different chemical structures and receptor binding affinity. Granisetron, dolasetron and its major metabolite are pure 5-HT3 antagonists, while ondansetron and tropisetron are weak antagonists at the 5-HT4 receptor. Ondansetron has also been demonstrated to bind at other serotonin receptors and to the opioid mu receptor. The half-lives of granisetron, tropisetron and the active metabolite of dolasetron are 2 to 3 times longer than that of ondansetron. These observations initially suggested that more frequent ondansetron administration would be required; however, it has now been shown that receptor blockade does not correlate with elimination half-life and all 5-HT3 antagonists can be effectively administered once daily. Clinical trials have been conducted that directly compare the 5-HT3 antagonists. To compare these studies, it is necessary to assess trial design, including known risk factors for the development of chemotherapy-induced nausea and vomiting, and response criteria. Stratification for risk factors, use of strict efficacy criteria and randomisation to a blinded trial using an appropriate comparative regimen are essential for a well designed antiemetic trial. Comparative clinical trials using various doses, routes and regimens of administration have been conducted with 5-HT3 antagonists. Despite some trial design shortcomings, most of the studies show equal efficacy between the agents, especially in moderately emetogenic chemotherapy and mild, infrequently occurring adverse effects. The addition of steroids also appears to improve outcome. However, since many doses and regimens of ondansetron were used, further study is needed to determine the optimal regimen. The efficacy of 5-HT3 antagonists in controlling delayed nausea and vomiting from chemotherapy is less well studied. Further, there is no good scientific rationale for the use of 5-HT3 antagonists in controlling delayed nausea and vomiting since serotonin has not been shown to be released during the delayed phase. In fact, most studies show no benefit or modest benefit of 5-HT3 antagonists over placebo. Because the 5-HT3 antagonists perform similarly in the clinical setting, pharmacological differences do not seem to translate into therapeutic differences. There is also no appreciable difference in the incidence or severity of adverse effects among the 5-HT3 antagonists. Determination of clinical use may then be driven by cost.

The clinical application of research utilization: amphotericin B.

PURPOSE/OBJECTIVES: To describe the first application of the research utilization process by clinical nurses using the Stetler-Marram Model of Research Utilization to the practice of amphotericin B administration; to share the findings; and to discuss issues encountered in the process and their solutions. DATA SOURCES: Published articles identified through computerized literature searches, published abstracts and books, personal communication with one author, and an informal survey of other cancer centers' amphotericin B infusion practices; research articles were selected for review if studies included settings and patient populations similar to those of the authors and if they used experimental designs. DATA SYNTHESIS: Studies were reviewed for scientific merit and clinical applicability according to the Stetler-Marram model; findings were used to develop a specific nursing protocol for infusion times of amphotericin B based on clinical criteria. CONCLUSIONS: The Stetler-Marram model helped staff nurses decide how to apply research findings to practice, although using it was difficult and required mentorship. A research base exists for amphotericin B administration time but not for test doses or premedications to prevent or minimize side effects. IMPLICATIONS FOR NURSING PRACTICE: Staff nurses can use the Stetler-Marram model but need resources and support from individuals, committees, and administration. A specific protocol representing a practice change was implemented and may be applicable to other settings.

Paclitaxel: a new antineoplastic agent for refractory ovarian cancer.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of paclitaxel are reviewed. Paclitaxel is a diterpenoid taxane derivative found in the bark and needles of the western yew, Taxus brevifolia. Although it shares some structural similarities with other natural alkaloids, it contains a unique taxane ring. It is also unique in that its mechanism of action involves interruption of mitosis by promoting and stabilizing microtubule formation. Paclitaxel doses greater than 60 mg/sq m i.v. consistently produce mean peak plasma concentrations of 2-13 microM. Liver metabolism and biliary excretion are probably responsible for most of the drug's elimination. In clinical trials, paclitaxel has shown substantial activity against advanced, refractory ovarian cancer, metastatic breast cancer, and lung cancer. Paclitaxel may slow the course of melanoma and is being investigated in patients with advanced head and neck cancer and gastrointestinal cancer. Neutropenia is the major dose-limiting toxic effect of paclitaxel. Other adverse effects include hypersensitivity reactions, cardiac toxicity, and neurotoxicity. The recommended dosage for the treatment of recurrent metastatic ovarian cancer is 135 mg/sq m i.v. given over 24 hours every three weeks. It is recommended that neutrophil-count and platelet-count recovery be allowed to occur before the next treatment cycle is begun. Paclitaxel's activity against refractory ovarian cancer has not been matched since the inclusion of cisplatin in treatment regimens.

Raised plasma methotrexate concentrations following intrathecal administration in children with renal dysfunction.

Plasma methotrexate (MTX) concentrations were measured following intrathecal (IT) MTX treatment in four patients with acute lymphocytic leukemia and acute renal dysfunction. All four patients had raised serum MTX concentrations to potentially cytotoxic concentrations for a prolonged period of time, (96-120 h). In contrast, serum MTX concentrations after the same dosage of IT treatment ranged from undetectable to 0.11 microM by 15-24 h in seven control patients with normal renal function, and were undetectable by 48 h in all controls. The terminal MTX T1/2 was 19-44 h in the patients with renal dysfunction. Decreased renal clearance or a rapid efflux of MTX from cerebrospinal fluid, or both, could account for the high and sustained concentrations. Plasma MTX concentrations after IT treatment were normal in two patients treated after their renal function returned to normal. Patients with renal dysfunction should be carefully monitored for plasma MTX concentrations and may require leucovorin to prevent systemic side-effects after IT MTX treatment.

Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing.

Despite the clinical experience with Ommaya reservoir-facilitated intraventricular methotrexate (MTX) therapy, established age-related dosage guidelines do not exist. In an attempt to design such a schedule, 49 courses of intra-Ommaya MTX (median dose, 6 mg) administered to 12 patients were studied. Using a fluorescence polarized immunoassay (TDx; Abbott, Dallas, TX), the median peak intraventricular CSF MTX concentration (CSF [MTX]) was 423 mumol/L. Median CSF [MTX] at 24 hours was 4.6 mumol/L, and at 48 hours was 1.05 mumol/L. Median MTX half-life (t1/2) was 5.7 hours. A CSF [MTX] greater than 1 mumol/L was maintained for 24 hours in all but one course and for 48 hours in half of the courses. No correlations were found between MTX dose, patient age, [MTX], t1/2 or prior therapy. Considerable intra- and interpatient variability was seen in MTX disposition, emphasizing the need to monitor [MTX] with each course. A schedule for intraventricular MTX with an initial dose of 6 mg and supplemental doses of 6, 4, or 2 mg at 24 and 48 hours according to serial measurements of intraventricular [MTX] should be initiated to provide a minimum CSF [MTX] of 1 mumol/L for 72 hours.

Effect of acute ozone exposure on the proteinase-antiproteinase balance in the rat lung.

Lung disease may result from a persisting proteinase excess or a depletion of antiproteinase in pulmonary parenchyma. We investigated the in vivo effect of a 48-hr exposure to ozone at 0.5, 1.0, or 1.5 ppm on proteinase and antiproteinase activity of rat lungs. Elastase inhibitory capacities of serum, lung tissue, and airway washings were measured as indicators of antielastase activity. Trypsin inhibitory capacity was measured using an esterolytic procedure. Proteinase was measured as radioactive release from a 14C-globin substrate. The 48-hr exposures to O3 at levels up to 1 ppm produced concentration-dependent decreases of 35-80% of antiproteinase activities in serum and in lung tissue. However, exposure to 1.5 ppm O3 resulted in no decrease in antiproteinase activities. Acid proteinase activities (pH 4.2) were increased 65-120% by exposure to 1 or 1.5 ppm O3, which correlated with inflammatory cells noted histologically. At 1.5 ppm O3, pulmonary edema and hemorrhage were noted in histologic sections. These changes led to a flooding of the alveoli with up to 40 times normal protein levels and a greater than fivefold increase in airway antiproteinase. These data suggest that serum and soluble lung tissue antiproteinase activity decreased upon exposure to low levels of ozone. However, if O3 exposure is high enough to produce pulmonary hemorrhage, antiproteinase may increase following serum exudation. These changes may be important in the development of ozone-induced lung diseases, especially emphysema.

An in vitro model for the exposure of lung alveolar epithelial cells to toxic gases.

An in vitro model of lung alveolar tissue was developed by growing rat lung epithelial cells of Type II origin on hydrated collagen gels and subsequently maintaining the cultures at an air/liquid interface. The cultures provide a system to expose lung cells directly to toxic aerosols, fumes and gases. Nitrogen dioxide (NO2) was used to test the responsiveness of the cultures to toxic gases. Exposure to NO2 resulted in cytotoxicity and morphological alterations similar to those found in vivo, but at lower doses. Cell viability was analyzed by trypan blue dye exclusion, clonal survival and 3H-lysine incorporation. Dose-response relationships were determined at NO2 concentrations from 0-6.0 ppm (one hr exposure, room temperature) using cell viability assays. Decreased cell viability also resulted from increasing the time of exposure to 6 ppm of NO2 for up to one hr. This lung cell test system provides a rapid and economical system for the short-term toxicological testing of toxic gases, fumes, and aerosols.

Identification of plasma proteins containing sulfite-reactive disulfide bonds.

Plasma protein S-sulfonate compounds (RS-SO-3) have previously been shown to form, presumably by sulfitolysis of disulfide bonds, as a result of exposure to sulfite. In the investigations reported here, we identify two proteins in rabbit plasma, namely albumin and plasma fibronectin, which contain reactive sites for S-sulfonate formation. Separation and identification of these proteins following in vitro and in vivo exposure to sulfite was accomplished primarily by column chromatographic and electrophoretic techniques. In addition, the structure of presumed S-sulfonate groups was confirmed by the identification of cysteinyl-S-sulfonate residues in protein hydrolysates generated by enzymatic digestion. The molar ratio of RS-SO-3 in both albumin and plasma fibronectin was less than one. Data from our experiments suggest that the mixed disulfide site of non- mercaptalbumin is the reactive site for S-sulfonate formation. The site(s) of formation within the plasma fibronectin molecule was not investigated. The possible physiological significance of disulfide sulfitolysis of albumin and plasma fibronectin is discussed.

A comparison of starvation and elastase models of emphysema in the rat.

Starvation and elastase-induced changes in rat lung structure, biochemistry, and function were compared as models of human pulmonary emphysema. Ten-week-old male rats were instilled intratracheally with either porcine pancreatic elastase in saline (E) or with saline alone. A group of the saline-instilled rats were fed one third of their normal food intake until a 45% loss of body weight occurred (S). The remaining saline-instilled rats served as control animals (C). Post-treatment evaluations included in vivo respiratory function, lung histopathologic and morphometric analyses, lung tissue proteinolytic activity, and lung collagen. The E rats had in vivo respiratory function changes more similar to human emphysema than those of S rats. All lung volume subdivisions were decreased in S rats and increased in E rats. The volume-pressure curve of S rats was shifted to the right of the C curve, whereas that of E rats was shifted to the left. Forced expiratory flow rates of E rats were decreased at all lung volumes, but those of S rats were not. Both E and S rats had larger terminal air spaces and less alveolar surface area than did C rats. The S rats had more collagen per gram lung and higher proteinolytic activity than did C or E rats. These results show that, although starvation induces some changes characteristic of human emphysema, elastase-treatment provides a model more similar to the human disease.

Pulmonary effects of intermittent subacute exposure to low-level nitrogen dioxide.

The pulmonary biochemical and morphological changes resulting from the inhalation of relatively low levels of NO2 for up to 15 wk were investigated. Specific pathogen-free Fischer 344 rats were exposed to 0, 1, or 5 ppm NO2 or 1 ppm with two spikes to 5 ppm NO2 for 7 h/d, 5 d/wk for up to 15 wk. These exposures produced a mild concentration-related pulmonary injury, with the 5-ppm group sustaining the most damage. The other NO2-exposed animals showed similar types of damage, although the extent was less than that observed in the 5-ppm-exposed group. After 15 wk of exposure, histopathological examination revealed focal areas of hyperinflation and alveolar macrophage accumulation in some of the 5-ppm- and 1-5-ppm-exposed-exposed animals. These changes were preceded by a series of biochemical changes in the bronchoalveolar lavage fluid. Cell necrosis was indicated by elevated lavage fluid concentrations of lactate dehydrogenase after 1.7 to 2.7 wk of exposure. Also elevated were alkaline phosphatase and glutathione peroxidase. Lung tissue levels of glutathione reductase and glucose-6-phosphate dehydrogenase were also increased, indicating a possible protective response to the oxidant gas. After 15 wk of exposure, all biochemical indicators of injury has resolved. These data suggest that intermittent exposure to relatively low levels of NO2 with spike concentrations produces biochemical changes that resolve with continued exposure but produce histopathological changes that may persist with continued exposure.