Assessment of the emetogenic potential of intrathecal chemotherapy and response to prophylactic treatment with ondansetron.

The purpose of this study was to document the emetogenic potential of intrathecal chemotherapy (IC) in children and to evaluate the efficacy of ondansetron in reducing nausea and vomiting with this chemotherapy treatment. Patients less than 18 years of age with acute lymphoblastic leukemia were eligible to participate in a survey project measuring the emetogenic potential of various chemotherapy treatments. Patients surveyed for 1 or more IC treatments were included in this report. The IC consisted of methotrexate, hydrocortisone and cytarabine, dosed according to patient age. A nausea/vomiting survey instrument was completed by each patient and/or parent following IC treatment. The instrument rated nausea, vomiting and daily activity interference (DAI) on a 4-point scale of 0 = none, 1 = mild, 2 = moderate and 3 = severe, and collected data on the number of vomiting and/or retching episodes in addition to the child's appetite following the chemotherapy treatment. When ondansetron was employed, it was administered in an i.v. infusion at a dose of 0.15 mg/kg before and after chemotherapy or as an oral dose of 4 mg or 8 mg before chemotherapy. Courses of IC without antiemetics were analyzed to determine the emetogenic potential of IC. For patients receiving IC both with and without ondansetron, courses were compared with each patient used as their own control to determine the influence of ondansetron upon survey responses. Statistical analysis consisted of nonparametric Friedman 2-way ANOVA for ordinal variables and a paired t-test for continuous variables. The binomial test was employed to analyze for differences between ondansetron and no antiemetic in the number of patients with complete control of both nausea and vomiting or vomiting alone. A total of 63 children with a mean age of 7.6 +/- 4.2 years were each studied on one or more occasions. Thirty-seven children were surveyed for 87 IC treatments without antiemetics (group I), and 17 children from this group were surveyed for 48 IC courses with i.v. ondansetron (group IA). An additional 18 children were subsequently surveyed for 39 IC courses with i.v. ondansetron (group II). Fifteen patients (7 of whom were members of group I) were surveyed following 33 IC courses with oral ondansetron (group III). The survey scores for group I patients were: nausea severity 1.3 +/- 1.1, vomiting severity 1.2 +/- 1.1, DAI 1.2 +/- 1.0 and mean number of emetic episodes 4.7 +/- 8.4. The mean appetite score was 1.5 +/- 1.1. For patients in group IA, nausea severity (0.8 +/- 0.9), vomiting severity (0.5 +/- 0.8), DAI (0.7 +/- 0.8), and the number of emetic episodes (1.4 +/- 2.8) were all significantly lower than with prior IC treatments without ondansetron. For complete protection, children receiving i.v. ondansetron had greater complete protection rates from both nausea and vomiting or vomiting alone than did patients receiving no antiemetic. Survey responses were also lower for patients receiving oral ondansetron, but insufficient control data did not allow for statistical analysis. IC results in mild to moderate nausea and vomiting in children. The emetogenic potential of IC is significantly reduced by i.v. ondansetron.

Differences among raters evaluating the success of EMLA cream in alleviating procedure-related pain in children with cancer.

We evaluated the analgesic efficacy of EMLA cream after repeated bone marrow aspirations or lumbar punctures (LPs) in children with cancer, and compared the ratings among patients, their parents, physicians, and nurses. Data from LPs were analyzed at the last procedure without EMLA (T1) and the first and last procedures with EMLA (T2 and T3). Friedman's nonparametric analysis of variance was used for statistical analysis. A total of 272 procedures in 29 children were analyzed. For 179 procedures without EMLA, physicians rated pain lower than other raters, and for the 93 with EMLA physicians rated pain less than the children. Children rated pain at T2 lower than at T1 or T3. Physicians rated pain at T2 less than at T3. Both children and physicians rated pain at T3 as not different from that at T1. No differences were noted at these time points for other raters in LP distress ratings, or in bone marrow aspiration pain or distress ratings. Thus EMLA was associated with decreased pain ratings for LPs, but this effect was not sustainable with repeated procedures. The cream alone should not be relied on to control pain of bone marrow aspiration or repeated LPs in children. Physicians underestimated pain, which may have implications for undertreatment in this patient population.

Identifying hospitalized older patients at varying risk for physical performance decline: a new approach.

OBJECTIVE: A classification tree analysis identifies patient groups at varying risk for decline in physical performance 1 year after hospitalization. DESIGN: Prospective cohort study. SETTING: Tertiary care VAMC. PARTICIPANTS: A total of 507 acutely ill hospitalized male veterans aged 65 years and older. MEASUREMENTS: Eighteen admission characteristics were considered as potential predictors: demographic data, medical diagnoses, functional status (e.g., ADL and IADL), geriatric conditions (e.g., incontinence, vision impairment, weight change), mental status, depression, and physical functioning (measured by self-report (MOS-PFR) and the Physical Performance and Mobility Examination (PPME)). Outcome measure was change in PPME status at 12-months post-admission. RESULTS: Patients with the greatest risk for decline had both high baseline physical performance (PPME > or = 9) and at least moderate self-report limitations on physical functioning (MOS-PFR < or = 36, mean = 30.8). Patients with the lowest risk of decline had impaired baseline physical performance (PPME < or = 8) but fewer self-report limitations on physical functioning (MOS-PFR > or = 31, mean = 37.4) and two or less geriatric conditions. CONCLUSIONS: The predictive role of self-report functioning suggests that perception of the impact of health on one's own physical functioning is associated with future performance. The number of geriatric conditions is also an important predictor of physical performance change. By identifying patient risk groups based on geriatric conditions, physical performance, and self-report physical functioning, future targeting strategies may improve physical performance outcomes for hospitalized older adults.

Low level determination of a novel 4-azasteroid and its carboxylic acid metabolite in human plasma and semen using high-performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

Compound I (4.7beta-dimethyl-4-azacholestan-3-one, MK-0386) is a potent 5alpha-reductase type 1 (5alphaR1) inhibitor. Sensitive (0.2 ng/ml), specific and separate assays have been developed and validated for the analysis of I and its carboxylic acid metabolite (II) in human semen and plasma based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. After liquid-liquid extraction of the analytes from biological matrix, the extracts were chromatographed on a short (50 mm) analytical column during analysis of I, and on a longer (150 mm) column with a weaker mobile phase during the analysis of II. This additional chromatographic separation was required to separate II from a secondary metabolite present in post-dose plasma samples interfering with the quantification of II. The MS-MS detection was performed on a Sciex API III Plus tandem mass spectrometer using the heated nebulizer probe. Monitoring the parent-->product ion combinations of m/z 416-->114 and 404-->114, in the multiple reaction monitoring (MRM) mode, after chromatographic separation, allowed quantification of both analytes. The standard curve in plasma was linear in the concentration range of 0.2 to 200 ng/ml for both I and II with correlation coefficients greater than 0.99 and coefficients of variation of less than 15% for replicate (n=5) analysis at all concentrations within the standard curve range. For the semen assay the linear range for determination of I was from 0.2 to 50 ng/ml. These assays were applied to support a number of clinical studies with I and their validity and long-term performance was confirmed during analyses of clinical samples from these studies. The need for careful assessment of the specificity of MS-MS assays in post-dose biological fluid samples in the presence of metabolites was emphasized.

Low level determination of dorzolamide and its de-ethylated metabolite in human plasma by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific method for the determination of dorzolamide (I) and its de-ethylated metabolite (II) in human plasma has been developed utilizing high pressure liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection. The analytes and internal standard (III) were isolated from the deproteinized pH 8.0 buffered plasma, using a liquid-liquid extraction with a mixture of ethyl acetate, toluene, and isopropanol. The analytes were then back extracted into 0.085% phosphoric acid (200 microliters) and after washing the acidic extract with hexane, the organic layer was discarded and a fraction (50 microliters) of the acid extract was injected into the LC/MS/MS system. The MS/MS detection was performed on a PE Sciex API III tandem mass spectrometer using a heated nebulizer interface. Multiple reaction monitoring of the parent-->product ion combinations of m/z 325-->199, 297-->199, and 397-->306 were used to quantify I, II, and III, respectively. The assay was validated in the concentration ranges of 0.5-100 and 2.5-100 ng ml-1 of plasma for I and II, respectively. The precision of the assays, expressed as coefficients of variation (C.V.%), were less than 10% over the entire concentration range, with adequate assay specificity and accuracy. The LC/MS/MS method provided a 10-fold increase in the sensitivity of I over the previously reported HPLC/UV method [1].

Economic impact with home delivery of chemotherapy to pediatric oncology patients.

OBJECTIVE: To examine the economic impact of a home chemotherapy program (HCP) for pediatric oncology patients. RATIONALE: Factors that led to initiation of an HCP included availability of specially trained nurses and programmable ambulatory infusion devices at local home care agencies, routine central venous catheter placement, inpatient bed space shortages, and the availability of ondansetron. SETTING: Chemotherapy delivery in the home setting from June 1991 through June 1994. DESIGN: Charge data and nausea and vomiting severity data were collected for patients treated through the HCP. METHODS: Economic impact was calculated by incorporating and summing all charge categories associated with hospital admission for chemotherapy (HAC) versus delivery by the HCP. All data were adjusted for 1993 dollars, and reflect changes for the average patient size (1 m2). Charge data for each chemotherapy protocol delivered in the home were analyzed by calculating the differences between HAC and HCP charges using the following formula: charge difference (HAC - HCP) per protocol times the number of courses. Total economic impact was calculated by summing the differences in charges for each protocol. RESULTS: A total of 262 chemotherapy courses were given to 44 patients (mean age 9.5 +/- 5.1 y) through the HCP, which represented 1012 patient care days and 24 different chemotherapy protocols. Monetary savings from the HCP ranged from $5180 per course of ifosfamide plus etoposide to $367 per course for high-dose methotrexate. Total monetary savings from the HCP during the 3-year period was $640,793. Successful control of nausea and vomiting with a combination of ondansetron plus methylprednisolone was achieved in approximately 80% of the patients receiving highly emetogenic chemotherapy protocols. CONCLUSIONS: HCP for pediatric oncology patients results in substantial monetary savings to payors. Effective control of nausea and vomiting can be accomplished at home in the majority of patients with an ondansetron-based antiemetic regimen.

Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men.

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.

Determination of pirenzepine in human plasma using liquid chromatography with tandem mass spectrometric detection.

A sensitive (LOQ = 1 ng ml-1) and specific method based on liquid chromatography with tandem mass spectrometric (MS/MS) detection has been developed and validated for the analysis of pirenzepine (I) in plasma. Sample preparation involved liquid-liquid extraction of drug and internal standard (IS) from basified plasma. The organic extract was evaporated to dryness, and the residue was reconstituted in the mobile phase and then injected into the liquid chromatography/MS/MS system. Drug, IS, and endogenous impurities were separated using reverse-phase chromatography. A Sciex API III tandem mass spectrometer equipped with a heated nebulizer was operated in the positive ion mode. Multiple reaction monitoring using the parent-->daughter ion combinations of m/z 352-->113 and 629-->422 was used to quantify I and IS, respectively. The method was validated in the concentration range of 1-100 ng ml-1 plasma with adequate assay precision and accuracy, and was utilized to support human safety and tolerability study with I.

Assessment of chemotherapy-induced emesis and evaluation of a reduced-dose intravenous ondansetron regimen in pediatric outpatients with leukemia.

OBJECTIVE: To measure the severity of nausea and vomiting in pediatric patients receiving intravenous or intrathecal chemotherapy for acute lymphoblastic leukemia and to evaluate the effectiveness of 2 intravenous doses of ondansetron for this condition. DESIGN: Patients were surveyed during repeated treatments of maintenance chemotherapy, given with or without ondansetron, using a repeated measures pretest/posttest design. SETTING: Outpatient pediatric oncology clinic. PATIENT POPULATION: Sixteen pediatric patients (aged 2-15 years, mean 6.2) with acute lymphoblastic leukemia. METHODS: Surveys to assess nausea and vomiting and the extent of interference with daily activities were administered following emetogenic chemotherapy with or without ondansetron. RESULTS: A total of 255 surveys following emetogenic chemotherapy with daunorubicin, cyclophosphamide, carmustine, and etoposide and cytarabine combined, as well as intrathecal therapy with methotrexate, hydrocortisone, and cytarabine, were analyzed. Analysis was performed on surveys of 149 courses without antiemetic therapy and 106 courses after 2 doses of ondansetron 0.15 mg/kg iv. The most emetogenic chemotherapy treatment was the etoposide/cytarabine combination (p < 0.05). Ondansetron completely protected patients (defined as no nausea or no vomiting) during most (> 50%) of the chemotherapy treatments, except for those in which cyclophosphamide was used. Ondansetron provided greater control of nausea and vomiting, a higher percentage of complete protection, and decreased the daily activity interference rating for carmustine and etoposide/cytarabine compared with courses of chemotherapy without antiemetics (p < 0.05). Two intravenous doses of ondansetron also provided durable antiemetic efficacy over time for the most emetogenic chemotherapy treatment (etoposide/cytarabine). CONCLUSIONS: Etoposide/cytarabine proved to be the most emetogenic of the chemotherapy treatments studied. A reduced-dose regimen of intravenous ondansetron was shown to be an effective antiemetic for the outpatient treatments with etoposide/cytarabine and carmustine, but not with cyclophosphamide.

Continuous midazolam infusion for the management of morphine-induced myoclonus.

OBJECTIVE: To describe a patient with morphine-induced myoclonus treated with a continuous infusion of midazolam and continued morphine dose escalation. DESIGN: Single case report. SETTING: Delivery, monitoring, and titration of morphine and midazolam in the patient's home by a homecare agency. RESULTS: The use of high dosages of morphine (i.e., 500 mg/h) produced myoclonic spasms in this patient, which in turn resulted in increasing pain. To allow for continuation of effective analgesia and to control the myoclonic spasms, an infusion of midazolam was initiated and titrated. The midazolam infusion allowed for continuation of the morphine dosage and also permitted further dosage escalation. As morphine dosages were further escalated, it was also necessary to increase the midazolam infusion to control additional myoclonic spasms. CONCLUSIONS: Use of a concomitant midazolam infusion with high doses of morphine appears to be safe and is an effective means of controlling morphine-induced myoclonus. If further dosage increase of morphine are necessary in this setting, increases in the midazolam infusion also may be required.

Picogram determination of finasteride in human plasma and semen by high-performance liquid chromatography with atmospheric-pressure chemical-ionization tandem mass spectrometry.

A method based on high-performance liquid chromatography (HPLC) with atmospheric-pressure positive-ion chemical ionization (APCI)-tandem mass spectrometric (MS-MS) detection for the determination of finasteride (MK-906, I) in human plasma and semen has been developed. The drug and internal standard (II) were extracted from biological matrices using a single solid-phase cyano cartridge. The eluent from the cartridge was injected directly onto the a 33 x 4.6 mm I.D. C18, 3-microns column coupled with a base deactivated C18 20 x 4.6 mm I.D., 5-microns guard column. The column eluate was passed into the corona discharge APCI source by means of a heated nebulizer interface. The analyte and its internal standard were detected using multiple reaction monitoring (MRM) mode for enhanced selectivity and sensitivity. The chromatographic run time was 3 min, and the method had sufficient sensitivity, precision, accuracy and selectivity for the analysis of clinical samples containing finasteride at concentration of 0.2 ng/ml. The assay methodology confirms the versatility of APCI-MS-MS detection, combined with HPLC, for the quantitation of selected drugs in the sub-ng/ml range in biological fluids.

Resection of posterior ventricular aneurysm, replacement of mitral valve, and coronary bypass.

A 58-year-old man had sudden and progressive heart failure after a severe myocardial infarction. Aggressive medical treatment consisting of diuretics, vasopressors, and digitalis failed to improve his condition significantly. Cardiac catheterization disclosed a critical stenosis in the left anterior descending branch of the left coronary artery, a large posterior left ventricul aneurysm, and severe mitral insufficiency. Intermittent third degree heart block developed after admission. Surgical correction resulted in a dramatic recovery, and three years after operation he is fully recovered and asymptomatic.

Pulmonary dirofilariasis in man. A case report and review of the literature.

Pulmonary dirofilariasis in man is becoming a well-recongnized entity. Its pathogenesis and histopathologenical picture have been well characterized but the preoperative diagnosis still remains a challenge. The roentgenographic picture, usually described as a "coin lesion," is nonspecific and easily mistaken for other inflammatory and neoplastic nodules. Forty-seven clinical instances of pulmonary dirofilariais have been reported in the literature, with most of them in the last two decades. Considering the entire clinical picture, a strong suspicion can be based on serological studies, thus improving the possibilities of a correct preoperative diagnosis.

Septicemia secondary to impacted infected pacemaker wire. Successful treatment by removal with cardiopulmonary bypass.

Infection of an intravenous pacemaker electrode developed in a 78-year-old man after multiple replacements and revisions of the pulse generator and the pacemaker lead. Spread of the infective process to the endocardium was followed by septicemia with Serratia marcescens and Staphyloccus epidermids. Failure of medical treatment and external traction on the pacemaker electrode led to thoracotomy and removal of the pacemaker electrode wires with the use of extracorporeal circulation. The tip of one of the pacemaker electrodes was found imbedded in the wall of the right ventricle and attached to the base of the tricuspid valve. Cultures from the endocardium removed with the electrode rendered the same organisms as cultured preoperatively. There has been no recurrence after 2 years following the removal of the infected electrodes. Although the problem described herein is not frequently found, radical treatment becomes necessary whenever infection and septicemia develop.

False aneurysms of the femoral artery: a challenge in management.

Forty patients with aneurysms of the femoral arteries were evaluated. Thirty had 34 false aneurysms and 23 were secondary to disruption of the suture line of a graft-to-artery anastomosis. All the false aneurysms were found in association with a synthetic material used as a bypass or arterial substitute. No direct relationship was found between the suture material and the incidence of anastomotic aneurysms in this series. Infection associated with the development of a false aneurysm was followed by a high incidence of amputation. Various techniques of repair have been used to restore the flow and preserve the viability of the limb. Recommendations are made to decrease the incidence of this complication.

Aneurysms of the popliteal artery.

Thirty-one aneurysms of the popliteal artery in 23 patients have been studied. Twenty-nine aneurysms were secondary to atherosclerosis, while one was secondary to trauma and one was associated with a coagulopathy. The lesions were bilateral in eight patients and were associated with extra-popliteal aneurysms in ten patients; the abdominal aorta was the most frequent extrapopliteal site. All except two of the 23 patients were over 50 years of age, and many exhibited atherosclerosis and related symptoms in other vessels. Ischemic rest pain was the most common presenting symptom in patients with popliteal aneurysm, but three of the patients were asymptomatic. The most common physical sign was a palpable popliteal mass in 25 patients, with impending gangrene distal to the aneurysm in four. Thrombosis occurred in 11 of the aneurysms, embolism in three, and rupture in two. Amputation was eventually necessary in five patients with thrombosis and in one patient with embolism. Of 16 patients presenting with a complication of popliteal aneurysm, six patients eventually required amputation. All popliteal aneurysms should be treated surgically and arterial continuity restored unless contraindicated by the over-all condition of the patient. The saphenous vein represents the optimal replacement material available at this time, but fabric grafts can be used successfully.