Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer.

PURPOSE: To evaluate the quality of life (QOL) of breast cancer patients who survived 2 to 5 years following initiation of adjuvant cytotoxic and/or hormonal therapy and to characterize relationships between QOL and patient physical symptoms, sexual function, and preferences regarding adjuvant treatment. PATIENTS AND METHODS: Eighty-six patients who had completed systemic adjuvant therapy for early-stage breast cancer between 1988 and 1991 were surveyed by written questionnaire and telephone interview. Sociodemographic information was obtained for each patient, and patients were asked to complete the Functional Living Index-Cancer (FLIC), the Symptom Distress Scale (SDS), the Medical Outcomes Study (MOS) Short Form 36 (SF-36), a series of questions regarding sexual function, and a survey about preferences for adjuvant therapy in relation to possible benefit. RESULTS: The mean FLIC score among all patients was 138.3 (+/- 12.2), which suggests a high level of QOL. The reported frequency of moderate to severe symptoms was generally low (ie, < 15%), with fatigue (31.4%), insomnia (23.3%), and local numbness at the site of surgery (22.1%) occurring with greatest frequency. Patients reported a wide range of sexual difficulties. Preference assessment showed that more than 65% of patients were willing to undergo 6 months of chemotherapy for a 5% increase in likelihood of cancer cure. CONCLUSION: Self-rated QOL in breast cancer patients 2 to 5 years following adjuvant therapy was generally favorable. Less than one third of patients reported moderate to severe symptoms. Selected aspects of sexual function appeared to be compromised. The majority of patients indicated a willingness to accept 6 months of chemotherapy for small to modest potential benefit.

Appropriate use of heparin. Empiric vs nomogram-based dosing.

BACKGROUND: A study involving two groups of patients with cardiovascular disease was conducted to compare empiric (clinician-directed) heparin therapy with therapy based on a nomogram-determined dosage. The comparison was based on (1) the average weight-referenced infusion rate yielding a therapeutic activated partial thromboplastin time (APTT) and (2) the time required to reach a therapeutic APTT (55 to 95 seconds) after empiric or nomogram-based heparin therapy was initiated. METHODS: Data were collected for patients admitted to the cardiology service at a university health science center in two phases: phase 1 (April 1 through June 30, 1992), involving 95 patients receiving heparin therapy, with 88 patients included in the data analysis, and phase 2 (March 11 through June 11, 1993), involving 156 patients receiving heparin therapy, with 45 patients receiving nomogram-guided therapy included in the data analysis. RESULTS: In phase 1, 66 patients (75.0%) achieved a therapeutic APTT some time during their heparin therapy, with an average time to therapeutic APTT of 20.7 + 19.1 hours. Regression analysis demonstrated a statistically significant relationship between the heparin infusion rate at the time of the patient's first therapeutic APTT and the patient's total body weight (r2 = .3043). An initial infusion rate based on total body weight (13 U/kg per hour) was therefore used as the basis for the nomogram in phase 2. In phase 2, 41 patients (91.1%) achieved a therapeutic APTT at some time during their heparin therapy, with an average time to therapeutic APTT of 13.1 + 11.9 hours, statistically significantly shorter than that in phase 1. A greater proportion of patients in phase 2 compared with patients in phase 1 reached the therapeutic range within 12 hours (62.2% vs 34.1%) and within 24 hours (77.8% vs 54.5%). CONCLUSIONS: Use of a weight-based nomogram to determine the initial and maintenance heparin infusion rates was associated with a higher percentage of patients admitted to the cardiology service reaching the targeted therapeutic APTT range at a time earlier in the course of therapy compared with empiric dosing.

Pharmacokinetics and pharmacodynamics of recombinant factor VIIa.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa). METHODS: Single-dose pharmacokinetics of three dose levels (17.5, 35, and 70 micrograms/kg) of rFVIIa were investigated in 15 patients with hemophilia with severe factor VIII or factor IX deficiency (with or without inhibitors) while they were in the nonbleeding state and during bleeding episodes. Factor VII clotting activity (FVII:C) was determined 5 minutes before and at 10, 20, and 50 minutes and 2, 4, 6, 8, 12, and 24 hours after rFVIIa administration. Model-independent pharmacokinetic analysis of FVII:C plasma concentration-time data included determination of plasma clearance, mean residence time, and volume of distribution. rFVIIa recovery was determined from the plasma FVII:C observed 10 minutes after administration. Pharmacodynamic assessments of prothrombin time, activated partial thromboplastic time, and Factor X values obtained concurrently with FVII:C samples were performed. RESULTS: Sufficient data to allow pharmacokinetic parameter calculation were available for 25 nonbleeding episodes in 11 patients (17.5 micrograms/kg, n = 8; 35 micrograms/kg, n = 9; 70 micrograms/kg, n = 8) and for five bleeding episodes in three patients (17.5 micrograms/kg, n = 2; 35 micrograms/kg, n = 2; 35 micrograms/kg, n = 1). Recovery was calculated during 27 nonbleeding and 17 bleeding episodes. rFVIIa distribution volume is two to three times that of plasma. Median clearance was low--31.0 ml/hr.kg in nonbleeding episodes and 32.5 mg/hr.kg in bleeding episodes. In nonbleeding episodes, median mean residence time was 3.44 hours and median half-life was 2.89 hours. In bleeding episodes, the elimination rate appears to be higher, with a median mean residence time of 2.97 hours and a median half-life of 2.30 hours. Recovery was 45.6% during nonbleeding conditions and 43.5% during bleeding episodes (p = 0.0006); it was statistically lower with the highest dose level than with the 17.5 and 35 micrograms/kg doses (p = 0.007). A significant statistical relationship was observed between values of the prothrombin time and activated partial thromboplastin time, and values of FVII:C with use of maximum effect model. CONCLUSIONS: The pharmacokinetics of rFVIIa are linear in the dose range evaluated. The results suggest potential value of prothrombin time determination in the monitoring of rFVIIa therapy.

A case of severe acute desipramine overdose.

The authors describe a patient who ingested a toxic quantity of desipramine. His initial desipramine plasma concentration of 1627 ng/ml was associated with generalized seizures, bradycardia, and a respiratory arrest.

A multicenter evaluation of variables affecting the predictability of creatinine clearance.

Data from 722 urine collections (627 patients) from 14 medical facilities were used to compare measured creatinine clearance values with clearance estimates calculated using three "urine-free' mathematical formulas. The influence of two patient weight variables (actual weight, lean body weight) and the level of renal function on clearance prediction was assessed. In addition, site parameters (region, facility), time parameters (month, day, day of the week), and patient parameters (age, sex, height, weight, diagnoses) were evaluated for their statistical influence on the relationship between measured clearance and estimates calculated with one of the methods. Strong, statistically significant correlations were observed between clearance values estimated with each prediction method and measured clearances. Although statistical differences were noticed between mean values predicted with each method, these differences were clinically insignificant. Use of lean body weight for calculation of creatinine excretion produced clearance estimates that were significantly lower than those obtained with actual weight and substantially closer to measured clearance values. Among patient variables, age and two specific diagnoses (congestive heart failure and pregnancy), were statistically associated with variability in the relationship between measured and predicted clearance. Interregional and interfacility differences in the measured-predicted clearance relationship, variability associated with the day of the week of collection, and tendency of the urine-free formulas to over-predict clearance support potential inaccuracy of measured clearance determination. The results suggest that inaccuracies in clearance determination, rather than inadequacies of urine-free prediction methods, account for the majority of the observed variability in the relationship.

Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan.

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.

Assessment and predictability of renal function in spinal cord injury patients.

Creatinine clearance values were determined by duplicate urine collections in 18 patients with spinal cord injury, cerebrovascular accident, or multiple sclerosis. Measured creatinine clearance values were compared with estimates predicted by a urine-free mathematical method for estimation of renal function. Measured creatinine clearance values were considerably lower than would be ordinarily expected on the basis of patient body size, age, sex, and serum creatinine. In addition, creatinine clearances calculated using the urine-free method were considerably higher than measured values, suggesting that techniques for the prediction of creatinine clearance may not be routinely applicable in patients with these conditions.

Safety and initial clinical efficacy of three dose levels of recombinant activated factor VII (rFVIIa): results of a phase I study.

The safety and efficacy of recombinant DNA-produced factor VIIa (rFVIIa) was investigated in 15 haemophilic patients in non-bleeding states and during bleeding episodes (mild to moderate joint bleed). Patients with severe haemophilia A without inhibitors (n = 4), haemophilia A with inhibitors (n = 10), and haemophilia B with inhibitor (n = 1) received one or more doses of rFVIIa during 32 non-bleeding study episodes and 23 bleeding episodes. The study was an open, uncontrolled, dose-escalation (17.5 micrograms/kg, 35 micrograms/kg, 70 micrograms/kg) trial. Physical evaluation, laboratory assessment, and immunology testing were conducted at baseline, monthly for 3 months and every 3 months thereafter. The immediate safety of rFVIIa was assessed by monitoring of D-dimer, fibrinogen, platelet count, antithrombin III, thrombin-antithrombin complex, and alpha 2-antiplasmin 5 min before and at multiple times throughout the following 24 h. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) values were also obtained. Pain, swelling, joint circumference, and range of motion were recorded before administration of the initial dose of rFVIIa in bleeding patients and at 6, 12, and 24 h. Haemostatic response to rFVIIa was observed in patients with severe VIII and IX deficiency with and without inhibitors. Therapy with rFVIIa was judged effective in 19 of the 22 evaluable bleeding episodes at one or more time points. The 35 micrograms/kg and 70 micrograms/kg doses were associated with higher response rates at 6 and 12 h compared to the 17.5 micrograms/kg dose level. A second dose of rFVIIa was administered in 20 of the 22 bleeding episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictability of warfarin dose requirements: theoretical considerations.

The theoretical basis of the predictability of warfarin maintenance dose requirements was evaluated using computer-generated hypothetical patient responses to a 10-mg/day "loading" dose regimen. Correlations between these responses and projected maintenance dose requirements were evaluated statistically, and a significant relationship was identified.

Task analysis of Air Force pharmacy practice.

The frequency with which United States Air Force pharmacists perform specific professional tasks and the pharmacists' views as to the importance of those tasks were studied. A questionnaire was prepared that asked recipients to rate each of 36 tasks selected as representing the spectrum of practice activities. There were four categories of tasks: managerial tasks, dispensing tasks, drug information tasks, and patient care tasks. Recipients rated the tasks with respect to frequency of performance and importance on separate 6-point scales. The questionnaire was mailed in May 1991 to the 225 pharmacists then serving in the Air Force worldwide. Of the 225 questionnaires, 150 usable questionnaires were returned (response rate, 67%). All the tasks in the survey were performed by at least one Air Force pharmacy officer, although the frequency of task performance varied. In particular, the frequency of many patient care tasks was low. All the tasks were perceived to have some importance, but drug information tasks were rated as being significantly more important than tasks in the other categories; patient care tasks were rated lowest in importance. The results varied with the respondents' demographic characteristics. Pharmacy officers with more years of service, more senior positions, higher rank, or an advanced degree in a field other than pharmacy tended to give responses that diverged from those of the population. A 1991 survey showed an awareness among Air Force pharmacists of the need to orient practice around patient care; however, they were not spending substantial time on patient care and tended to view it as less important than more traditional pharmacy tasks.

Clinical and economic impact of replacing divalproex sodium with valproic acid.

The impact of replacing divalproex sodium with valproic acid on patient outcomes and direct drug costs was studied. Before-and-after medical chart review was performed in a state-supported facility for mentally retarded adults in which a pharmacy and therapeutics (P&T) committee recommended replacement of divalproex with valproic acid. Patients were studied if they had received divalproex for at least three months and if their antiepileptic drug was changed from divalproex to valproic acid between October 1993 and June 1994. Clinical, economic, and prescribing-pattern data were recorded for the periods extending 12 months before and 18 months after the change in therapy. Data for 46 patients were analyzed. Replacing divalproex with valproic acid was effective in 41 (89%) of the patients. There was no significant difference between the divalproex and valproic acid periods in seizure rate or frequency of new drug therapy for GI disorders. Between fiscal year 1992-93 and fiscal year 1995-96 there was a 56% decrease in total direct divalproex plus valproic acid costs, including drug products and packaging materials and labor. The rate of valproic acid prescriptions increased steadily after the replacement was recommended, and then plateaued. Replacing divalproex sodium with valproic acid in a group of institutionalized mentally retarded adults with epilepsy was clinically effective and economically advantageous.

Task analysis of home care pharmacy.

The demographics of home care pharmacists and the frequency and perceived importance of home care pharmacy tasks were studied. Two questionnaires were mailed in August 1994 to each of 1420 sites that provide home care pharmacy services. Home care pharmacists were asked to provide information on themselves and their companies and to rate 47 home care pharmacy tasks (administrative, clinical, distributive, and miscellaneous) on how often they are performed as part of the job and how essential they are for successful job performance. Of the 2840 surveys mailed to the 1420 sites, questionnaires for 87 sites were not deliverable, leaving an adjusted gross sample of 1333 sites. A total of 393 usable questionnaires were received from 326 sites (net site response rate 24.5%). Respondents tended to be male, have a B.S. degree only, and have more than six years' home care experience. The most commonly identified type of employer was an independent company. Some 34% of respondents said their company had only 1 site; another 33% stated more than 50 sites. Forty-three percent of locations had 2 pharmacist full-time equivalents. Distributive tasks had the highest frequency scores; clinical tasks were performed second most frequently. Distributive and clinical tasks also received high importance scores. The data suggests that, despite other demands on their time, home care pharmacists give considerable attention to tasks consistent with pharmaceutical care. A survey of home care pharmacists provided baseline information on demographics and the frequency and perceived importance of specific tasks.

A pocket calculator program for prediction of warfarin maintenance dose.

A 398 step program, written for the TI59 programmable calculator, has been presented. The procedure allows the user to estimate a patient's maintenance warfarin dose requirements after administration of three 10 mg doses or after any series of doses which produces a PT value greater than or equal to 20. The equation used, although based on published literature data, require further evaluation to adequately assess their clinical accuracy. They may, however, provide a starting point for maintenance dose treatment after initial therapy.

Observations on the management of a clinical department.

Successful management of a contemporary pharmacy department requires a unique blend of skills. Perhaps one way to concisely describe the principal role of a manager of a clinical department is as one of advocacy. The manager must be an advocate for the patient, as a member of a clinical profession. The manager must be an advocate for the profession, in the belief that the profession has a unique contribution to make to patient care. The manager must be an advocate for the department in a hospital or institutional organization that is administratively compartmentalized and in which limited resources are available. Finally, the manager must be an advocate for the institution, having accepted the role of employee. Advocacy requires understanding the divergent points of view held by managers and professionals; the acceptably selfish interests of sick patients who are unconcerned with issues of autonomy, cost, and efficiency; and the ultimate goal of health care institutions. This is not an impossible challenge to achieve, but it calls forth the best in people who are to be successful.

Malabsorption of flucytosine in a pediatric patient with Shwachman syndrome.

The malabsorption of drugs from the gastrointestinal tract in patients with pancreatic insufficiency is not well documented in the literature. We describe a case of flucytosine malabsorption in a pediatric patient with Shwachman syndrome, a rare disease in the pediatric age group characterized by pancreatic insufficiency. A significant increase in serum concentrations of flucytosine was noted when the drug was administered in a lipophilic vehicle, possibly due to enhanced absorption.

Do we have to document pharmacotherapeutic interventions?

We have suggested that some pharmacotherapists may resist documentation because they view it as administrative intrusion rather than an essential component of continuity of care. In the final analysis, it is also a matter of the pharmacotherapist's belief. Pharmacists must understand what it is that they contribute, and must believe that it is both valuable and unique. It is not just an information management function--they are making patient-specific decisions and must be willing to be held accountable for their outcome. The pharmacy manager must also believe that such a responsible decision-making role represents that preferred future for the profession. Unfortunately, because many pharmacy managers have never truly functioned in such a role, developing such a belief system is difficult at best. The hospital administrator must also be made to believe that the contribution of the pharmacist to patient care not only extends beyond materials management but represents an entirely separate professional function. This will not occur simply through documentation of interventions. Yes, we believe that it is necessary to document pharmacotherapeutic interventions, however, not for the reasons that it is most frequently demanded.

Effect of retrograde aminophylline administration on calcium and phosphate solubility in neonatal total parenteral nutrient solutions.

The effect of retrograde administration of aminophylline injection on calcium and phosphate solubility in neonatal total parenteral nutrient (TPN) solutions was studied. Neonatal TPN solutions containing two amino acids solutions in three concentrations (Travasol 1% and 2% and TrophAmine 2%) were formulated. Calcium and phosphate salts were added to achieve calcium concentrations of 10, 15, 20, 25, 30, or 40 meq/L and phosphorus concentrations of 10, 15, 20, 25, 30, or 40 mmol/L. Samples were inspected visually after 18-24 hours; solutions free of precipitation were then infused through two parallel syringe-pump systems designed to simulate clinical conditions for TPN solution administration to a 1-kg neonate. To one system, a 7.5-mg aminophylline dose was added as a manual retrograde injection; sterile water for injection was added as a manual retrograde injection to the other system. The solutions were inspected throughout a one-hour infusion period for precipitate formation in the i.v. apparatus, and the pH of the effluents was determined. Concurrent aminophylline administration resulted in visible precipitate in all but a few of the solutions tested. The solution containing Travasol 2%, calcium 10 meq/L, and phosphorus 10 mmol/L remained clear, as did the solutions containing TrophAmine 2% and the following concentrations of calcium and phosphorus: calcium 10 meq/L and phosphorus 10, 15, or 20 mmol/L; calcium 15 meq/L and phosphorus 10 or 15 mmol/L; and calcium 20 meq/L and phosphorus 10 or 15 mmol/L. An average increase in pH of 0.63 unit was noted in all solutions.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacy staff training and development: upside-down thinking in a changing profession.

We suggest that the most fundamental change in staff development that must occur is recognition of the need for a professional belief system as the basis for any pharmaceutical care activity. Values derived from fundamental moral ideals and professional beliefs foster the development of attitudes and behaviors. It would be wrong to suggest or imply that such a change need only occur in postbaccalaureate training. The development of personal and professional value systems in existing primary professional training programs is inadequate--we do not yet do enough to develop people before they enter practice. Nevertheless, to say that this failure of the professional education system precludes us from taking action within professional departments is unwise. The primary skills that must be developed during the next decade involve the ability of the practitioner to competently make informed, patient-specific decisions necessary for effective pharmaceutical care. Such decisions are made not only on the basis of a practitioner's knowledge but on the basis of his or her beliefs and values as well. The practitioner also must be willing to assume responsibility for the consequences of those decisions. The pharmacist who professes to deliver pharmaceutical care can no longer be shielded by assigning to the physician the ultimate responsibility for the patient's drug-therapy outcomes. Facilitating the development of a value system and attitude that enhance the pharmacist's ability to make such decisions must be a principal focus of staff training and development in the coming years.(ABSTRACT TRUNCATED AT 250 WORDS)

Warfarin-induced intramural hematoma of the small intestine.

A case of warfarin-induced intramural hematoma and hemorrhagic infarction of the small intestine is described, and the literature on this adverse effect is reviewed. A 32-year-old white woman who had been receiving warfarin and carbamazepine came to a clinic complaining of lower back and stomach pain. She had a history of iliofemoral deep venous thromboses and seizures. A pelvic sonogram showed a large quantity of fluid present. Her prothrombin time (PT) was 29.2 sec. Her hemoglobin concentration and hematocrit were within the normal ranges. The patient was admitted to the hospital when her back pain increased and she vomited. The warfarin was discontinued. On day 5 the patient was still having abdominal pain and nausea. Her hemoglobin concentration and hematocrit had fallen to 6.6 g/dL and 20%, although her PT had decreased to 12.5 sec. On the same day, the patient underwent an exploratory laparotomy, and an indurated and ischemic area of jejunum was found and resected. The pathology report indicated the presence of hemorrhage and infarction consistent with an anticoagulant-related disorder. About 100 cases of intramural hematoma of the small intestine induced by anticoagulant therapy have been reported. Most patients are white males about 60 years of age. The sites most frequently involved are the duodenum and proximal jejunum. Symptoms include constipation, nausea, vomiting, and abdominal pain. Laboratory test and radiological findings are fairly nonspecific, but when found together in a patient receiving an anticoagulant, the diagnosis can be made with some confidence. Management may be complicated by the bleeding disorder, the intestinal obstruction if present, and the original indication for warfarin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Simple method to predict digoxin serum concentration.

The predictability of a method of determining serum digoxin concentration was assessed in a retrospective study of 35 hospitalized patients taking digoxin orally for maintenance therapy. Simple pharmacokinetic expressions were used to estimate digoxin concentration. Clinically, the mean measured digoxin concentration (1.35 ng/ml) was in close agreement with the mean predicted value (1.36 ng/ml). There was also a strong statistical correlation between measured and predicted values (r = .82). The predictability of serum digoxin concentration was statistically equivalent in men and women. Our results indicate that a reasonably accurate prediction of digoxin concentration is possible using simple mathematical formulas that require only routine clinical data.