Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone.

The steady-state kinetics of amitriptyline (AMI), fluoxetine (FLU), and their active metabolites nortriptyline (NTRIP) and norfluoxetine (NFLU) were studied in 15 patients treated once daily for long durations with 50 mg of AMI and 20 mg of FLU. These compounds were analyzed simultaneously in plasma by liquid chromatography. The means and (SEM) of the steady-state concentrations (Css) of AMI, NTRIP, FLU, and NFLU were 80.6 (14.2), 52.6 (10.3), 85.3 (16.1), and 90 (13.6) ng/mL, respectively, and the apparent oral clearances (CLor) of AMI and FLU were 42.4 (8.6) and 14.9 (2.5) L/hr, respectively. The metabolite/drug steady-state concentration ratio (Css(m)/Css) for NTRIP/AMI was 0.75 (0.14) and for NFLU/FLU was 1.27 (0.17). There was a significant correlation (P < 0.05) between Css of FLU and that of AMI or NTRIP. The Css and Css(m)/Css values obtained for AMI were higher (P < 0.056 and P < 0.0034, respectively) than those we observed in 10 patients treated solely with the same dose of AMI. The twofold increase in Css of AMI and ninefold increase in Css of NTRIP seem to be the result of inhibition of the metabolism of these compounds by FLU, particularly the ring hydroxylation. Norfluoxetine may have a small inhibitory influence on the metabolism of NTRIP but lacks this effect on the metabolism of AMI.

N-acetylation polymorphism and diabetes mellitus among Saudi Arabians.

The acetylator phenotypes of 200 Saudi diabetics and an equal number of control subjects of the same origin were determined by measuring the peak height ratio of two urinary caffeine metabolites, 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (1MX), using a simplified high-performance liquid chromatographic method. Urine samples were collected from the diabetics and the control subjects who regularly drink coffee, tea, or caffeinated beverages as part of their normal daily diet. The patients were classified as either type 1 (insulin-dependent) (28 patients) or type 2 (insulin-independent) diabetics (172 patients) according to standard criteria. The reproducibility of acetylator phenotype was established by examining the peak height ratio of AFMU/1MX in 18 diabetics and 6 control subjects on different days. Significant differences in the proportion of rapid acetylators were observed between type 1 (53.6%) and type 2 (33.7%) diabetics (P < or = .0436), and between the control group (26%) and the overall diabetics (36.5%) (P < or = .024) or those with type 1 disease (P < or = .0028). Also, there was a significant (P < or = .0436) association between rapid acetylator status and type 1 diabetes mellitus.

Pharmacokinetics of mesna and dimesna after simultaneous intravenous bolus and infusion administration in patients undergoing bone marrow transplantation.

This study was undertaken to examine the pharmacokinetics of mesna and its dimer form, dimesna, in the plasma and urine of patients undergoing bone marrow transplantation who received 130 mg/kg of mesna divided intravenously into a 30-mg/kg bolus dose followed immediately by 100 mg/kg infused over 12 hours for uroprotection. The relationship between and urinary excretion of mesna and dimesna also was examined by comparing the data obtained in patients who developed hemorrhagic cystitis versus those who did not. Blood and urine samples were collected at different time intervals after administration, and the plasma or urine was analyzed by liquid chromatography with electrochemical detection. Dimesna was analyzed in these samples after reduction back to mesna with sodium borohydride. The concentration-time data of mesna exhibited the characteristics of the two-compartment model well, and the mean +/-SD values of the distributive phase half-life (t1/2 alpha), postdistributive phase half-life (t1/2 beta), volume of distribution of the central compartment (Vdc), volume of distribution at steady state (Vdss), volume of distribution during the postdistributive phase (Vd beta), total clearance (Cl), and mean residence time (MRT) observed were 0.12 +/- 0.15 hours, 2.12 +/- 1.61 hours, 0.324 +/- 0.336 L/kg, 1.09 +/- 1.18 L/kg, 2.09 +/- 3.0 L/kg, 0.755 +/- 0.507 L/hr.kg, and 6.77 +/- 0.72 hours, respectively. The mean +/-SD values of t1/2 and MRT of dimesna were 1.29 +/- 0.6 hours and 6.68 +/- 1.05 hours, respectively, and the ratio of the area under the concentration-time curve (AUC) of mesna to that of dimesna was 1.21 +/- 0.57. The fractions of dose excreted in urine in the form of mesna and dimesna in 20 hours (fu) were 0.361 +/- 0.15 and 0.482 +/- 0.25, and the renal clearance (ClR) values were 0.244 +/- 0.201 L/hr.kg and 0.157 +/- 0.156 L/hr.kg, respectively. The urinary excretion of mesna in these patients was higher than that required for uroprotection for the whole duration of infusion, and there was no significant difference in the pharmacokinetics of mesna between patients who developed hemorrhagic cystitis and those who did not. This was not the case with dimesna, in which patients with hemorrhagic cystitis excreted in urine less than 50% of the amount of dimesna excreted by those without hemorrhagic cystitis.

Relationship between antipyrine metabolism and acetylation phenotype in health and chronic liver diseases.

The authors examined the activity of N-acetyltransferase and that of microsomal P-450 isoenzymes in health and hepatic disease state by determining the acetylation phenotype and the total (CLAP) and metabolic clearances of antipyrine to form norantipyrine or N-demethylantipyrine (MCLnora), 3-hydroxymethylantipyrine (MCLhma), and 4-hydroxyantipyrine (MCLha) in 21 healthy subjects and in 33 patients with chronic liver diseases (CLD) and investigated the relationship between the activities of these two enzyme systems. The acetylation phenotype was determined according to the urinary caffeine metabolites test. The mean and (SEM) of CLAP, MCLhma, MCLha, and MCLnora in healthy subjects were 2.42 (0.264), 0.193 (0.031), 0.322 (0.045), and 0.288 (0.04) L/h, and those observed in patients with CLD were 0.98 (0.1), 0.076 (0.015), 0.131 (0.026), 0.103 (0.022) L/h, respectively. The prevalence of fast acetylation among the healthy subjects and patients with CLD was 38% and 39%, respectively. Although all metabolic clearances appear to be reduced in healthy slow acetylators, the reduction was only significant in MCLnora, indicating a direct association between the activity of N-acetyltransferase and that of P-450 IIIA3 responsible for the N-demethylation of antipyrine. Conversely, slow acetylators with CLD exhibited significantly higher CLAP and near-significantly larger metabolic clearances including MCLnora, which suggests that P-450 activity in fast acetylators is more sensitive to chronic liver diseases than in slow acetylators.

Optimization of oral etoposide dosage in elderly patients with non-Hodgkin's lymphoma using the fraction of dose absorbed measured for each patient.

This study was undertaken to investigate the pharmacokinetics of etoposide for optimizing its oral dosage in elderly patients with non-Hodgkin's lymphoma (NHL) using the fraction of dose absorbed calculated from the data generated from first oral and intravenous doses in the same patient. Twenty-three NHL patients (ages 61-95 years) entered this study. Each received 50 mg/m2 of etoposide by 1-hour i.v. infusion, which was repeated every 24 hours for 5 days. The second cycle commenced on day 21, with etoposide being administered by mouth at a dose as close to 50 mg/m2 as possible. Serial blood samples were collected and analyzed for etoposide by HPLC. The fraction of dose absorbed (F) was calculated as F = (AUCor/AUCi.v.) (Di.v./Dor), and etoposide was then given orally for the following 20 days at a daily dose equivalent to Dor/F. After 1 week free of etoposide administration, a second cycle of oral etoposide at the adjusted dose was given for 21 days. The mean +/- SD values for t1/2 beta, tmax, Cmax, CLTor, and MRT observed following the first oral dose were 8.98 +/- 4.84 h, 1.39 +/- 0.96 h, 0.083 +/- 0.046 mg.L-1/mg.m-2, 1.89 +/- 1.2 L.h-1/m2, and 10.37 +/- 2.76 h, respectively, and those observed following the first intravenous dose were 8.05 +/- 5.11 h, 1.57 +/- 0.17 h, 0.142 +/- 0.043 mg.L-1/mg.m-2, 1.25 +/- 0.44 L.h-1/m2, and 7.69 +/- 1.53 h, respectively. The mean +/- SD of F was 0.80 +/- 0.34. The data obtained indicate that optimization of etoposide oral dosage using F yielded good clinical results while keeping the morbidity at a level that is similar to that of the i.v. administration.

Sensitive assay for the determination of cefazolin or ceftriaxone in plasma utilizing LC.

A rapid, specific and very sensitive liquid chromatographic assay using standard ultraviolet detection has been developed to measure cefazolin (CFZ) or ceftriaxone (CFX) in small samples (200 microl) of plasma using either drug as the internal standard for measurement of the other. A rapid extraction was performed using C18 bonded Sep Pak cartridges with high extraction efficiency for both drugs. The chromatographic system employed the use of a Nova-Pak C18 4-microm cartridge with a radial compression system preceded by a Guard-Pak with a C18 insert. The mobile phase consisted of an aqueous solution containing 10 mM of dibasic potassium phosphate and 10 mM cetyltrimethylammonium bromide (pH 6.5) with acetonitrile (73:27 v/v). The drug and internal standard (CFZ/CFX) were detected using a UV detector set at a wavelength of 274 nm. Assay results were linearly related to the concentration (r > 0.997) for the wide range which was examined (0.005-120 microg/ml) for either drug. We report the precision, accuracy, recovery, linearity, sensitivity and specificity of this assay. The intra-run and inter-run CV was less than 9.02%. This method is currently being used for clinical therapeutic monitoring and pharmacokinetic studies of CFZ and CFX in patients undergoing cesarean section.

Plasma and urinary selenium in Saudi Arabian patients with dilated cardiomyopathy.

We measured selenium (Se) levels in the urine and blood plasma samples of 72 Saudi Arabian patients with dilated cardiomyopathy (DCM) and 70 control subjects of the same origin. To correct for differences in the hydration state of the subjects, the selenium concentration for each urine sample was normalized by dividing it by the concentration of creatinine (CREAT) in the same sample. The median (and range) of the values found for the concentration of Se in plasma, urine, and normalized concentration in urine for the control subjects was 1.306 (0.66-2.50) microM, 0.478 (0.05-2.00) microM, and 56.7 (10.6-426.5) microM Se/M CREAT, respectively, whereas, for the patients, it was 1.246 (0.53-2.45) microM, 0.39 (0.05-1.90) microM, and 75.1 (4.9-656.2) microM Se/M CREAT, respectively. Additionally, the patients were separated into three subgroups according to the severity of their disease state as judged by NYHA procedure, and were then compared to the control group. Only group 4 (the most severe state of the disease) had a significantly lower concentration of urinary Se than the control group. However, the difference became nonsignificant when normalized for CREAT levels. There was no significant difference in the plasma Se levels between the controls and any of the patient groups. As the plasma Se in the control group and in the DCM patients both fell on the low end of the "normal" range, with the patients being marginally lower than the controls, there is no firm evidence from this study to suggest that Se is related to the high incidence rate of DCM found in Saudi Arabia.

Elimination studies of antipyrine and its metabolites in healthy Saudi Arabians.

1. We measured the antipyrine clearance in 18 healthy Saudi subjects and determined the urinary excretion of three of its metabolites: 4-hydroxyantipyrine (4-OH AP), norantipyrine (NOR AP) and 3 hydroxymethylantipyrine (3-OHM AP) in 21 subjects. 2. The mean +/- SD of the antipyrine clearance was 2.4 +/- 1.1 h-1 (range 1.0-5.5 l h-1) and the corresponding value per kg body weight was 0.6 +/- 0.2 ml min-1 kg-1. Urinary excretion of antipyrine (AP), 4-OH AP, NOR AP and 3-OHM AP expressed as a percentage of the oral dose of antipyrine given was 2.8 +/- 2.2, 14.5 +/- 6.9, 12.3 +/- 5.6 and 7.6 +/- 3.2 respectively. 3. Compared to Africans, Saudis preferentially metabolize AP to NOR AP and compared to Caucasians to 3-OHM AP, rather than to 4-OH AP. These discrepancies may reflect age differences between the study populations rather than genetic or ethnic variations.

Elimination of antipyrine and its metabolites in interferon treated hepatitis C.

1. To study the effect of interferon on hepatic drug metabolism in chronic hepatitis C, we examined nine patients before and at the end of 6 months of interferon treatment. 2. Routine liver function was determined together with the salivary clearance of antipyrine and the 48 h urinary excretion of the main metabolites of antipyrine: 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine before and after 6 months of interferon treatment. 3. Liver pathology, routine liver function, and antipyrine metabolism remained unchanged after patients were treated for 6 months with interferon for a histologically advanced but clinically compensated chronic hepatitis C.

Fetal surveillance: issues and implications.

In the past, the fetus was considered healthy until evidence was presented to the contrary. With the acceptance of fetal surveillance as part of the pregnancy experience, diagnostic testing and data are thought to be necessary to prove the healthiness of the fetus. The availability of fetal surveillance techniques has transformed the pregnancy experience from a developmental process and a miracle of nature to a risk-dominated and technology-guided event. The implications of this trend significantly affect the care of pregnant women and the role of nurses as providers of comprehensive, individualized nursing care.

Positioning during the second stage of labor: moving back to basics.

The advantages of an upright position during labor are presented, with historic, physiologic, and psychosocial aspects discussed. The influences of modern obstetric practices such as electronic fetal monitoring and anesthesia practices are discussed with findings related to the use of upright positions from the Association of Women's Health, Obstetric, and Neonatal Nursing National Research Utilization Project on Second Stage Labor Management integrated. Recommendations for facilitating upright positions on the labor and delivery unit are presented.

Neonatal skin care: the scientific basis for practice.

OBJECTIVE: To review the literature addressing the care of neonatal skin. DATA SOURCES: Computerized searches in MEDLINE and CINAHL, as well as references cited in articles reviewed. Key concepts in the searches included neonatal skin differences; neonatal skin and care practices for skin integrity; neonatal skin and toxicity; permeability; and contact irritant sensitization. STUDY SELECTION: Articles and comprehensive works relevant to key concepts and published after 1963, with an emphasis on new findings from 1993 to 1999. One hundred two citations were identified as useful to this review. DATA EXTRACTION: Data were extracted and organized under the following headings: anatomy and physiology of the skin; physiologic and anatomic differences in neonatal skin; nutritional deficiencies; skin care practices; and care of skin breakdown. DATA SYNTHESIS: Newborns' skin is at risk for disruption of normal barrier function because of trauma. In light of available evidence about differences in neonatal skin development, clinical practice guidelines are suggested for baths, lubrication, antimicrobial skin disinfection, and adhesive removal. In addition, basic care practices are suggested for maintaining skin integrity, reducing exposure to potentially toxic substances, and promoting skin health beyond the neonatal period. Preventive care recommendations are made for reducing trauma, protecting the skin's immature barrier function, and promoting skin integrity. CONCLUSIONS: This review generated evidence with which to create a new and comprehensive practice guideline for clinicians. Evaluation of the guideline is under way at 58 U.S. sites.

Neonatal skin care: evaluation of the AWHONN/NANN research-based practice project on knowledge and skin care practices. Association of Women's Health, Obstetric and Neonatal Nurses/National Association of Neonatal Nurses.

OBJECTIVE: To develop and evaluate an evidence-based clinical practice guideline for assessment and routine care of neonatal skin, educate nurses about the scientific basis for practices recommended in the guideline, and design procedures that facilitate implementation of the project guideline into clinical practice. DESIGN: Descriptive report of the collaborative neonatal skin care research-based practice project of the Association of Women's Health, Obstetric and Neonatal Nurses and the National Association of Neonatal Nurses. SETTING: Neonatal intensive-care unit (NICU) and special-care nurseries and well-baby nurseries in 51 hospitals located throughout the United States. PARTICIPANTS: Member site coordinators (N = 51), nurses who work at the selected sites, and the neonates observed during both the pre- and postimplementation phases of the project (N = 2,820). METHOD: An evidence-based clinical practice guideline was developed, sites were selected from all respondents of the call for sites, site coordinator training was provided, data collection was facilitated by project-specific data collection tools, and the project was evaluated by the science team. MAIN OUTCOME MEASURES: Diversity and numbers of sites represented, patient representation, site coordinator knowledge of neonatal skin care pre- and postimplementation, use of project-designed implementation tools, satisfaction with project guideline and the data collection process, changes in practices and product use, and site coordinators' experiences during guideline implementation. RESULTS: Fifty-one sites completed the project, representing NICU, special-care, and well-baby nurseries in both academic and community hospital settings in 27 states. Registered nurses working in these sites totaled 4,754 full-time equivalent positions (FTEs) (in NICU/special-care and well-baby nurseries). Site coordinators demonstrated increased knowledge of research-based neonatal skin care and satisfaction with the implementation tools and data collection process. Product use changed, reflecting acquisition of new knowledge. Barriers to implementation of the guideline were identified. CONCLUSIONS: The AWHONN/NANN Neonatal Skin Care Research-Based Practice Project demonstrated increased knowledge among site coordinators who received training, facilitated changes in neonatal skin care as defined by the practice guideline, and thus advanced evidence-based clinical practice.

Neonatal skin care: clinical outcomes of the AWHONN/NANN evidence-based clinical practice guideline. Association of Women's Health, Obstetric and Neonatal Nurses and the National Association of Neonatal Nurses.

OBJECTIVE: To test the effectiveness of an evidence-based clinical practice guideline for neonatal skin care on selected clinical outcomes for newborns in neonatal intensive-care units (NICU), special-care units (SCU), and well-baby nurseries. DESIGN: Prospective evaluation of the collaborative neonatal skin care research-based practice project of the Association of Women's Health, Obstetric and Neonatal Nurses and the National Association of Neonatal Nurses. SETTING: NICU and well-baby units in 51 hospitals located throughout the United States. PARTICIPANTS: Member site coordinators (N = 51) and the neonates (N= 2,820) observed during both the pre- and postimplementation phases of the project. METHOD: Site coordinators received specialized education in neonatal skin care and implemented an evidence-based clinical practice guideline addressing 10 aspects of neonatal skin care. Baseline observations of skin condition, care practices, and environment of newly admitted neonates were collected by site coordinators. Postimplementation observations were then completed. MAIN OUTCOME MEASURES: Skin condition was assessed with the Neonatal Skin Condition Score (NSCS), which ranges from a score of three (best condition) to a score of nine (worst condition), based on dryness, erythema, and skin breakdown. Changes in frequency of selected skin care practices were used to assess the effectiveness and feasibility of using the practice guideline in everyday clinical practice. Aspects of the care environment with potential effect on skin integrity were monitored to determine risk factors. RESULTS: Fifty-one site coordinators made 11,468 systematic assessments of 2,464 NICU and SCU newborns and 356 well newborns. Baseline skin scores were better in well newborns compared with premature newborns. After implementation of the guideline, skin condition was improved, as reflected by less visible dryness, redness, and skin breakdown in both the NICU/SCU and well newborns. The guideline was integrated into care, as evidenced by increased use of emollients, particularly with premature infants, and decreased frequency of bathing. A relationship was shown between selected aspects of the environment and alterations in skin integrity. CONCLUSIONS: Use of the AWHONN/NANN Neonatal Skin Care Research-Based Clinical Practice Guideline was successfully implemented at 51 sites, and effectiveness was demonstrated by changed care practices and improved skin condition in premature and full-term newborns. The results of this project support a wider dissemination of the project's practice guideline for neonatal skin care.

Values influencing neonatal nurses' perceptions and choices.

The purpose of this research was to identify the values influencing the nurses' perception and choice of behavior in a hypothetical clinical situation. The theoretical framework was Rokeach's theory on the nature of human values and value systems. A descriptive study using a mailed survey was conducted on a random sample of 331 members of the National Association of Neonatal Nurses. Data on individual nurse's values, perception of information, and behavioral choices were collected with an investigator-developed questionnaire consisting of a values scale, and an information scale and choice alternatives related to three hypothetical vignettes: a low-birthweight infant, an infant with chromosomal anomalies, and a chronically ill infant. Results of this study indicate that nurses identified a hierarchy of values related to their practice. Information related to infant characteristics was consistently most important; however, in uncertain situations, rules or external protocols had an increased influence on the behavioral choice process. The behavioral choice option with the greatest agreement was different for each situation. A consistently negative correlation between the options within each vignette indicates that nurses have clearly defined choice preferences. Model testing revealed a consistent relationship across the three vignettes between the variable being just and protocol, doing right and infant characteristics, and infant characteristics and the choice options (p < .05).

Ethical implications of genetic testing.

Advances in biotechnology have created previously unforeseen possibilities to determine the genetic make-up of individuals and to predict the health of future societies. This article identifies some of the issues and dilemmas confronted by health professionals and consumers as these technologic advances move from the laboratory to the clinical setting.

Antipyrine clearance and metabolite excretion in Saudi patients with non-alcoholic chronic liver disease.

In this report, we examined the hepatic microsomal enzyme activity in 34 Saudi patients with chronic liver disease (CLD) and in 21 healthy Saudi subjects by measuring antipyrine clearance (APCI) and the fraction (%) of antipyrine (AP) dose excreted in urine unchanged (fAP) and in the form of its main metabolites: 3-hydroxymethylantipyrine (fHMAP), norantipyrine(fNORAP), and 4-hydroxyantipyrine (f4OHAP). While APCI, fHMAP, fNORAP, f4OHAP were significantly reduced in patients with CLD, fAP was significantly higher in these patients. Correlation was observed between serum albumin and APCI, fHMAP, fNORAP, or f4OHAP and between each two of the last three variables. We conclude that Saudis with CLD have uniform rather than selective reduction of hepatic microsomal enzyme activity and that serum albumin is a sensitive indicator of this activity.

The role of selenium deficiency in dilated cardiomyopathy in Saudi Arabia.

BACKGROUND: Selenium deficiency is implicated in the etiology of endemic juvenile dilated cardiomyopathy in China, and in sporadic cases in other countries. The aim of this study was to evaluate the role of selenium deficiency in the pathophysiology of dilated cardiomyopathy in the Saudi Arabian population. PATIENTS AND METHODS: Plasma and urine selenium concentrations from 72 Saudi patients with confirmed dilated cardiomyopathy were compared with corresponding values from 70 control subjects of the same national origin who had normal ventricular function. RESULTS: Plasma and urine selenium concentrations (mean+/-SD) were 1.347plusmn;0.45 and 0.49+/-0.37 micromol/L, respectively, for the patient group, and 1.32+/-0.41 and 0.60+/-0.41 micromol/L, respectively, for the control group. The differences in the values between the two groups were statistically insignificant. CONCLUSION: In the Saudi population, dilated cardiomyopathy is not caused by selenium deficiency.

Moral agency in nursing.

Moral agency involves risk. It is an action that is at odds with the traditional role of the nurse. However, as nurses assume more responsibility and accountability for client management and outcomes in an increasingly complex and uncertain environment, it is essential to approach ethical dilemmas in a manner consistent with the caring component of nursing. Case examples are utilized to illustrate the attributes necessary for nurses to fulfill their obligations in their nurse-client relationships.