Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are effective agents in lowering cholesterol and triglycerides and are being used by human immunodeficiency virus-positive patients to treat the lipid elevation that may be associated with antiretroviral therapy. Many HMG-CoA reductase inhibitors and protease inhibitors are metabolized by the same cytochrome P450 enzyme 3A4 (CYP3A4). In addition, many protease inhibitors are potent inhibitors of CYP3A4. Therefore, coadministration of these two classes of drugs may cause significant drug interactions. This open-label, multiple-dose study was performed to determine the interactions between nelfinavir, a protease inhibitor, and two HMG-CoA reductase inhibitors, atorvastatin and simvastatin, in healthy volunteers. Thirty-two healthy subjects received either atorvastatin calcium (10 mg once a day) or simvastatin (20 mg once a day) for the first 14 days of the study. Nelfinavir (1,250 mg twice a day) was added on days 15 to 28. Pharmacokinetic assessment was performed on days 14 and 28. The study drugs were well tolerated. Nelfinavir increased the steady-state area under the plasma concentration-time curve during one dosing period (AUC(tau)) of atorvastatin 74% and the maximum concentration (C(max)) of atorvastatin 122% and increased the AUC(tau) of simvastatin 505% and the C(max) of simvastatin 517%. Neither atorvastatin nor simvastatin appeared to alter the pharmacokinetics of nelfinavir. It is recommended that coadministration of simvastatin with nelfinavir should be avoided, whereas atorvastatin should be used with nelfinavir with caution.

The contribution of nurses' perceptions and actions in defining scope and stabilising professional boundaries of nursing practice.

This paper reports on the findings of a naturalistic inquiry study that explored the scope and boundaries of nursing practice. Findings from interview and observation data suggest that nurses negotiate and adjust professional boundaries on an individual, case-by-case basis, thereby managing the scope of their practice as they see it in that circumstance. The strategies they used are presented in four major categories: 1) maintaining a comfort zone, 2) expanding into safe territory, 3) moving into the grey zone and 4) stepping over the line. Findings show that nurses' efforts to maintain the comfort zone serve to perpetuate the status quo and may threaten holistic care. Expanding nursing actions to include functional roles such as coordinating care, sharing information, advocating (for patients), collaborating and innovating offers the profession critical building blocks for defining the scope of nursing practice. Clarifying the grey zone (or overlapping territory) is an essential task for the profession in determining the boundaries of nursing practice. The data revealed that, partly due to the ambiguity of the grey zone, nurses may step over the line into medical decision-making and outside the legal sanctions for the professional nursing role. The implications of this study highlight the need for nursing to define its scope of practice and in so doing stabilise professional boundaries.

Registered nurses' descriptions of their health assessment practices.

The delivery of health-care services in Australia is undergoing many changes. The move towards home-based acute care has precipitated a review of many nursing care practices. An important consequence of these changes is the need for registered nurses to be adequately equipped to conduct systematic health assessments. This descriptive study used a questionnaire designed to elicit short-answer responses in order to investigate how registered nurses described their health assessment practices and what type of data they collected. The findings indicate that respondents possess divergent conceptualizations of health assessment, and that they predominately use health assessment data to support medical therapies. Discussion focuses on the implications of these findings for nursing practice.

Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate.

In vitro studies with human liver microsomes and P450 probe substrates were performed to characterize selectivity and mechanism of cytochrome P450 inhibition by nelfinavir mesylate. At therapeutic concentrations (steady-state plasma concentrations approximately 4 microM), nelfinavir was found to be a competitive inhibitor of only testosterone 6beta-hydroxylase (CYP3A4) with a Ki concentration of 4. 8 microM. At supratherapeutic concentrations, nelfinavir competitively inhibited dextromethorphan O-demethylase (CYP2D6), S-mephenytoin 4-hydroxylase (CYP2C19), and phenacetin O-deethylase (CYP1A2) with Ki concentrations of 68, 126, and 190 microM, respectively. Nelfinavir did not appreciably inhibit tolbutamide 4-hydroxylase (CYP2C9), paclitaxel 6alpha-hydroxylase (CYP2C8), or chlorzoxaxone 6beta-hydroxylase (CYP2E1) activities. The inhibitory potency of nelfinavir toward CYP3A4 suggested the possibility of in vivo inhibition of this isoform, whereas in vivo inhibition of other P450s was considered unlikely. In a one-sequence crossover study in 12 healthy volunteers, nelfinavir inhibited the elimination of the CYP3A substrate terfenadine and the carboxylate metabolite of terfenadine. The 24-hr urinary recoveries of 6beta-hydroxycortisol were reduced by an average of 27% during nelfinavir treatment, consistent with CYP3A inhibition by nelfinavir. Inhibition of CYP3A4 by nelfinavir in vitro was NADPH-dependent requiring the catalytic formation of a metabolite or a metabolic intermediate. The catechol metabolite of nelfinavir (M3) was considered unlikely to be responsible for inhibition as the addition of catechol O-methyl transferase, S-adenosyl methionine, and ascorbic acid to the preincubation mixture did not protect against the loss of testosterone 6beta-hydroxylase activity. Also, the addition of M3 to human liver microsomes did not inhibit CYP3A4. Although incubations with nelfinavir showed a time- and concentration-dependent loss of CYP3A4 activity, the partial or complete recovery of enzyme activity upon dialysis indicated that inhibition was reversible. Microsomal incubations with nelfinavir and NADPH did not result in a loss of spectral P450 content compared with the NADPH control. Glutathione, N-acetylcysteine, and catalase did not attenuate CYP3A4 inhibition by nelfinavir. Collectively, these results suggest that the probable mechanism for CYP3A4 inhibition by nelfinavir is a transient metabolic intermediate or stable metabolite that coordinates tightly but reversibly to the heme moiety of the P450.

Time of day urinary catheters are removed: a study of current practices.

Nursing abounds with rituals and routines that guide every day clinical practice, including nursing practices concerned with the timing of urinary catheter removal in adult acute care patients. Many of the underlying assumptions regarding the time of day that urinary catheters are removed are questionable and indicate a need for further study. An understanding of current practices has the potential to contribute to establishing scientific principles on which rational nursing care can be based.

Metabolism of lisofylline and pentoxifylline in human liver microsomes and cytosol.

The metabolism of lisofylline and pentoxifylline were examined in cytosol and microsomes prepared from four human livers to determine whether pentoxifylline is likely to serve as an efficient prodrug for the more active inhibitor of phosphatidic acid-dependent cell signaling, lisofylline, and to determine the extent to which lisofylline is converted to pentoxifylline, a hemorheologic agent used for the treatment of intermittent claudication. Pentoxifylline is exclusively reduced to the optical antipode of lisofylline (S M-1) in human liver cytosol, whereas the reduction in microsomes is 85% stereoselective in favor of S M-1 formation. The intrinsic clearance (Vmax/KM) of S M-1 formation in cytosol was 4 times that in microsomes. In human liver microsomes, S M-1 is exclusively converted to pentoxifylline, whereas approximately 45% of lisofylline oxidation is accounted for by the formation of pentoxifylline and the balance by aliphatic diols. It is concluded that pentoxifylline is an inefficient prodrug for delivery of lisofylline and that formation of pentoxifylline accounts for approximately 40% of the microsomal metabolites formed from lisofylline at substrate concentrations likely to be encountered in human therapeutic applications.

Protein-reactive metabolites of carbamazepine in mouse liver microsomes.

The character of reactive metabolites formed from carbamazepine (CBZ) was sought in incubations of [14C]CBZ in hepatic microsomes prepared from adult female mice of a strain (SWV/Fnn) susceptible to CBZ-induced teratogenicity. The formation of radio-labeled protein adducts was used as an index of reactive metabolite exposure. A dependence on cytochrome P450 was shown by a requirement for NADPH and inhibition by carbon monoxide, 1-aminobenzotriazole, piperonyl butoxide, and stiripentol. The addition of ascorbic acid, caffeic acid, N-acetylcysteine, and glutathione decreased the rate of binding of the radiolabel from [14C]CBZ to microsomal protein by more than 50%. The addition of glutathione transferases diminished protein adduct formation beyond that seen with glutathione alone. Evidence for the formation of an arene oxide was sought through the use of inhibitors of epoxide hydrolases, including cyclohexene oxide, chalcone oxides (with the addition of cytosol as appropriate), and by the addition of recombinant human soluble and microsomal epoxide hydrolases and recombinant rat microsomal epoxide hydrolase. The microsomal epoxide hydrolases decreased the velocity of 14C-labeled protein adduct formation by approximately 23%, whereas inhibitors had no effect, most likely because of the low native activity of microsomal epoxide hydrolase in mice. Both DT-diaphorase and catechol-O-methyltransferase diminished 14C-labeled protein adduct formation by 54% and 45%, respectively. The data suggest that the major reactive metabolites formed from CBZ by adult female SWV/Fnn liver microsomes are quinones and arene oxides.

Effects of caffeine and theophylline on acetaminophen pharmacokinetics: P450 inhibition and activation.

Metabolism of acetaminophen (APAP) to its reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is mediated by cytochrome P450. A pharmacokinetic study was conducted to quantitate changes in the formation clearance (Cl(f)) of NAPQI to assess in vivo the activation and inhibition of NAPQI formation by methylxanthines. Cl(f) of NAPQI was unaltered by methylxanthine administration in saline-pretreated rats. In phenobarbital-induced rats receiving a nontoxic dose of APAP (100 mg/kg i.v.), a single dose of caffeine (100 mg/kg i.p.) co-administered with APAP increased the Cl(f) of NAPQI formation from 0.58 +/- 0.47 to 2.08 +/- 1.1 1 ml/min/kg (P = .01). Unlike caffeine, theophylline (93 mg/kg i.p.) had no effect on the Cl(f) of NAPQI in phenobarbital-induced rats. The increase in the Cl(f) of NAPQI immediately after a single dose of caffeine demonstrates that P450 activation by caffeine can occur in vivo, as we observed previously in microsomes. The same dose of APAP and methylxanthines also was administered to rats induced with methylcholanthrene. The co-administration of either a single dose of caffeine or theophylline diminished the Cl(f) of NAPQI by 86% (P = .01) and 52% (P = .03), respectively. These in vivo results agree with our previous studies of the effects of the methylxanthines on the formation of NAPQI in rat liver microsomes.

Health assessment: a study of registered nurses' knowledge and skill level.

In Australia, there is a paucity of published studies which investigate the role of health assessment in nursing practice. The purpose of the following study was to establish whether registered nurses perceived health assessment to be a central component of their nursing practice. A pre- and post-test design was used to evaluate if any changes were evident in perceived nursing knowledge and skill level following an educational program. The target population was all registered nurses enrolled in a health assessment subject offered in a post-registration Bachelor of Nursing course. A paired, two-tailed t-test showed statistically significant changes in the registered nurses' attitudes towards health assessment. In addition, statistically significant changes were demonstrated in the group's perceived comfortableness with health assessment knowledge and skill level. The results of this project have been used to guide and shape nursing curricula in the area of teaching health assessment.

Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1.

Disulfiram and its reduced metabolite diethyldithiocarbamate have been identified previously as selective mechanism-based inhibitors of human liver microsomal cytochrome P450 2E1 in vitro. In animals, a single oral dose of disulfiram has been shown to produce a rapid and selective inactivation of hepatic P450 2E1 content and catalytic activity in vivo. This investigation explored the efficacy of single dose disulfiram as an inhibitor of human P450 2E1 activity in vivo. Clinical P450 2E1 activity was assessed by the 6-hydroxylation of chlorzoxazone, a metabolic pathway catalyzed selectively by P450 2E1. Six healthy volunteers received 750 mg oral chlorzoxazone on two occasions in a crossover design, 10 hours after 500 mg oral disulfiram, or after no pretreatment (control subjects). Disulfiram pretreatment markedly decreased chlorzoxazone elimination clearance to 15% of control values (from 3.28 +/- 1.40 to 0.49 +/- 0.07 ml/kg/min, p < 0.005), prolonged the elimination half-life (from 0.92 +/- 0.32 to 5.1 +/- 0.9 hours, p < 0.001), and caused a twofold increase in peak plasma chlorzoxazone concentrations (20.6 +/- 9.9 versus 38.7 +/- 10.3 micrograms/ml, p < 0.001). Disulfiram also profoundly decreased the formation clearance of 6-hydroxychlorzoxazone, from 2.30 +/- 0.93 to 0.17 +/- 0.05 ml/kg/min (p < 0.005). These findings show that a single dose of disulfiram significantly diminishes the activity of human P450 2E1 in vivo. The efficacy of single-dose disulfiram as an inhibitor of human P450 2E1 suggests that this modality for manipulating clinical P450 2E1 activity may provide a useful probe for delineating P450 2E1 participation in human drug biotransformation or for the treatment of poisoning by P450 2E1-activated toxins.

Prominence of IgG4 antibodies in the human responses to Strongyloides stercoralis infection.

The participation of the four subclasses of IgG in the humoral response to Strongyloides stercoralis was assessed by analyzing total and parasite-specific responses of each IgG subclass in 20 patients with uncomplicated strongyloidiasis and 21 immunocompromised patients with extraintestinal disease. The total component of each subclass was normal in most patients. IgG4 antibodies (measured by ELISA) were the most prominent parasite-specific response in both groups. Specific IgG2 and IgG4 responses were significantly more elevated in immunocompetent than in immunosuppressed patients. When the reactivity of each IgG subclass was analyzed by immunoblotting on SDS-PAGE-separated larval antigens, IgG4 recognized more antigens than did any other subclass. No parasite antigens were selectively recognized by either clinical group. Thus the continuous antigenic stimulation of chronic strongyloidiasis may result in an enhanced IgG4 subclass response. However, no presence or absence of humoral responses specific for filariform larval antigens was associated with the extraintestinal dissemination of the parasite.