Cavernous sinus and jugular thromboses, base of skull osteomyelitis and cranial nerve palsies: catastrophic complications of sphenoid sinusitis.

Sphenoid sinusitis is a clinically important entity as it may be associated with catastrophic complications including cavernous sinus thrombosis (CST), cerebral abscess or infarction, meningitis, base of skull osteomyelitis and cranial nerve palsies. We report a case of occult sphenoid sinusitis presenting as Streptococcus intermedius bacteraemia, bilateral jugular vein and CST, cranial nerve palsy and base of skull osteomyelitis.

Use of Lt Systems in Large Class Lab Delivery.

The attainment of laboratory-based skills is essential for the development of all students who study the Life Sciences. When the COVID-19 pandemic hit and Universities worldwide closed campuses, there was great uncertainty around how long people would have to work from home, leading to a real risk that students could miss out on obtaining laboratory practice for one or perhaps 2 years. It, therefore, became critical that processes were put in place that would allow students the opportunity to gain insight into what the laboratory environment is like, and to also gain experience in data collection, interpretation, and analysis. The adoption of Lt systems (a cloud-based learning platform for the Life Sciences) to create laboratory-based teaching allowed for these issues to be addressed. Detailed planning, teamwork and production of online lab sessions allowed for the creation of bespoke lessons that replicated as best as possible the 'face-to-face' experience. This was achieved by taking aspects of pre-existing labs, filming new material and utilising interactive data analysis tools in order to create online Lt labs that gave students a feel of what it would be like to be in a laboratory on campus. Lt systems also doubled as a revision tool to enhance student learning and ultimately allowed intended learning outcomes to be successfully met. The labs were well received by students and the online material meant that they could access content at a time convenient to them. This 'online anytime' possibility was crucial for such a large class (n = 378) who were working from home in many different countries worldwide during a pandemic. Going forward, the online lessons built during the pandemic can be integrated with future face-to-face sessions to create a more enhanced learning experience for the student.

A How-To Compendium for GammaPod Treatments, Clinical Workflow, and Clinical Program at an Early Adopting Institution.

In 2019, our institution became the second in the world to go live with GammaPod (Xcision Medical Systems, LLC, Columbia, MD), a device dedicated for stereotactic radiation therapy of breast cancer, with breast immobilization, real-time imaging, and highly-conformal dosimetry. At our institution, GammaPod is used for 5-fraction adjuvant partial breast irradiation, single-fraction tumor cavity boost before whole-breast irradiation, single-fraction preoperative radiation, and (in poor surgical candidates), single-fraction definitive radiation. Here, we describe our workflow, observed procedure step times, and homegrown techniques for improved efficiency in our institutional experience of 93 patients treated between 2019 and 2021.

A woman with visual loss, amenorrhoea and polyuria: the first reported case of nodular lymphocyte-predominant Hodgkin lymphoma presenting with hypopituitarism.

SUMMARY: A 34-year-old woman presented 18 months post-partum with blurred vision, polyuria, amenorrhoea, headache and general malaise. Comprehensive clinical examination showed left superior temporal visual loss only. Initial investigations revealed panhypopituitarism and MRI demonstrated a sellar mass involving the infundibulum and hypothalamus. Lymphocytic hypophysitis was suspected and high dose glucocorticoids were commenced along with desmopressin and thyroxine. However, her vision rapidly deteriorated. At surgical biopsy, an irresectable grey amorphous mass involving the optic chiasm was identified. Histopathology was initially reported as granulomatous hypophysitis. Despite the ongoing treatment with glucocorticoids, her vision worsened to light detection only. Histopathological review revised the diagnosis to partially treated lymphoma. A PET scan demonstrated avid uptake in the pituitary gland in addition to splenic involvement, lymphadenopathy above and below the diaphragm, and a bone lesion. Excisional node biopsy of an impalpable infraclavicular lymph node confirmed nodular lymphocyte-predominant Hodgkin lymphoma. Hyper-CVAD chemotherapy was commenced, along with rituximab; fluid-balance management during chemotherapy (with its requisite large fluid volumes) was extremely complex given her diabetes insipidus. The patient is now in clinical remission. Panhypopituitarism persists; however, her vision has recovered sufficiently for reading large print and driving. To the best of our knowledge, this is the first reported case of Hodgkin lymphoma presenting initially as hypopituitarism. LEARNING POINTS: Lymphoma involving the pituitary is exceedingly rare and, to the best of our knowledge, this is the first reported case of nodular lymphocyte-predominant Hodgkin lymphoma presenting as hypopituitarism. There are myriad causes of a sellar mass and this case highlights the importance of reconsidering the diagnosis when patients fail to respond as expected to appropriate therapeutic intervention. This case highlights the difficulties associated with managing panhypopituitary patients receiving chemotherapy, particularly when this involves large volumes of i.v. hydration fluid.

Clival prolactinoma masquerading as a chordoma: a case report.

Ectopic pituitary adenomas are a rare clinical entity and are frequently mistaken for other base of skull lesions on imaging. We report the clinical presentation and management of a woman presenting with an ectopic prolactinoma located in the clivus. A 66-year-old female presented with a 6-month history of headaches and light-headedness. Anatomical imaging demonstrated a clival lesion most suspicious for chordoma. Endocrinological assessment revealed modestly increased prolactin level with lower-than-expected gonadotrophins levels for her age. Surgical resection confirmed an ectopic prolactinoma. A skull base lesion in a patient with hormonal derangement should lend to a high clinical suspicion of an EPA as they may be treated with medications before surgery. Guidelines could assist clinicians investigating skull-based lesions to identify the rare, but important diagnosis of ectopic pituitary adenomas.

Physical activity interventions in early life aimed at reducing later risk of obesity and related non-communicable diseases: A rapid review of systematic reviews.

To identify useful components of interventions aimed at prevention of childhood obesity and related non-communicable diseases (NCDs), which included physical activity and which targeted any or all of four life-course stages: peri-conception; pregnancy; infancy and toddlerhood (0 to 23 months); and early childhood (24 to 59 months). In May 2016, WHO Geneva searched the Cochrane Library and PubMed for systematic reviews of interventions including physical activity to prevent childhood obesity or risk factors for obesity-related NCDs. Using a narrative synthesis, the efficacy of randomized controlled trials (RCTs) to alter energy balance outcomes (measures of weight status or body fatness) was characterized by life-course stage, study characteristics, intervention functions (as defined in the behaviour change wheel), and level of the socio-ecological model (SEM) targeted. The quality of included systematic reviews was assessed. We retrieved 82 reviews from the World Health Organization (WHO) search, of which 23 were eligible for the present synthesis. The number of eligible studies by life-course stage was: 0 (peri-conception); 0 (pregnancy); 8 (infancy and toddlerhood, age 0 to 23 months; seven RCTs; age); and 37 (early childhood, age 24 to 59 months; 30 RCTs;). Thus, there was a lack of evidence for physical activity interventions during peri-conception and pregnancy. Almost all relevant studies in the 0- to 23- and 24- to 59-month life-course stages were multicomponent interventions (ie, targeted physical activity, dietary, and/or sedentary behaviours). Interventions with evidence of efficacy tended to target multiple levels of the SEM, with emphasis on parents, and extend over long periods. Effective intervention elements for early life obesity prevention included classes on parenting skills, alteration of the kindergarten playground, and financial incentives. Evidence from low- and middle-income countries was scarce, and evidence for intervention effect on obesity-related NCDs was missing. Future physical activity interventions in toddlerhood and early childhood aimed at prevention of obesity should adopt the characteristics typical of effective interventions identified by the present synthesis. There is an urgent need for more evidence on physical activity interventions set in low- and middle-income countries and which target the peri-conception and pregnancy periods.

Expansion of inpatient clinical pharmacy services through reallocation of pharmacists.

PURPOSE: The redesign of an inpatient pharmacy practice model through reallocation of pharmacy resources in order to expand clinical services is described. METHODS: A pharmacy practice model change was implemented at a nonprofit academic medical center to meet the increasing demand for direct patient care services. In order to accomplish this change, the following steps were completed: reevaluation of daily tasks and responsibilities, reallocation of remaining tasks to the most appropriate pharmacy staff member, determination of the ideal number of positions needed to complete each task, and reorganization of the model into a collection of teams. Data were collected in both the preimplementation and postimplementation periods to assess the impact of the model change on operational workflow and clinical service expansion. RESULTS: The mean ± S.D. times to order verification were 17 ± 52 minutes during the preimplementation period and 21 ± 70 minutes in the postimplementation period (p < 0.001). During the 3 months before and after implementation of the model change, the mean number of medication reconciliations performed increased from 114 to 144. After implementation of the model change, total interventions increased 194%. Notably, there was a 736% increase in the number of interventions focused on facilitating safe discharge. CONCLUSION: A pharmacy practice model change was successfully implemented by reallocating existing pharmacist and technician roles and increasing incorporation of pharmacy residents and students. This change led to an expansion of direct patient care coordination services without negatively affecting the operational responsibilities of the pharmacy or the need to hire additional staff.

Inhaled epoprostenol therapy for pulmonary hypertension: Improves oxygenation index more consistently in neonates than in older children.

The purpose of this study was to determine the efficacy of inhaled epoprostenol for treatment of acute pulmonary hypertension (PH) in pediatric patients and to formulate a plan for a prospective, randomized study of pulmonary vasodilator therapy in this population. Inhaled epoprostenol is an effective treatment for pediatric PH. A retrospective chart review was conducted of all pediatric patients who received inhaled epoprostenol at a tertiary care hospital between October 2005 and August 2007. The study population was restricted to all patients under 18 years of age who received inhaled epoprostenol for greater than 1 hour and had available data for oxygenation index (OI) calculation. Arterial blood gas values and ventilator settings were collected immediately prior to epoprostenol initiation, and during epoprostenol therapy (as close to 12 hours after initiation as possible). Echocardiograms were reviewed during two time frames: Within 48 hours prior to therapy initiation and within 96 hours after initiation. Of the 20 patients in the study population, 13 were neonates, and the mean OI for these patients improved during epoprostenol administration (mean OI before and during therapy was 25.6±16.3 and 14.5±13.6, respectively, P=0.02). Mean OI for the seven patients greater than 30 days of age was not significantly different during treatment (mean OI before and during therapy was 29.6±15.0 and 25.6±17.8, P=0.56). Improvement in echocardiographic findings (evidence of decreased right-sided pressures or improved right ventricular function) was demonstrated in 20% of all patients. Inhaled epoprostenol is an effective therapy for the treatment of selected pediatric patients with acute PH. Neonates may benefit more consistently from this therapy than older infants and children. A randomized controlled trial is needed to discern the optimal role for inhaled prostanoids in the treatment of acute PH in childhood.

General job stress: a unidimensional measure and its non-linear relations with outcome variables.

This article aims to examine the non-linear relations between a general measure of job stress [Stress in General (SIG)] and two outcome variables: intentions to quit and job satisfaction. In so doing, we also re-examine the factor structure of the SIG and determine that, as a two-factor scale, it obscures non-linear relations with outcomes. Thus, in this research, we not only test for non-linear relations between stress and outcome variables but also present an updated version of the SIG scale. Using two distinct samples of working adults (sample 1, N = 589; sample 2, N = 4322), results indicate that a more parsimonious eight-item SIG has better model-data fit than the 15-item two-factor SIG and that the eight-item SIG has non-linear relations with job satisfaction and intentions to quit. Specifically, the revised SIG has an inverted curvilinear J-shaped relation with job satisfaction such that job satisfaction drops precipitously after a certain level of stress; the SIG has a J-shaped curvilinear relation with intentions to quit such that turnover intentions increase exponentially after a certain level of stress.

Costing hospital resources for stroke patients using phase-type models.

Optimising resources in healthcare facilities is essential for departments to cope with the growing population's requirements. An aspect of such performance modelling involves investigating length of stay, which is a key performance indicator. Stroke disease costs the United Kingdom economy seven billion pounds a year and stroke patients are known to occupy long periods of time in acute and long term beds in hospital as well as requiring support from social services. This may be viewed as an inefficient use of resources. Thrombolysis is a therapy which uses a clot-dispersing drug which is known to decrease the institutionalisation of eligible stroke patients if administered 3 h after incident but it is costly to administer to patients. In this paper we model the cost of treating stroke patients within a healthcare facility using a mixture of Coxian phase type model with multiple absorbing states. We also discuss the potential benefits of increasing the usage of thrombolysis and if these benefits balance the expense of administering the drug.

Risk factors for sporadic shigellosis, FoodNet 2005.

BACKGROUND: An estimated 450,000 cases of shigellosis occur annually in the United States. Outbreaks have been associated with food, water, child daycare centers, and men who have sex with men. However, for sporadic infections, which account for the majority of cases, risk exposures are poorly characterized. METHODS: Foodborne Diseases Active Surveillance Network (FoodNet) conducts active, laboratory-based shigellosis surveillance in 10 US sites. We interviewed cases with illness onset during 2005 about exposures during the week before symptom onset using a standardized questionnaire. The proportion of patients who denied nonfood risks was used to estimate the burden attributable to foodborne transmission. RESULTS: Overall, 1494 cases were identified. The approximate incidence was 3.9/100,000, with the highest rates among children aged 1-4 years (16.4) and Hispanics (8.4). Of the 929 cases interviewed, 223 (24%) reported international travel in the week before symptom onset. Of the 626 nontraveling cases with complete risk factor information, 298 (48%) reported exposure to daycare or a household member with diarrhea; 99 (16%) reported drinking untreated water or recreational exposure to water; and 16 (3%) reported sexual contact with a person with diarrhea. Two hundred and fifty-nine (41%) denied all nonfood exposures examined. CONCLUSIONS: Sporadic shigellosis is most common among young children and Hispanics. Common exposures include international travel and contact with ill persons or daycare. However, more than one-third of US shigellosis cases annually might be due to food consumed in the United States.

FoodNet survey of food use and practices in long-term care facilities.

Foodborne illness is an important problem among the elderly. One risk factor for foodborne illness and diarrhea-associated mortality among the elderly is residence in a long-term care facility (LTCF); thus, these facilities must implement measures to ensure safe food. To assess safe food practices, knowledge, and policies, we used a mailed, self-administered questionnaire to survey food service directors at LTCFs that were certified to receive Medicare or Medicaid at eight Foodborne Diseases Active Surveillance Network (FoodNet) sites. Surveys were distributed to 1,630 LTCFs; 55% (865 of 1,568) of eligible facilities returned a completed questionnaire. Only three LTCFs completely followed national recommendations for prevention of Listeria monocytogenes contamination. Nine percent of LTCFs reported serving soft cheeses made from unpasteurized milk. Most LTCFs reported routinely serving ready-to-eat deli meats; however, few reported always heating deli meats until steaming hot before serving (only 19% of the LTCFs that served roast beef, 13% of those that served turkey, and 11% of those that served ham). Most LTCFs (92%) used pasteurized liquid egg products, but only 36% used pasteurized whole shell eggs. Regular whole shell eggs were used by 62% of facilities. Few LTCFs used irradiated ground beef (7%) or irradiated poultry products (6%). The results of this survey allowed us to identify several opportunities for prevention of foodborne illnesses in LTCFs. Some safety measures, such as the use of pasteurized and irradiated foods, were underutilized, and many facilities were not adhering to national recommendations on the avoidance of certain foods considered high risk for elderly persons. Enhanced educational efforts focusing on food safety practices and aimed at LTCFs are needed.

Outbreak of Pseudomonas aeruginosa infections after transrectal ultrasound-guided prostate biopsy.

OBJECTIVES: After the Georgia Department of Human Resources Division of Public Health was notified about 4 patients who were hospitalized with Pseudomonas aeruginosa infections after outpatient transrectal ultrasound-guided prostate biopsies in July 2005, we investigated the cause of, and risk factors for, the infections. METHODS: We enhanced surveillance for additional cases, reviewed medical records, evaluated biopsy equipment and infection control practices, and collected environmental samples. Transrectal ultrasound-guided prostate biopsy procedures were discontinued during the investigation. RESULTS: A total of 4 cases were identified. All patients were men aged 57 to 71 years. All 4 recovered with antimicrobial therapy. P. aeruginosa was isolated from the narrow lumen of the steel biopsy needle guide that had been soaking in high-level disinfectant for several days. The needle guide isolate and three available clinical isolates were indistinguishable by pulsed-field gel electrophoresis. A review of the reprocessing procedures of the biopsy needle guide revealed that it was disinfected by submersion in high-level disinfectant rather than sterilization, the reprocessing procedure recommended by the manufacturer. Manual cleaning of the lumen was limited to flushing. After disinfection, the guide was rinsed with nonsterile tap water. CONCLUSIONS: The outbreak resulted from a contaminated needle guide. The needle guide reprocessing procedures were inadequate. Potential causes of P. aeruginosa contamination include the lack of adequate manual cleaning before disinfection, failure to sterilize the needle guide, and the use of a tap-water rinse after disinfection. Clinicians performing transrectal ultrasound-guided prostate biopsy procedures should follow the manufacturers' needle guide reprocessing recommendations or use disposable needle guides.

A motivated action theory account of goal orientation.

Rapid organizational change is increasing the pressure on employees to continually update their skills and adapt their behavior to new organizational realities. Goal orientation is a promising motivational construct that may explain why some individuals adapt to change better. Unfortunately, the current goal orientation literature is in a state of conceptual and methodological disarray. This presentation reviews the goal orientation literature and identifies numerous conceptual ambiguities, including definitional inconsistencies, dimensional inconsistencies, and inconsistencies in the conceptualization of stability. These conceptual ambiguities result in a confusing array of goal orientation measures and manipulations and ultimately an incoherent empirical database. A dynamic self-regulation model of goal orientation, termed motivated action theory, is presented to integrate the various conceptual perspectives and to provide guidelines for future goal orientation research.

Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo.

OBJECTIVES: Tadalafil was examined in vitro and in vivo for its ability to affect human cytochrome P450 (CYP) 3A-mediated metabolism. METHODS: Reversible and mechanism-based inhibition of CYP3A by tadalafil was examined in human liver microsomes. The ability of tadalafil to influence CYP3A activity was also examined in primary cultures of human hepatocytes. The effect of tadalafil on the pharmacokinetics of CYP3A probe substrates was evaluated in human volunteers before and after coadministration with either a single dose or multiple doses of tadalafil (10 or 20 mg). RESULTS: Negligible competitive inhibition of CYP3A was observed in vitro. Mechanism-based inhibition of CYP3A was detected, albeit with a low potency. In human hepatocytes, exposure to 1 micromol/L or greater of tadalafil resulted in increased CYP3A protein expression; however, as with a combined effect of induction and inhibition, a corresponding increase in CYP3A activity did not occur. The clinical pharmacokinetics of midazolam and lovastatin, probe substrates of CYP3A, were unaffected by up to 14 days of tadalafil administration (90% confidence intervals for the ratio of least squares means for the pharmacokinetic parameters of tadalafil were contained within the no-effect boundaries of 0.7 to 1.43). CONCLUSIONS: In vitro results suggested that tadalafil would have little effect on the pharmacokinetics of drugs metabolized by CYP3A. Clinical studies demonstrated that the pharmacokinetics of 2 different CYP3A substrates, midazolam and lovastatin, were virtually unchanged after tadalafil coadministration. Thus therapeutic concentrations of tadalafil do not produce clinically significant changes in the clearance of drugs metabolized by CYP3A.

Atomoxetine hydrochloride: clinical drug-drug interaction prediction and outcome.

In the studies reported here, the ability of atomoxetine hydrochloride (Strattera) to inhibit or induce the metabolic capabilities of selected human isoforms of cytochrome P450 was evaluated. Initially, the potential of atomoxetine and its two metabolites, N-desmethylatomoxetine and 4-hydroxyatomoxetine, to inhibit the metabolism of probe substrates for CYP1A2, CYP2C9, CYP2D6, and CYP3A was evaluated in human hepatic microsomes. Although little inhibition of CYP1A2 and CYP2C9 activity was observed, inhibition was predicted for CYP3A (56% predicted inhibition) and CYP2D6 (60% predicted inhibition) at concentrations representative of high therapeutic doses of atomoxetine. The ability of atomoxetine to induce the catalytic activities of CYP1A2 and CYP3A in human hepatocytes was also evaluated; however, atomoxetine did not induce either isoenzyme. Based on the potential of interaction from the in vitro experiments, drug interaction studies in healthy subjects were conducted using probe substrates for CYP2D6 (desipramine) in CYP2D6 extensive metabolizer subjects and CYP3A (midazolam) in CYP2D6 poor metabolizer subjects. Single-dose pharmacokinetic parameters of desipramine (single dose of 50 mg) were not altered when coadministered with atomoxetine (40 or 60 mg b.i.d. for 13 days). Only modest changes (approximately 16%) were observed in the plasma pharmacokinetics of midazolam (single dose of 5 mg) when coadministered with atomoxetine (60 mg b.i.d. for 12 days). Although at high therapeutic doses of atomoxetine inhibition of CYP2D6 and CYP3A was predicted, definitive in vivo studies clearly indicate that atomoxetine administration with substrates of CYP2D6 and CYP3A does not result in clinically significant drug interactions.

The interactions of a selective protein kinase C beta inhibitor with the human cytochromes P450.

Studies were performed to determine the cytochromes P450 (P450) responsible for the biotransformation of (S)-13[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) to its equipotent metabolite, N-desmethyl LY333531, and to examine the ability of these two compounds to inhibit P450-mediated metabolism. Kinetic studies indicated that a single enzyme in human liver microsomes was able to form N-desmethyl LY333531 with an apparent K(M) value of approximately 1 microM. The formation rate of N-desmethyl LY333531 was correlated with markers of nine P450s in a bank of 20 human liver microsomes. The only significant correlation observed was with the form-selective activity for CYP3A. Of the nine cDNA-expressed P450s examined, only CYP3A4 and CYP2D6 formed N-desmethyl LY333531. However, CYP3A4 formed N-desmethyl LY333531 at a rate 57-fold greater than that observed with CYP2D6. In incubations with human liver microsomes, quinidine, an inhibitor of CYP2D6, demonstrated little inhibition of metabolite formation while ketoconazole, an inhibitor of CYP3A, demonstrated almost complete inhibition. Thus, CYP3A is responsible for the formation of N-desmethyl LY333531. LY333531 and N-desmethyl LY333531 were also examined for their ability to inhibit metabolism mediated by CYP2D6, CYP2C9, CYP3A, and CYP1A2. LY333531 and N-desmethyl LY333531 were found to competitively inhibit CYP2D6 with calculated K(i) values of 0.17 and 1.0 microM, respectively. Less potent inhibition by these compounds of metabolism mediated by the other three P450s examined was observed. In conclusion, CYP3A is primarily responsible for forming N-desmethyl LY333531. Therefore, alterations in the activity of this enzyme have the potential to affect LY333531 clearance. In addition, LY333531 and its metabolite are predicted to be potential inhibitors of CYP2D6-mediated reactions in vivo.

Identification of the human cytochromes P450 responsible for atomoxetine metabolism.

Studies were performed to determine the human enzymes responsible for the biotransformation of atomoxetine to its major metabolite, 4-hydroxyatomoxetine, and to a minor metabolite, N-desmethylatomoxetine. Utilizing human liver microsomes containing a full complement of cytochrome P450 (P450) enzymes, average K(m) and CL(int) values of 2.3 microM and 103 microl/min/mg, respectively, were obtained for 4-hydroxyatomoxetine formation. Microsomal samples deficient in CYP2D6 exhibited average apparent K(m) and CL(int) values of 149 microM and 0.2 microl/min/mg, respectively. In a human liver bank characterized for P450 content, formation of 4-hydroxyatomoxetine correlated only to CYP2D6 activity. Of nine expressed P450s examined, 4-hydroxyatomoxetine was formed at a rate 475-fold greater by CYP2D6 compared with the other P450s. These results demonstrate that CYP2D6 is the enzyme primarily responsible for the formation of 4-hydroxyatomoxetine. Multiple P450s were found to be capable of forming 4-hydroxyatomoxetine when CYP2D6 was not expressed. However, the efficiency at which these enzymes perform this biotransformation is reduced compared with CYP2D6. The formation of the minor metabolite N-desmethylatomoxetine exhibited average K(m) and CL(int) values of 83 microM and 0.8 microl/min/mg, respectively. Utilizing studies similar to those outlined above, CYP2C19 was identified as the primary enzyme responsible for the biotransformation of atomoxetine to N-desmethylatomoxetine. In summary, CYP2D6 was found to be the primary P450 responsible for the formation of the major oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine. Furthermore, these studies indicate that in patients with compromised CYP2D6 activity, multiple low-affinity enzymes will participate in the formation of 4-hydroxyatomoxetine. Therefore, coadministration of P450 inhibitors to poor metabolizers of CYP2D6 substrates would not be predicted to decrease the clearance of atomoxetine in these individuals.