Enzalutamide-warfarin interaction necessitating warfarin dosage adjustment: A case report of successful clinical management.

WHAT IS KNOWN AND OBJECTIVES: Enzalutamide package labeling recommends avoiding concurrent warfarin use due to potential reductions in warfarin concentrations via enzalutamide-associated hepatic enzyme induction. A case of successful management of this interaction via warfarin adjustments is reported. CASE DESCRIPTION: A 77-year-old Caucasian male, previously relatively stable on warfarin 42-45 mg weekly, reported to clinic after the recent start of enzalutamide and subsequent hospitalization with a subtherapeutic International Normalized Ratio (INR). A 50% increase in weekly warfarin dose resulted in a therapeutic INR. Enzalutamide was temporarily discontinued, and a 33% weekly warfarin dose decrease resulted in two therapeutic INRs. WHAT IS NEW AND CONCLUSION: This is the first case to highlight the clinical significance of this interaction, noting that patients taking enzalutamide may require approximately 30%-50% adjustment in their warfarin dosage to maintain a therapeutic INR.

Real-time monitoring of intracellular Staphylococcus aureus replication.

A high-throughput system to rapidly assess the intracellular replication of Staphylococcus aureus has been developed utilizing S. aureus transformed with a dual gfp-luxABCDE reporter operon under the control of a growth-dependent promoter. Replication of tagged bacteria internalized into bovine mammary epithelial cells (MAC-T) could be measured by monitoring fluorescence and bioluminescence from the reporter operon following removal of extracellular bacteria from the plates. Bacterial replication inside cells was confirmed by a novel ex vivo time-lapse confocal microscopic method. This assay of bacterial replication was used to evaluate the efficacy of antibiotics which are commonly used to treat staphylococcal infections. Not all antibiotics tested were able to prevent intracellular replication of S. aureus and some were ineffective at preventing replication of intracellular bacteria at concentrations above the MIC determined for bacteria in broth culture. Comparison of the fluorescence and bioluminescence signals from the bacteria enabled effects on protein synthesis and metabolism to be discriminated and gave information on the entry of compounds into the eukaryotic cell, even if bacterial replication was not prevented. Elevated resistance of S. aureus to antibiotics inside host cells increases the likelihood of selecting S. aureus strains which are resistant to commonly used antimicrobial agents within the intracellular niche. The approach presented directly assesses intracellular efficacy of antibiotics and provides an evidence-based approach to antibiotic selection for prescribing physicians and medical microbiologists.

Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations.

Mutations in Myo7a cause hereditary deafness in mice and humans. We describe the effects of two mutations, Myo7a(6J) and Myo7a(4626SB), on mechano-electrical transduction in cochlear hair cells. Both mutations result in two major functional abnormalities that would interfere with sound transduction. The hair bundles need to be displaced beyond their physiological operating range for mechanotransducer channels to open. Transducer currents also adapt more strongly than normal to excitatory stimuli. We conclude that myosin VIIA participates in anchoring and holding membrane-bound elements to the actin core of the stereocilium. Myosin VIIA is therefore required for the normal gating of transducer channels.

Are there gender differences in the use of peak flow meters?

To determine if there are gender differences in correct use of peak flow meters (PEM), third-year doctor of pharmacy students (n = 83; 52 females, 31 males) were instructed in a classroom on correct use of a PFM, including demonstrations. Students were then immediately divided into five groups, given a PFM, and assessed for three attempts in private individual sessions. Males had superior performance on the first attempt for total score (p < 0.05) and for "inhale fully" (p < 0.05). On the second attempt, the total score was not different, but males scored higher on "exhale as fast and as hard as you can" (p < 0.05). Controlled gender studies examining use of PFM in adult and pediatric patients with asthma are warranted.

Gut morphology and morphometry in the epauletted Wahlberg's fruit bat (Epomophorus wahlbergi, Sundevall, 1846).

The morphological adaptations of the fruit bat small intestine to which the high functional efficiency could be related and the possible landmarks delineating the various parts of the gut were examined. The stomach was the carnivorous type with large rugae spanning the entire luminal aspect down to the pyloric sphincter, which was reflected internally as a prominent fold. Externally, the intestine was a continuous tube uninterrupted by any structures. The cranial fifth of the small gut had long, branching and anastomosing villi, which caudally turned to finger-like discrete structures that became rather short and stumpy and diminished at the beginning of the colon. The colon had longitudinal folds that were macroscopically discernible from the mucosal aspect of the opened intestine and that continued into the rectum. The small gut formed 94% of the whole intestinal length, the colon and the rectum taking 4 and 2%, respectively. Ultrastructurally, the enterocyte showed a prominent brush border and the lateral membranes were modified into numerous tortuous interdigitating processes. Adjacent enterocytes were joined by these processes through desmosomes. The processes also participated in pinocytotic fluid uptake from the intercellular spaces with resultant numerous intracellular vacuoles of varied sizes. Solutes absorbed into the cells were probably first passed into the intercellular compartment to create a concentration gradient thus enhancing further absorption into the cell. We conclude that the uniquely elaborate ultrastructure of the enteric epithelium coupled with the vast microvillous surface areas reported elsewhere are partly responsible for the very high absorption rates reported in the fruit bat small intestine.

Nocturnal asthma uncontrolled by inhaled corticosteroids: theophylline or long-acting beta2 agonists?

Asthma is an inflammatory disease of the airways that is frequently characterised by marked circadian rhythm. Nocturnal and early morning symptoms are quite common among patients with asthma. Increased mortality and decreased quality of life are associated with nocturnal asthma. Although numerous mechanisms contribute to the pathophysiology of nocturnal asthma, increasing evidence suggests the most important mechanisms relate to airway inflammation. According to international guidelines, patients with persistent asthma should receive long term daily anti-inflammatory therapy. A therapeutic trial with anti-inflammatory therapy alone (without a long-acting bronchodilator) should be assessed to determine if this therapy will eliminate nocturnal and early morning symptoms. If environmental control and low to moderate doses of inhaled corticosteroids do not eliminate nocturnal symptoms, the addition of a long-acting bronchodilator is warranted. Long-acting inhaled beta2 agonists (e.g. salmeterol, formoterol) are effective in managing nocturnal asthma that is inadequately controlled by anti-inflammatory agents. In addition, sustained release theophylline and controlled release oral beta2 agonists are effective. In patients with nocturnal symptoms despite low to high doses of inhaled corticosteroids, the addition of salmeterol has been demonstrated to be superior to doubling the inhaled corticosteroid dose. In trials comparing salmeterol with theophylline, 3 studies revealed salmeterol was superior to theophylline (as measured by e.g. morning peak expiratory flow, percent decrease in awakenings, and need for rescue salbutamol), whereas 2 studies found the therapies of equal efficacy. Studies comparing salmeterol to oral long-acting beta2 agonists reveal salmeterol to be superior to terbutaline and equivalent in efficacy to other oral agents. Microarousals unrelated to asthma are consistently increased when theophylline is compared to salmeterol in laboratory sleep studies. In addition to efficacy data, clinicians must weigh benefits and risks in choosing therapy for nocturnal asthma. Long-acting inhaled beta2 agonists are generally well tolerated. If theophylline therapy is to be used safely, clinicians must be quite familiar with numerous factors that alter clearance of this drug, and they must be prepared to use appropriate doses and monitor serum concentrations. Comparative studies using validated, disease specific quality of life instruments (e.g. Asthma Quality of Life Questionnaire) have shown long-acting inhaled beta2 agonists are preferred to other long-acting bronchodilators. Examination of costs for these therapeutic options reveals that evening only doses of long-acting oral bronchodilators are less expensive than multiple inhaled doses. However, costs of monitoring serum concentrations, risks, quality of life and otheroutcome measures must also be considered. Long-acting inhaled beta2 agonists are the agents of choice for managing nocturnal asthma in patients who are symptomatic despite anti-inflammatory agents and other standard management (e.g. environmental control). These agents offer a high degree of efficacy along with a good margin of safety and improved quality of life.

Thrombocytopenia associated with octreotide.

A 42-year-old woman with a history of hepatitis C-induced cirrhosis, gastrointestinal bleeding, and alcohol abuse presented to the hospital with hematemesis and melena. Based on our previous experience, octreotide (Sandostatin) therapy was started at 50 mg/hr and continued for 5 days. Platelet count on admission (122 x 10(9)/L) dropped immediately after octreotide therapy was started; upon discontinuation, platelet count began trending up from 72 x 10(9)/L. However, octreotide was not suspected at this point as the cause of thrombocytopenia. In a subsequent admission, octreotide was again administered with a resultant prompt decrease in platelet count. To our knowledge, this is only the second case report of octreotide-induced thrombocytopenia, and the first case of this adverse effect demonstrated by inadvertent rechallenge.

Effect of a brief educational intervention on medical students' use of asthma devices.

Several studies have shown that a significant percentage of housestaff and attending physicians are deficient in both skill and knowledge of the metered-dose inhaler (MDI). There are no studies involving medical students, or any including the peak flow meter (PFM). The setting was a large health science center with investigators in private conference rooms with individual medical students. Twenty-two medical students in the last semester before graduation were scored in the use of these devices pre-education and post-education (instruction included both discussion and demonstration). Results revealed a lack of skill initially, followed by dramatic improvement after the intervention. The total number of correct steps for each device (MDI with spacer and PFM) improved significantly (p < 0.0001). This group of medical students was deficient in the use of common asthma devices. A short educational intervention was effective in improving skill.

Gender differences in metered-dose inhaler-spacer device technique.

STUDY OBJECTIVE: To determine whether gender affects the correct use of a metered-dose inhaler (MDI)-spacer device. DESIGN: Prospective, observational study. SETTING: University classrooms. PATIENTS: Eighty-three students in their third year of a Doctor of Pharmacy program. INTERVENTION: Students were given the device and received 20 minutes of education on its use. They then were asked to perform the technique. Assessment and retraining were done, as necessary, by clinicians who were experienced with the device. Students returned 1 week later to perform the technique again. MEASUREMENTS AND MAIN RESULTS: The performance of men versus women was analyzed with chi 2 tests and the Student's t test. Power analysis indicated that 30 students were needed in each group. CONCLUSION: There were no significant differences between men and women in proper MDI-spacer technique.

Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14.

CONTEXT: Gastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A few reports have suggested, however, that a genetic component may contribute to the incidence of GER, especially in its severe or chronic forms. OBJECTIVE: To identify a genetic locus that cosegregates with a severe pediatric GER phenotype in families with multiple affected members. DESIGN: A genome-wide scan of families affected by severe pediatric GER using polymorphic microsatellite markers spaced at an average of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkage analyses. SETTING: General US community, with research performed in a university tertiary care hospital. SUBJECTS: Affected and unaffected family members from 5 families having multiple individuals affected by severe pediatric GER, identified through a patient support group. MAIN OUTCOME MEASURES: Determination of inheritance patterns and linkage of a genetic locus with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidence of linkage. RESULTS: In these families, severe pediatric GER followed an autosomal dominant hereditary pattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained for marker D13S1253 at map position 35 cM when presumptively affected persons were modeled as unknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons were modeled as unaffected). CONCLUSION: These data suggest that a gene for severe pediatric GER maps to chromosome 13q14. JAMA. 2000;284:325-334

Response to warfarin and other oral anticoagulants: effects of disease states.

BACKGROUND: Warfarin is associated with numerous drug and food interactions, and much attention has been appropriately focused on this subject. Because several disease states may also affect response to oral anticoagulants, we present a summary of the literature. METHODS: We searched MEDLINE for original articles on the effect of disease states on response to warfarin. RESULTS: Liver disease and thyroid dysfunction are well-documented as affecting warfarin response. Further study is needed to establish whether febrile illness, congestive heart failure, and other disease states enhance the effect of warfarin in some patients. CONCLUSION: Careful monitoring of anticoagulant therapy in patients with diseases that have the potential to affect warfarin response could increase safety and efficacy of this important agent.

Importance of beta(2)adrenergic receptor genotype, gender and race on albuterol-evoked bronchodilation in asthmatics.

To determine whether race and gender affect beta(2)receptor-stimulated bronchodilation, we quantified FEV(1)and plasma concentrations of albuterol at various times following the oral administration of a single 8-mg dose of albuterol in 15 black and 15 white male and female asthmatics. No important racial or gender differences in albuterol-evoked FEV(1)or percent-predicted FEV(1)were evident, although females tended to be more sensitive compared to males. Pharmacodynamic (PD) models were fitted to data in 19 patients (63%); FEV(1)was too erratic to fit in three, and a clockwise hysteresis in the FEV(1)vs. albuterol concentration relationship was observed in eight asthmatics. Mean +/- SD baseline (E(0)), maximal FEV(1)(E(max)) and C(50)were: 3.18 + 1.03 l, 4.00 +/- 1.12 l, 7.84 +/- 10.2 microg/l, respectively. beta(2)receptor genotype was determined in 16 patients. All Arg 16 homozygotes exhibited proportional FEV(1)response vs. plasma albuterol concentration relationships, and thus were fitted by PD models. All those having a poor FEV(1)vs. albuterol concentration relationship carried the Gly 16 allele. We conclude that receptor genotype, but not race or gender, is an important determinant of albuterol pharmacodynamics.

Salmeterol administration by metered-dose inhaler alone vs metered-dose inhaler plus valved holding chamber.

STUDY OBJECTIVE: To determine whether a spacer device designed as a valved holding chamber with a flow signal increases the efficacy of the long-acting beta(2)-agonist, salmeterol, in patients who use incorrect technique with metered-dose inhaler (MDI) alone. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: University hospital outpatient rooms. PATIENTS: Twenty adult outpatients with stable persistent asthma, receiving a daily anti-inflammatory drug. INTERVENTIONS: Patients were randomized to either salmeterol MDI (incorrect use: 1 s after actuating MDI, inhale rapidly) and placebo plus spacer (correct use: inhale slowly as MDI is actuated, continue to inhale slowly and deeply) or placebo MDI (incorrect use) and salmeterol plus spacer (correct use). The following week, patients received the opposite treatment. The dose was two puffs from each device on each treatment day; each puff was separated by 1 min. MEASUREMENTS AND RESULTS: After baseline peak expiratory flow (PEF), salmeterol was administered and serial PEF determined (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h). Administration of salmeterol MDI plus spacer resulted in significantly greater increases in PEF from baseline vs MDI at 4 h (44 L/min vs 10 L/min; p < 0.01) and 6 h (49 L/min vs 24 L/min; p < 0.05). Both methods of administration were equally well tolerated. CONCLUSION: We conclude that patients who have poor timing and rapid inhalation with salmeterol MDI alone will have greater increases in PEF at 4 h and 6 h and no additional side effects if the dose is administered with a valved holding chamber that is used correctly. Further study is needed regarding other errors in MDI technique with salmeterol.

Effect of disease states on theophylline serum concentrations: are we still vigilant?

The use of theophylline has decreased over the past decade because of concerns over the risks of serious adverse effects as well as availability of more effective, safer drugs. Because of this decline in use, some clinicians may not be alert to the marked effect of some disease states on theophylline serum concentrations. The purpose of this review is to heighten awareness of the effect of decompensated heart failure, cor pulmonale, hepatic dysfunction, thyroid disease, and febrile illness on theophylline serum concentrations. Because many patients receive some benefit from this drug, safe use by clinicians requires closer monitoring of serum concentrations in patients with factors that alter theophylline clearance, including several disease states.

Role of myosin VI in the differentiation of cochlear hair cells.

The mouse mutant Snell's waltzer (sv) has an intragenic deletion of the Myo6 gene, which encodes the unconventional myosin molecule myosin VI (K. B. Avraham et al., 1995, Nat. Genet. 11, 369-375). Snell's waltzer mutants exhibit behavioural abnormalities suggestive of an inner ear defect, including lack of responsiveness to sound, hyperactivity, head tossing, and circling. We have investigated the effects of a lack of myosin VI on the development of the sensory hair cells of the cochlea in these mutants. In normal mice, the hair cells sprout microvilli on their upper surface, and some of these grow to form a crescent or V-shaped array of modified microvilli, the stereocilia. In the mutants, early stages of stereocilia development appear to proceed normally because at birth many stereocilia bundles have a normal appearance, but in places there are signs of disorganisation of the bundles. Over the next few days, the stereocilia become progressively more disorganised and fuse together. Practically all hair cells show fused stereocilia by 3 days after birth, and there is extensive stereocilia fusion by 7 days. By 20 days, giant stereocilia are observed on top of the hair cells. At 1 and 3 days after birth, hair cells of mutants and controls take up the membrane dye FM1-43, suggesting that endocytosis occurs in mutant hair cells. One possible model for the fusion is that myosin VI may be involved in anchoring the apical hair cell membrane to the underlying actin-rich cuticular plate, and in the absence of normal myosin VI this apical membrane will tend to pull up between stereocilia, leading to fusion.

Can we justify ipratropium therapy as initial management of acute exacerbations of COPD?

Although inhaled ipratropium is commonly accepted as the drug of choice for long-term management of chronic bronchitis and emphysema, little evidence is available to promote its administration in conjunction with a beta2-agonist as part of initial management of exacerbations of chronic obstructive pulmonary disease (COPD) in the acute care setting. Reasons for its widespread acceptance for acutely ill patients may include its status as a first-line agent for long-term therapy, its relative safety, and attempts to provide optimal patient care. Since inhaled ipratropium is beneficial as immediate therapy for asthma in the emergency department, some practitioners attempted to extrapolate these findings to treatment of COPD. Review of available studies reveals wide variability in methodologies and results. Although some studies reported improvement in pulmonary function tests, no clinically significant differences in patient outcomes, including shorter hospitalization, were evident. In patients who fail traditional therapies, inhaled ipratropium is reasonable. Double-blind, randomized, placebo-controlled trials in patients receiving emergency department care and in hospitalized patients that reveal shorter length of stay or other improved outcomes, are necessary to establish routine addition of inhaled ipratropium to beta2-agonists in the initial management of acute COPD.

Peak expiratory flow associated with change in positioning of the instrument: comparison of five peak flow meters.

To determine if peak expiratory flow (PEF) is altered by incorrect positioning of five peak flow meters (PFMs), 16 adults with clinically stable persistent asthma were evaluated. After inhaling two puffs of albuterol via AeroChamber, patients were instructed over the next 15 min in correct PFM technique and two incorrect techniques (PFM angled 20 degrees left in mouth and PFM pointed 20 degrees downward as patient leaned forward with maximal exhalation). Order of use of five peak flow meters and correct vs. incorrect techniques were random. Although mean values generally indicated no clinically meaningful effect of positioning of the PFM, inaccurate PEFs were recorded for several subjects with both incorrect methods and all PFMs.

Interaction between rifampin and levothyroxine.

Rifampin is a potent inducer of hepatic enzymes and is well documented to cause many clinically significant drug interactions. Studies in normal volunteers have shown its ability to decrease circulating levels of thyroid hormone, while having no effect on thyroid-stimulating hormone (TSH). Reports of rifampin's effects on patients on hormone replacement in the clinical setting are of interest since we believe only one such case has been described. We report the case of a man, stable on levothyroxine, who exhibited significantly elevated TSH levels during therapy with rifampin. Thyroid-stimulating hormone levels returned to baseline 9 days after discontinuance of rifampin.