Assessment of drug-drug interactions: concepts and approaches

1. A priori knowledge of the enzyme inhibitory potential of new drug entities and the drug-metabolizing enzymes involved can be used in support of important decisions on the future progress of a drug in clinical development. 2. Important advances in the knowledge of human drug-metabolizing enzymes have largely fuelled the integration of in vitro drug metabolism and clinical drug interaction studies for use in drug development programmes. 3. The likelihood of correctly predicting in vivo drug-drug interactions appears highly dependent on selecting the correct enzyme inhibition model for use in deriving the inhibitor constant (K_i) and correctly determining the available concentration of inhibitor at the active site of the enzyme(s) of interest. 4. The uncertainty and inaccuracy of predicting the extent and duration of in vivo drug interactions currently stems from a lack of definitive models by which to assess likely substrate and inhibitor concentrations at the active site of metabolism. Additional issues contributing to the uncertainty of predicting drug interactions include assumptions of the contribution of presystemic drug extraction and the effect of inhibitors on the processes involved. 5. This review considers the practical aspects of in vitro enzyme inhibition studies and the use of in vitro-in vivo correlation approaches described in the literature to predict in vivo drug-drug interactions.     

Development and psychometric testing of a new tool for detecting moral distress: the Moral Distress Thermometer

Aim. To report the development and psychometric testing of the Moral Distress Thermometer. The Moral Distress Thermometer is a new screening tool to measure moral distress in nurses who practise in the hospital setting. Background. Moral distress occurs when one knows the ethically correct thing to do, but is prevented from acting on that perceived obligation. It is a well documented phenomenon with negative consequences that may be experienced by nurses. Creating an instrument to effectively and efficiently measure moral distress in a timely way has been identified as a priority for nursing. Design. This study used a cross‐sectional survey design. Methods. Data collection for this research occurred in 2009. Participants simultaneously completed either the adult or pediatric version of the Moral Distress Scale version 2009 and the Moral Distress Thermometer. A total of 529 participants from various clinical areas completed both tools. Results. Coefficients alpha were adequate for both Adult (0·90) and Pediatric (0·92) Moral Distress Scale 2009 scales. Statistically significant Pearson correlations were found for the Moral Distress Thermometer with Adult Moral Distress Scale 2009 and Pediatric Moral Distress Scale 2009 and higher Moral Distress Thermometer, Adult Moral Distress Scale 2009 and Pediatric Moral Distress Scale 2009 means for participants who had left or who considered leaving a position because of moral distress. Conclusion. These findings provide support for the validity of the Moral Distress Thermometer.     

Neuropsychologic and Functional Recovery From Severe Carbon Monoxide Poisoning Without Hyperbaric Oxygen Therapy

Study objective: To test the hypothesis that neuropsychologic test results and functional outcome will be abnormal if hyperbaric oxygen (HBO) is not used in patients with severe carbon monoxide (CO) poisoning. Methods: For a 1-year interval, we retrospectively identified all CO-poisoned patients who were comatose on presentation at a large, urban tertiary hospital and did not receive HBO therapy. Prospectively, 6 and 12 months after CO poisoning, we administered standardized questionnaires to assess functional outcome. At 6 months, we performed extensive neuropsychologic testing. Results: All four patients exhibited normal performance on a neuropsychologic test battery at 6 months. The Folstein Mini-Mental Status Examination was normal in all patients. All patients had normal functional outcomes. Conclusion: Normal neuropsychologic and functional outcomes are possible after severe CO poisoning without the use of HBO therapy. [Weaver LK, Hopkins RO, Larson-Lohr V: Neuropsychologic and functional recovery from severe carbon monoxide poisoning without hyperbaric oxygen therapy. Ann Emerg Med June 1996;27:736-740.]     

Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with the tempo of engraftment after transplantation

Factors affecting mobilization and engraftment were analysed in 54 patients undergoing transplant using autologous PBSCs mobilized with high-dose recombinant granulocyte stimulating factor (rhG-CSF). Patients received 5-7 d of rhG-CSF. 16 μg/kg/d, administered subcutaneously. PBSCs were harvested by leukapheresis using automated continuous-flow blood cell separators beginning on day 4 of rhG-CSF, processing 10 litres of whole blood, for 2-6 consecutive days. Transplants were performed for the following diseases: breast cancer (n = 22), non-Hodgkin's lymphoma (n = 18), multiple myeloma (n = 7) and other (n = 7). Engraftment was rapid with patients reaching a neutrophil count of 1 × 10⁹/1a median of 12 d (range 9-22) after transplant. Platelets > 20 × 10⁹/1 independent of transfusion support were achieved a median of day 10 (range 7-60) after infusion. Multiple factors potentially influencing engraftment were examined using a Cox regression model. The number of CD34⁺ cells per kg was highly correlated with the time to achievement of granulocyte and platelet recovery (P < 0.012, 0.0001). The use of a post-infusion growth factor and a radiation preparative regimen was important for neutrophil recovery, and a diagnosis of breast cancer was important for platelet recovery. In an analysis by linear regression of the logarithm of CD34⁺ cells collected, lower age, marrow without disease, no prior radiation, and lower number of prior chemotherapy regimens, were important factors influencing larger numbers of CD34⁺ cells in collections.     

A practical approach to reporting treatment abandonment in pediatric chronic conditions

Treatment abandonment, the failure to complete therapy that is required for definitive disease control, frequently causes treatment failure for pediatric patients in low‐ and middle‐income countries with chronic conditions, particularly cancer. Other forms of incomplete treatment affecting children in all settings, such as nonadherence and loss to follow‐up, are often confused with treatment abandonment. Unclear definitions of incomplete treatment dramatically affect reported outcomes. To facilitate disease‐specific and cross‐sector analyses, we outline a practical approach to categorize forms of incomplete treatment, present distinct semantic categories with case examples and provide an algorithm that could be tailored to disease‐ and context‐specific needs. Pediatr Blood Cancer 2015;62:565–570. © 2015 Wiley Periodicals, Inc.     

The influence of gender on the short and long-term effects of growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults: a 5-year study

OBJECTIVES: The objectives of this study were to investigate the effects of GH replacement therapy in hypopituitary adults with growth hormone deficiency (GHD) on activation of bone remodelling during dose titration and on BMD over a median of 58 months of continuous therapy. STUDY DESIGN: Open label study in adult patients with GHD. rhGH was commenced at dose of 0.8 IU subcutaneously daily (0.4 IU if hypertensive or glucose tolerance impaired) with subsequent dose titration based on 2 weekly measurement of serum IGF-I until levels reached the target range (between the median and upper end of the age related reference range). In patients previously commenced on GH using weight based regimens the dose of GH was adjusted during clinical follow-up in order to maintain serum IGF-I in the target range. PATIENTS: Initial effects of GH on bone remodelling during dose titration were studied in 17 patients (8F). Long-term effects of GH were determined in a separate group of 13 GHD adults (6F) over a median period of 58 months (range 44-72). MEASUREMENTS: Osteoblastic activity was estimated by measuring serum bone specific alkaline phosphatase (S-BAP). BMD was determined at both lumbar spine (L2-L4) and femoral neck by dual energy X-ray absorptiometry (DEXA). RESULTS: During dose titration a significant increment in S-BAP was observed by 10 weeks in females but occurred later in males (12-26 weeks). In the long term treatment group there was a significant increment in S-BAP compared to baseline (P = 0.013) after 6 months GH treatment. After long-term GH treatment (median 58 months) S-BAP levels decreased and were no longer statistically significantly different from baseline at the end of the study period. A similar response was observed in male and female patients. There were no significant differences in baseline BMD between male and female patients at either lumbar spine or femoral neck in the long term treatment group. No significant changes were observed in BMD after 6 months GH treatment in either lumbar spine or femoral neck but BMD increased over the remainder of the study at both sites (P = 0.023 and P = 0.03 respectively). When analysed by gender male patients showed a clear positive change in BMD after longer-term replacement in both lumbar spine and femoral neck (P = 0.01 and P = 0.02 respectively) but female patients showed no significant changes. Qualitatively similar results were observed when analysing changes in BMD expressed as Z scores. CONCLUSION: This study demonstrates an earlier onset of GH activation of bone remodelling as reflected by S-BAP in females compared to males and confirms that long-term GH treatment in hypopituitary adults with GH deficiency increases or preserves BMD both at lumbar spine and femoral neck. However male patients seem to derive the greater benefits in BMD from long-term GH replacement; in females BMD appears simply to be stabilized rather than increased. This constitutes a genuine gender difference in susceptibility given that serum IGF-I was in the upper part of the reference range in all subjects.     

Management of Posttraumatic Ankle Arthritis: Literature Review

Purpose of Review

Trauma is the principle cause of osteoarthritis in the ankle, which is associated with significant morbidity. This review highlights the current literature for the purpose of bringing the reader up-to-date on the management of posttraumatic ankle arthritis, describing treatment efficacy, indications, contraindications, and complications.

Recent Findings

Recent studies on osteoarthritis have demonstrated variability among anatomic locations regarding the mechanisms and rates of development for posttraumatic osteoarthritis, which are attributed to newly discovered biological differences intrinsic to each joint. Regarding surgical management of posttraumatic ankle arthritis, osteochondral allograft transplantation of the talus, and supramalleolar osteotomies have demonstrated promising results. Additionally, the outpatient setting was found to be appropriate for managing pain following total ankle arthroplasty, associated with low complication rates and no readmission.

Summary

Management for posttraumatic ankle arthritis is generally progressive. Initial treatment entails nonpharmacologic options with surgery reserved for posttraumatic ankle arthritis refractory to conservative treatment. Patient demographics and lifestyles should be carefully considered when formulating a management strategy, as outcomes are dependent upon the satisfaction of each set of respective criteria. Ultimately, the management of posttraumatic ankle arthritis should be individualized to satisfy the needs and desires, which are specific to each patient.