Lincolnshire Knowledge and Resource Service

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1 Lincolnshire Knowledge and Resource Service This search summary contains the results of a literature search undertaken by the Lincolnshire Knowledge and Resource Service librarians in; June 2014 All of the literature searches we complete are tailored to the specific needs of the individual requester. If you would like this search re-run with a different focus, or updated to accommodate papers published since the search was completed, please let us know. This literature searching service is available to support public health / health and social care commissioning in Lincolnshire. Alison Price Janet Badcock alison.price@lincolnshire.gov.uk janet.badcock@lincolnshire.gov.uk Lincolnshire Knowledge and Resource Service Lexicon House, Stephenson Road North Hykeham, Lincoln LN6 3QU Disclaimer Every effort has been made to ensure that this information is accurate, up-to-date, and complete. However it is possible that it is not representative of the whole body of evidence available. No responsibility can be accepted for any action taken on the basis of this information. It is the responsibility of the requester to determine the accuracy, validity and interpretation of the search results. All links from this resource are provided for information only. A link does not imply endorsement of that site and the Lincolnshire Knowledge and Resource Service does not accept responsibility for the information displayed there, or for the wording, content and accuracy of the information supplied which has been extracted in good faith from reputable sources. Google can bring you back 100,000 answers, a librarian can bring you back the right one. Neil Gaiman

2 Google can bring you back 100,000 answers, a librarian can bring you back the right one. Neil Gaiman

3 Lincolnshire Knowledge and Resource Service Please find below the results of your literature search request. If you would like the full text of any of the abstracts included, or would like a further search completed on this topic, please let us know. Google can bring you back 100,000 answers, a librarian can bring you back the right one. Neil Gaiman Literature Search Results Search request date: 3rd May 2014 Search completion date: 2 nd June 2014 Search completed by: Jan Badcock Enquiry Details The effectiveness/cost-effectiveness of subcutaneous infusion of hydrocortisone in patients with Addison s disease. Disclaimer Every effort has been made to ensure that this information is accurate, up-to-date, and complete. However it is possible that it is not representative of the whole body of evidence available. No responsibility can be accepted for any action taken on the basis of this information. It is the responsibility of the requester to determine the accuracy, validity and interpretation of the search results. All links from this resource are provided for information only. A link does not imply endorsement of that site and the Lincolnshire Knowledge and Resource Service does not accept responsibility for the information displayed there, or for the wording, content and accuracy of the information supplied which has been extracted in good faith from reputable sources.

4 Opening Internet Links The links to internet sites in this document are live and can be opened by holding down the CTRL key on your keyboard while clicking on the web address with your mouse Full Text Papers Links are given to full text resources where available. For some of the papers, you will need a free NHS & Social Care Athens Account. If you do not have an account you can register by following the steps at: You can then access the papers by simply entering your username and password. If you do not have easy access to the internet to gain access, please let us know and we can download the papers for you. Guidance on Searching within Online Documents Links are provided to the full text documents where available. Relevant extracts have been copied and pasted into these Search Results. Rather than browse through a whole documents, you can search for specific words and phrases as follows: Portable Document Format / pdf. / Adobe Click on the Search button (illustrated with binoculars). This will open up a search window. Type in the term you need to find and links to all of the references to that term within the document will be displayed in the window. You can jump to each reference by clicking it. You can search for more terms by pressing search again. Word documents Select Edit from the menu, the Find and type in your term in the search box which is presented. The search function will locate the first use of the term in the document. By pressing next you will jump to further references.

5 Guidelines No guidelines found on subcutaneous hydrocortisone and Addison's disease Research Literature Reviews Current and emerging therapies for Addison's disease Current Opinion in Endocrinology, Diabetes and Obesity, June 2014, vol./is. 21/3( ), X; Napier C.,Pearce S.H.S. Purpose of review: The purpose of this article is to review the current therapy of Addison's disease and to highlight recent developments in this field. Recent findings: Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone; however, new treatment modalities such as modified-released hydrocortisone and continuous subcutaneous hydrocortisone infusion have recently been developed. These offer the potential for closer simulation of the physiological serum cortisol rhythm. Two studies have also looked at modifying the natural history of adrenal failure using adrenocorticotropic hormone (ACTH) stimulation and immunomodulatory therapies, leading to the concept of residual adrenal function in some Addison's disease patients. Summary: Following more than 60 years with no significant innovation in the management of Addison's disease, these new approaches hold promise for improved patient health and better quality of life in the future. Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy Sharon Chan and Miguel Debono Ther Adv Endocrinol Metab Jun;1(3): doi: / SEE BELOW for section on Circadian hydrocortisone infusions Full Text

6 Therapeutic Advances in Endocrinology and Metabolism 1 (3] hydrocortisone, may be associated with a reduction in insulin sensitivity that manifests itself 4-6 h after the cortisol elevation and may persist for more than 16h [Plat et al. 1996]. It is unlikely that patients on low-dose conventional therapy or those on physiological replacement develop steroid-induced diabetes, as very high peaks of cortisol should not occur, but clearly the risk increases with higher doses. Conventional hydrocortisone replacement therapy has made it possible for patients with adrenal insufficiency to live a relatively normal life but it is evident that mortality and morbidity risks are higher than in the normal population. Circadian hydrocortisone therapy : moving to improved replacement The management of patients with adrenal insufficiency should be improved to ameliorate health-related quality of life, improve biochemical control and to reduce long-term adverse effects. Physiological hormone replacement, using sustained formulations of hydrocortisone, should be the safest and most effective and practical solution. Over the past few years interventions introducing circadian cortisol therapy, using hydrocortisone infusions and modifiedrelease oral formulations, have shown that these treatments could potentially imitate physiological cortisol rhythm and hence result in more valuable options for patients with adrenal insufficiency. Circadian hydrocortisone inf usions In two proof-of-concept studies using circadian intravenous and subcutaneous infusions of hydrocortisone, replicating the physiological cortisol circadian rhythm, it was shown that morning ACTH and 170HP levels improved when compared with conventional hydrocortisone therapy [Lovas and Husebye, 2007; Merza et al. 2006] (Figure 3). These data support the notion that delivering physiological hydrocortisone replacement is likely to improve control in these patients. The problem with hydrocortisone infusions are their lack of practicality. An alternative regime is waking to take immediate-release hydrocortisone dose at 03:00, and such an approach resulted in a significant improvement in 170HP, testosterone and individual urinary 17-ketosteroids in five patients with congenital adrenal hyperplasia. This was not achieved by giving doses which were either higher or taken later on in the evening [Moeller, 1985]. Although effective this strategy is not practical as this I ti 150 < , -Infusion -Conventional OW :00 11:00 13:00 15:00 17:00 19:00 21:00 23:00 01:00 03:00 05:00 07:00 Time (hour) Figure 3. Com parison of mea n seru m ACTH levels in Addison's and co ngenital ad renal hy perplasia patient s during conven tional repla cem ent therapy and d u ring ci rca dian inf usion of hydrocortisone (to convert valu es f rom ng/l to pmo Vl x ( Reprodu ced with permissi on f rom John Wiley & Sons Ltd. and Merza et al. [2006)). would mean interrupting patients ' sleep and only extremely cooperative patients would benefit. Further, daytime fatigue may result from sleep fragmentation. A more practical solution is the development of oral modified-relea se formulation s of hydrocortisone. Delayed and sustained rel ease oral formulations of hydrocortisone One approach is a modified-relea se hydrocortisone (MR-HC) tablet that can be taken late at night and then allow a delayed and then sustained release that can then simulate the cortisol circadian rhythm, by allowing a rise in circulating cortisol starting in the early hours of the morning and peaking at approximately 08:00. This consists of an insoluble barrier coat covering all but the upper surface of the tablet, where a layer dissolving slowly retards relea se from an inner drug-containing layer. When giving a once-daily MR-HC at different doses at 22:00 in dexamethasone-suppressed individuals, the 24-h cortisol profile at this once-daily dose showed an earlier peak level at 06:00 compared with the physiological peak at 08:32, and only maintained a physiological cortisol level for less than 12h (Figure 4). By. pharmacokinetic modelling we showed that ta,king 15-20mg of MR-HC at 23:00 and 10mg at 07:00 the drug could potentially reproduce physiological circadian cortisol levels [Debono et al. 2009] over 24 h. 134 h ttp://tae.sagepub.com

7 Replacement therapy for Addison's disease: recent developments. Lovas K, Husebye ES Expert Opinion on Investigational Drugs, April 2008, vol./is. 17/4( ), ; BACKGROUND: The hormone deficiencies in Addison's disease (primary adrenal insufficiency) are conventionally treated with oral glucocorticoid and mineralocorticoid replacement but the available therapies do not restore the physiological hormone levels and biorhythm. Despite such treatment these patients self-report impaired health-related quality of life (HRQoL) and recent research has indicated increased mortality. OBJECTIVE/METHODS: We review the literature and recent developments in replacement therapy. RESULTS/CONCLUSION: Patients with Addison's disease require mineralocorticoid replacement, i.e., fludrocortisone mg once daily. Starting doses of glucocorticoids should be mg for hydrocortisone or mg for cortisone acetate, divided into two or three doses, and preferentially weight-adjusted. There are indications that the synthetic glucocorticoids have undesirable metabolic long-term effects, which make them less suitable as first-line treatment. Timed-release hydrocortisone tablets and continuous subcutaneous hydrocortisone infusion are promising new treatment modalities. Studies of replacement with the adrenal androgen dehydroepiandrosterone (DHEA) in adrenal failure have shown inconsistent benefit on HRQoL. DHEA, or possibly testosterone replacement is likely to be beneficial for selected groups of patients with Addison's disease but this remains to be shown. We here give our opinion of the best treatment and future direction of research in this area. Randomised Controlled Trials Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of Addison's disease: A randomized clinical trial. Oksnes M, et al. J Clin Endocrinol Metab May;99(5): CONTEXT: Conventional glucocorticoid replacement therapy fails to mimic the physiological cortisol rhythm, which may have implications for morbidity and mortality in patients with Addison's disease. Objective: The objective of the study was to compare the effects of continuous sc hydrocortisone infusion (CSHI) with conventional oral hydrocortisone (OHC) replacement therapy. Design, Patients, and Interventions: This was a prospective crossover, randomized, multicenter clinical trial comparing 3 months of treatment with thrice-daily OHC vs CSHI. From Norway and Sweden, 33 patients were enrolled from registries and clinics. All patients were assessed at baseline and after 8 and 12 weeks in each treatment arm. Main Outcome Measures: The morning ACTH level was the primary outcome measure. Secondary outcome measures were effects on metabolism, health-related quality of life (HRQoL), sleep, and safety. Results: CSHI yielded normalization of morning ACTH and cortisol levels, and 24-hour salivary cortisol curves resembled the normal circadian variation. Urinary concentrations of glucocorticoid metabolites displayed a normal pattern with CSHI but were clearly altered with OHC. Several HRQoL indices in the vitality domain improved over time with CSHI. No benefit was found for either treatments for any subjective (Pittsburgh Sleep Quality Index questionnaire) or objective (actigraphy) sleep parameters. CONCLUSION: CSHI safely brought ACTH and cortisol toward normal circadian levels without adversely affecting glucocorticoid metabolism in the way that OHC did. Positive effects on HRQoL were noted with CSHI, indicating that physiological glucocorticoid replacement therapy may be beneficial and that CSHI might become a treatment option for patients poorly controlled on conventional therapy.

8 Other Research Subcutaneous hydrocortisone administration for emergency use in adrenal insufficiency. Hahner S, Burger-Stritt S, Allolio B. Eur J Endocrinol Jun 29;169(2): OBJECTIVE: Evaluation of the pharmacokinetics and safety of s.c. hydrocortisone injection for use in adrenal emergency. DESIGN: Single-center, open-label, sequence-randomized, crossover study in a tertiary care center. PATIENTS AND METHODS: Twelve patients with chronic Addison's disease. Comparison of hydrocortisone pharmacokinetics after s.c. and i.m. injection (100 mg) and after s.c. administration of sodium chloride (0.9%) respectively at three different visits. MAIN OUTCOME MEASURE: maximum serum cortisol (Cmax), time to Cmax (tmax), and time to serum cortisol >36 μg/dl (tserum cortisol >36 μg/dl) after s.c. administration compared with i.m. administration, safety, and patient preference. RESULTS: Serum cortisol increased rapidly and substantially after both i.m. and s.c. injections (Cmax: 110±29 vs 97±28 μg/dl, P=0.27, tmax: 66±51 vs 91±34 min, P=0.17, and tserum cortisol >36 μg/dl: 11±5 vs 22±11 min, P=0.004 respectively). Both i.m. and s.c. injections were well tolerated. Eleven (91.7%) patients preferred s.c. injection, whereas one patient did not have any preference. CONCLUSIONS: S.c. administration of 100 mg hydrocortisone shows excellent pharmacokinetics for emergency use with only a short delay in cortisol increase compared with i.m. injection. It has a good safety profile and is preferred by patients over i.m. injection.

9 Pharmacokinetics of hydrocortisone after subcutaneous administration in chronic adrenal insufficiency (PHYSCA) This study has been completed. Sponsor: Bruno Allolio Information provided by (Responsible Party): Bruno Allolio, University of Wuerzburg ClinicalTrials.gov Identifier: NCT First received: September 29, 2011 Last updated: July 31, 2012 Last verified: July 2012 Purpose Patients with chronic adrenal insufficiency need to adapt their hydrocortisone replacement dose in conditions of physical or psychological stress to prevent life threatening adrenal crisis. In cases of more severe impairment or unsecure gastrointestinal absorption (e.g. gastroenteritis, severe infectious disease), parenteral administration of the hydrocortisone dose is crucial. The study is conducted to offer patients the possibility to perform hydrocortisone self administration in emergency situations in a way of administration which is easy to perform and accepted by the patient. Therefore, pharmacokinetics and safety of subcutaneous hydrocortisone administration will be studied and compared to intramuscular administration. Condition Intervention Phase Primary Adrenal Insufficiency Drug: Hydrocortisone intramuscular first Drug: Hydrocortisone subcutaneously first Phase 2 Study Type: Interventional Study Design: Allocation: Randomized Endpoint Classification: Bio-equivalence Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment

10 Modified-release hydrocortisone to provide circadian cortisol profiles Miguel Debono, Cyrus Ghobadi, Amin Rostami-Hodjegan, Hiep Huatan, Michael J. Campbell, John Newell-Price, Ken Darzy, Deborah P. Merke, Wiebke Arlt, and Richard J. Ross J Clin Endocrinol Metab. May 2009; 94(5): CONTEXT: Cortisol has a distinct circadian rhythm regulated by the brain s central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. OBJECTIVES: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. SETTING: The study was performed at a Clinical Research Facility. DESIGN AND METHODS: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an openlabel, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. RESULTS: The key variables in the physiological cortisol profile included: peak 15.5 μg/dl (95% reference range ), acrophase 0832 h (95% confidence interval ), nadir less than 2 μg/dl (95% reference range ), time of nadir 0018 h (95% confidence interval ), and quiescent phase (below the mesor) h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) μg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediaterelease hydrocortisone. Modeling suggested that MR-HC mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. CONCLUSION: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. Continuous subcutaneous hydrocortisone infusion in Addison's disease. Lovas K, Husebye ES European Journal of Endocrinology, July 2007, vol./is. 157/1(109-12), ; (2007 Jul) OBJECTIVE: The conventional replacement therapy in Addison's disease (AD) does not restore the normal diurnal cortisol rhythm. We explored the feasibility and safety of continuous s.c. hydrocortisone infusion (CSHI) as a novel mode of glucocorticoid replacement therapy. DESIGN AND METHODS: Seven patients with AD were treated with CSHI in an open-labelled clinical study for up to three months. Adequacy of glucocorticoid replacement was assessed by 24 h blood and saliva sampling in one patient and by salivary cortisol day curves in six outpatients. Subjective health status was monitored by the Short Form-36 questionnaire. RESULTS: CSHI re-established the circadian variation and normal levels of cortisol in the patients, with minor day-to-day variation. Most of the patients could reduce their glucocorticoid dose considerably without adverse reactions. The treatment was well tolerated and positively evaluated by the patients. CONCLUSIONS: CSHI is technically feasible and safe in patients with AD. A daily dose of approximately 10 mg/m(2) body surface area/day restores the circadian variation and normal levels of salivary cortisol in most patients, which is close to the estimated daily requirement. We hypothesise that selected patients will benefit from restoration of the circadian cortisol rhythm. Source: Medline Available in fulltext from European Journal of Endocrinology at Highwire Press

11 Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study. Samuels MH Journal of Clinical Endocrinology & Metabolism, April 2000, vol./is. 85/4( ), X; X Although pharmacological doses of glucocorticoids suppress TSH secretion, less is known regarding the effects of physiological variations in cortisol levels on TSH. To study this issue, seven subjects with primary adrenal insufficiency each underwent four studies. In the first study subjects received infusions of saline for 48 h (baseline study). In the second study subjects received infusions of hydrocortisone for 48 h in a pulsatile and diurnal pattern that replicated serum cortisol levels in healthy subjects (physiological study). In most cases, the dose of hydrocortisone was 19 mg/24 h, but this was adjusted as necessary until the resulting serum cortisol levels reproduced those seen in healthy, nonstressed control subjects. In the third study subjects received the same total dose of hydrocortisone as in the physiological study, but with pulses of equal magnitude spaced evenly throughout the time period (constant study). In the fourth study subjects received the same total dose of hydrocortisone, but with the diurnal pattern shifted 12 h from the physiological infusion (reversed study). TSH levels were measured every 15 min during the final 24 h of each study. During the baseline study, the 24-h mean TSH level was / mu/l and did not exhibit any diurnal variation. During the physiological study, daytime TSH levels decreased 39% compared to those during the baseline study due to decreased TSH pulse amplitude, and the normal TSH diurnal rhythm was reestablished. The constant and reversed studies did not lead to significant changes in serum TSH levels compared to baseline. These results suggest that the normal circadian variation in endogenous cortisol levels may control TSH secretion, with maximal TSH suppression seen during the time when cortisol levels are highest. However, changing the diurnal pattern of hydrocortisone infusion did not lead to reciprocal changes in TSH levels, and the specific nature of the interactions between cortisol and TSH within the physiological range remains to be fully elucidated.

12 Ongoing and/or Proposed Trials Ultradian subcutaneous hydrocortisone infusion in Addison disease This study is not yet open for participant recruitment. (see Contacts and Locations) Verified March 2014 by Haukeland University Hospital Sponsor: Haukeland University Hospital Information provided by (Responsible Party): Haukeland University Hospital ClinicalTrials.gov Identifier: NCT First received: November 28, 2013 Last updated: March 24, 2014 Last verified: March 2014 Purpose The aim of this study is to compare the effects of tablet treatment, circadian and combined circadian and ultradian subcutaneous hydrocortisone infusion on steroid metabolism and tissue responses to therapy. Condition Intervention Phase Addison Disease Drug: Solu-Cortef Drug: Cortef Phase 1 Phase 2 Study Type: Study Design: Interventional Allocation: Non-Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment Official Title: Ultradian Subcutaneous Hydrocortisone Infusion in Addison Disease Detailed Description: The conventional glucocorticoid replacement therapy in primary adrenal insufficiency (Addison's disease) renders the cortisol levels unphysiological, which may cause symptoms and long-term complications. This therapeutical approach does not enable to restore physiological circadian and ultradian rhythm of glucocorticoids. Current studies conclude that constant or unphysiological administration of glucocorticoids leads to abnormal gene transcription and causes sides effect of glucocorticoids treatment and long standing complications Glucocorticoid replacement is technically feasible by continuous subcutaneous hydrocortisone infusion, which can mimic not only the normal diurnal cortisol rhythm, but potentially also the ultradian cadence. This is a pilot trial with an open cross-over design of 3 x minimum 2 weeks in 10 patients comparing the effects of tablet treatment versus continuous subcutaneous hydrocortisone infusion versus ultradian subcutaneous hydrocortisone infusion on serum, salivary, tissue hormonal response and glucocorticoid related gene expression.

13 Eligibility Ages Eligible for Study: 18 Years to 65 Years Genders Eligible for Study: Both Accepts Healthy Volunteers: No Criteria Inclusion Criteria: 1. clinical diagnosis of primary adrenal insufficiency 2. Written informed consent Exclusion Criteria:. 1. Diabetes mellitus 2. Severe cardiovascular disease 3. Active malignant disease 4. Pregnancy or breast feeding 5. treatment with interfering drugs 6. Intake of grapefruit juice Continuous subcutaneous hydrocortisone infusion in Addison`s disease and Type 1 diabetes This study is currently recruiting participants. (see Contacts and Locations) Verified November 2013 by Haukeland University Hospital Sponsor: Haukeland University Hospital Information provided by (Responsible Party): Haukeland University Hospital ClinicalTrials.gov Identifier: NCT First received: April 23, 2013 Last updated: November 29, 2013 Last verified: November 2013 Purpose The conventional glucocorticoid replacement therapy in primary adrenal insufficiency (Addison's disease) renders the cortisol levels unphysiological, which may cause symptoms and long-term complications. The majority of Addison's patients have other organ-specific autoimmune disease, which poses challenges to the replacement therapy. Of particular interest is the combination of Addison`s disease and type 1 diabetes, since cortisol affects glucose homeostasis. The clinical experience is that this subgroup of patients is difficult to treat, but very little research has been done to understand and improve their situation. Glucocorticoid replacement is technically feasible by continuous subcutaneous hydrocortisone infusion, and can mimic the normal diurnal cortisol rhythm. This pilot study aims to further evaluate continuous subcutaneous hydrocortisone infusion treatment in terms of metabolic effects especially glycemic control in patients with the combination of Addison`s disease and type 1 diabetes in an 5 months cross-over design open clinical pilot study.

14 Condition Intervention Phase Addison Disease Type 1 Diabetes Other: Cortef Other: Solu-cortef Phase 2 Study Type: Study Design: Official Title: Interventional Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment Continuous Subcutaneous Hydrocortisone Infusion In Addison`s Disease and Type 1 Diabetes