No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Safe and effective use of lithium
Abstract
Lithium has proven efficacy in the treatment of bipolar disorder, both for acute mania and long-term mood stabilisation and prophylaxis. It is also useful in combating treatment-resistant depression. Compared to other mood stabilisers, lithium has a favourable efficacy-tolerability balance. Lithium is underused due to active marketing of alternatives and concerns regarding adverse effects, tolerability, and the perception that regular monitoring is difficult.
... Lithium is of proven efficacy in the treatment of bipolar disorder showing benefit in both the manic phase and the depressive phase. It is also effective in the prophylaxis of the condition [1][2]. ...
... Trough concentrations of lithium are recommended to be measured typically 12 hours post dosing. Serum lithium concentrations are affected by coadministered drugs such as carbamazepine and are also affected by changes in renal function [1][2]. Adverse effects are observed at the therapeutic range, as well as when the serum concentrations exceed the therapeutic range in a dose dependent manner [1]. ...
... Serum lithium concentrations are affected by coadministered drugs such as carbamazepine and are also affected by changes in renal function [1][2]. Adverse effects are observed at the therapeutic range, as well as when the serum concentrations exceed the therapeutic range in a dose dependent manner [1]. ...
... Interestingly, bipolar patients display abnormally high intracellular Ca 2+ levels and membrane-bound PKC activity. [8][9][10][11] Previous studies have shown that Li + , at therapeutic concentrations (0.6-1.2 Â 10 À3 M), 12 can interact with conventional PKCs, whereas larger monovalent cations such as Rb + and Cs + cannot, even at elevated concentrations of 8 mM. 13 They have also shown that long-term Li + treatment attenuated translocation of cytosolic PKC to the membrane, mitigating PKC hyperactivity. [9][10][11][13][14][15][16][17][18][19][20] Recently, we showed that, despite differences in the properties of monovalent Li + and divalent Ca 2+ (see Table 1), Li + may displace the native Ca 2+ from the monocationic trinuclear Ca 2+ -site of the PKCa/g C2 domain, but not if the trinuclear Ca 2+ -site has net zero charge. ...
... [9][10][11][13][14][15][16][17][18][19][20] Recently, we showed that, despite differences in the properties of monovalent Li + and divalent Ca 2+ (see Table 1), Li + may displace the native Ca 2+ from the monocationic trinuclear Ca 2+ -site of the PKCa/g C2 domain, but not if the trinuclear Ca 2+ -site has net zero charge. 21,22 The higher therapeutic concentration of Li + (0.6-1.2 Â 10 À3 M) 12 compared to the intracellular concentration of Ca 2+ (B10 À8 -10 À5 M) could also help Li + to displace Ca 2+ . Upon Ca 2+ -Li + substitution, the change in coordination geometry and overall charge of the Ca 2+ -site would attenuate interactions of the C2 domain with the membrane, and reduce the abnormally high membrane-associated PKCa/g levels, consistent with the aforementioned experimental findings. ...
Because Li+ and Ca2+ differ in both charge and size, the possibility that monovalent Li+ could dislodge the bulkier, divalent Ca2+ in Ca2+ proteins had not been considered. However, our recent density functional theory/continuum dielectric calculations predicted that Li+ could displace the native Ca2+ from the C2 domain of cytosolic PKCα/γ. This would reduce electrostatic interactions between the Li+-bound C2 domain and the membrane, consistent with experimental studies showing that Li+ can inhibit the translocation of cytoplasmic PKC to membranes. Besides the trinuclear Ca2+-site in the PKCα/γ C2 domain, it is not known whether other Ca2+-sites in human proteins may be susceptible to Li+ substitution. Furthermore, it is unclear what factors determine the outcome of the competition between divalent Ca2+ and monovalent Li+. Here we show that the net charge of residues in the first and second coordination shell is a key determinant of the selectivity for divalent Ca2+ over monovalent Li+ in proteins: neutral/anionic Ca2+-carboxylate sites are protected against Li+ attack. They are further protected by outer-shell Asp-/Glu- and the protein matrix rigidifying the Ca2+-site or limiting water entry. In contrast, buried, cationic Ca2+-sites surrounded by Arg+/Lys+, which are found in the C2 domains of PKCα/γ, as well as certain synaptotagmins, are prone to Li+ attack.
... Those on lithium therapy require regular therapeutic drug monitoring as lithium has a narrow therapeutic index. Such monitoring minimizes lithium toxicity and can be used to assess adherence to medication [11]. Long-term treatment with lithium is associated with occurrence of renal side effects such as chronic kidney disease and renal failure. ...
... Monitoring of patients is an essential component of treating BD to ensure medication safety, adherence to therapy and adequate control of the disease [11]. In this study, which assessed the safety monitoring of patients with BD, the lithium concentrations were measured in the past 6 months in less than half of patients and in one-year in 59%. ...
Abstract Background Safety monitoring of medicines is essential during therapy for bipolar disorder (BD). We determined the extent of safety monitoring performed according to the International Society for Bipolar Disorders (ISBD) guidelines in patients with BD attending the main tertiary care psychiatry clinics in Sri Lanka to give realistic recommendations for safety monitoring in resource limited settings. Methods Patients diagnosed with BD on mood stabilizer medications for more than 1 year were recruited. Data were collected retrospectively from clinic and patient held records and compared with the standards of care recommended by ISBD guidelines for safety monitoring of medicines. Results Out of 256 patients diagnosed with BD, 164 (64.1%) were on lithium. Only 75 (45.7%) had serum lithium measurements done in the past 6 months and 96 (58.5%) had concentrations recorded at least once in the past year. Blood urea or creatinine was measured in the last 6 months only in 30 (18.3%). Serum electrolytes and thyroid-stimulating hormone (TSH) concentrations were measured in the last year only in 34 (20.7%) and 30 (18.3%) respectively. Calcium concentrations were not recorded in any patient. None of the patients on sodium valproate (n = 119) or carbamazepine (n = 6) had blood levels recorded to establish therapeutic concentrations. Atypical antipsychotics were prescribed for 151 (59%), but only 13 (8.6%) had lipid profiles and only 31 (20.5%) had blood glucose concentration measured annually. Comorbidities experienced by patients influenced monitoring more than the medicines used. Patients with diabetes, hypothyroidism and hypercholesterolemia were more likely to get monitored for fasting blood glucose and (p
... ).Nebenwirkungen betreffend Stoffwechsel-und Organfunktionen (die Bestimmung von Elektrolyten einschliesslich Calcium, Harnsäure, Kreatinin, TSH und weiteren Parametern; vgl.Malhi et al. 2013;Nederlof et al. 2018). Neben obligatorischen Indikationen aus Gründen der Arzneimittelsicherheit (wie in den beispielhaften Fällen von Lithium und Carbamazepin) halten die aus der Schweiz, Österreich, Südtirol und Deutschland kommenden Autoren der aktuellen «Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017» ein TDM auch für Psychopharmaka mit einem «hohen Empfehlungsgrad» (Tab. ...
Zusammenfassung
In der Gesamtbetrachtung zeichnet sich das Gesundheitssystem der Schweiz im internationalen Vergleich gleichermassen durch seine grosse Leistungsfähigkeit ( pars pro toto : die Lebenserwartung der Schweizer wird nur von derjenigen der Japaner übertroffen) wie durch seine hohen Kosten aus.
Vor dem Hintergrund steigender Ansprüche an den Nachweis der Wirksamkeit und der Wirtschaftlichkeit medizinischer Massnahmen ist es das Ziel der vorliegenden Arbeit, den Nutzen der Laboratoriumsmedizin aus patientenbezogener und gesellschaftlicher Perspektive anhand exemplarischer Testverfahren zu dokumentieren.
... ).Nebenwirkungen betreffend Stoffwechsel-und Organfunktionen (die Bestimmung von Elektrolyten einschliesslich Calcium, Harnsäure, Kreatinin, TSH und weiteren Parametern; vgl.Malhi et al. 2013;Nederlof et al. 2018). Neben obligatorischen Indikationen aus Gründen der Arzneimittelsicherheit (wie in den beispielhaften Fällen von Lithium und Carbamazepin) halten die aus der Schweiz, Österreich, Südtirol und Deutschland kommenden Autoren der aktuellen «Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017» ein TDM auch für Psychopharmaka mit einem «hohen Empfehlungsgrad» (Tab. ...
Die Studie untersucht den gegenwärtigen und zukünftig zu erwartenden Nutzen von Laboranalysen aus der Perspektive von Patientinnen und Patienten und der Gesellschaft. Nach Expertenmeinung gilt die Labormedizin als ausschlaggebend für etwa 70 Prozent aller klinischen Entscheidungen; sie wird jedoch hinsichtlich ihrer Kosten und des Kosten-Nutzen-Verhältnisses diagnostischer Verfahren kritisch betrachtet.
Die Autoren publizieren mit diesem Buch eine wissenschaftliche Untersuchung, die für die Schweiz massgebliche Krankheitsbilder identifiziert und innerhalb dieser Gruppen die Bedeutung der Labordiagnostik anhand exemplarischer Analysen und Tests explizit herausstellt. Darüber hinaus werden die Zukunftspotenziale der Labormedizin eingehend beleuchtet.
... 6 Because of these limitations, lithium blood levels need to be monitored regularly in patients treated with lithium to ensure optimum efficacy and adequate tolerability. 7 This is currently done through trimonthly attendance to clinics, where a blood sample is taken and sent to the laboratory for analysis using the standard technique of flame emission photometry (FEP). Nevertheless, levels of treatment nonadherence are high and the quality of contemporary lithium monitoring falls short of NICE guidelines. ...
Bipolar disorder (BD) is a common mental health condition, characterized by extreme changes in mood, energy, and behavior. BD is often managed through mood-stabilizing medications, of which lithium formulations remain the most reliable and effective at reducing the risk of suicide. To achieve adequate and consistent efficacy, lithium concentrations need to be maintained within a narrow therapeutic range (0.4 to 1.2 mmol / L). Because of its narrow therapeutic index, long-term lithium therapy is associated with serious side effects and risks of toxicity. It is believed that the availability of a personal blood lithium analyzer would benefit patients who are on lithium treatment. We detail the results of a spectrophotometric method performed on ultramicro volumes to determine blood plasma lithium concentrations as compared with reference measurements of flame photometry, and validated in samples of unknown lithium content. Applying multiple linear regression, lithium concentrations could be determined in a rapid manner using full-range spectra or triwavelength data. Both techniques highly correlated with reference standards and could predict lithium levels accurately (R2 = 0.794214 and RMSEP = 0.209584, and R2 = 0.863921 and RMSEP = 0.167524, respectively). Therefore, this method can be a useful for rapid assessment of blood lithium in nonlaboratory settings i.e., general practices, hospital clinics, and community health centers by healthcare professionals and/or by patients. Future work will now focus on completion of a miniaturized and integrated system that will deliver a portable and personal lithium-monitoring device.
... Proponents of lithium have argued that the pattern of underutilizing lithium (despite its proven efficacy in the treatment of bipolar disorder) may be due in part to the abundance of marketing efforts for newer FDA-approved drugs, combined with concerns regarding adverse effects, tolerability, and the perception that regular toxicity monitoring is difficult. 11,12 Indeed, a recent analysis of VA administrative data for Veterans diagnosed with bipolar disorder from 2003 to 2010 demonstrated that second-generation antipsychotics have supplanted lithium, valproate, and carbamazepine/oxcarbazepine as frontline antimanic treatment for bipolar disorder. 9 The second goal was to see whether psychiatrists would be supportive of randomizing their patients to lithium or placebo and endorse the study design. ...
Background: The estimation of an effect size is an important step in designing an adequately powered, feasible clinical trial intended to change clinical practice. During the planning phase of VA Cooperative Study #590, “Double-Blind Placebo-Controlled Study of Lithium for Preventing Repeated Suicidal Self-Directed Violence in Patients with Depression or Bipolar Disorder (Li+),” it was not clear what effect size would be considered large enough to influence prescribing behavior among practicing clinicians.
Methods: We conducted an online survey of VA psychiatrists to assess their interest in the study question, their clinical experience with lithium, and their opinion about what suicide reduction rate would change their prescribing habits. The 9-item survey was hosted on SurveyMonkey© and VA psychiatrists were individually emailed an invitation to complete an anonymous online survey. Three email waves were sent over three weeks.
Results: Overall, 862 of 2713 VA psychiatrists (response rate = 31.8%) responded to the anonymous survey. 74% of the respondents would refer a patient to the proposed trial, 9% would not, and 17% were unsure. Presented with suicide reduction rates in 10% increments ranging from 10 to 100%, 61% of respondents indicated that they would use lithium if suicide attempts were reduced by at least 40%; 83% would use lithium if it reduced attempts by at least 50%.
Conclusions: Even with the limitations of response bias and the reliability of responses on future prescribing behavior, a survey of potential users of a clinical trial's results offers a convenient, empirical method for determining and justifying clinically relevant effect sizes.
... Lithium has been used to treat bipolar disorders for over sixty years as it acts as ant suicidal and neuroprotective drug (Malhi et al. 2013). Although it is well tolerated among the bipolar disorder patients, in recent years, the use of lithium seems to be diminished. ...
Background:
Lithium has been the gold standard in treating bipolar disorder. In recent years, the use of lithium seems to be diminished although it is well tolerated among the bipolar disorder patients.
Subjects and methods:
This study aimed to evaluate the efficacy and tolerability of lithium as well as to determine factors associated with lithium response among patient with bipolar disorder. A retrospective study was done in a tertiary care hospital in Malaysia which included 47 bipolar disorder patients that were prescribed with lithium maintenance therapy in the time frame of January 2009 until December 2013.
Results:
Of all the baseline characteristics tested, only psychotic feature differentiated lithium monotherapy group and combination therapy group significantly (χ(2)=4.732, p=0.03). When compared to period before lithium maintenance, all outcome measures (i.e. annual relapse rate, proportion time spent ill and duration of mood episode) showed significant improvement after lithium maintenance in both treatment groups. Lithium discontinuation only occurred in five cases of adverse effects. Predominant depressive mood episode before lithium maintenance (OR=0.159, p=0.033) and first euthymic interval after lithium maintenance (OR=1.109, p=0.047) significantly predicted lithium response.
Discussion:
Lithium significantly reduced the frequency and time spent in relapse in patients with bipolar disorder. Predominant depressive mood polarity before lithium maintenance and longer first euthymic interval after lithium maintenance had been identified to predict lithium response significantly.
... We suggest that renal function (based on estimated GFR derived from serum creatinine levels, and proteinuria tests) and serum lithium levels should be monitored more frequently than 6 months, and certainly more than every 12 months, which some authors have suggested. 18 This is most important for patients who have received lithium for many years. Clinicians should consider stopping lithium and using other suitable mood stabilisers (eg, sodium valproate 19 ) if two consecutive readings suggest decreasing renal function, or if the estimated GFR is < 45 mL/min/1.73 ...
... Lithium does not occur free in nature and is far from being abundant but it is one of the most effective drugs for the treatment of bipolar disorders. It also exerts profound effect on the development of diverse organisms from cellular slime moulds to human beings ( Hill et al. 2013;Kao and Elinson 1998;Malhi et al. 2013;Quiroz et al. 2004). It disrupts cell fate in Dictyostelium ( Peters et al. 1989;Van Lookeren Campagne et al. 1988), causes vegetalization in sea urchin eggs ( Livingston and Wilt 1990;Nocente-McGrath et al. 1991;Ransick et al. 1993;Wikramanayake and Klein 1997), brings about expansion of the dorsal mesoderm leading to duplication of dorsal axis in Xenopus and zebrafish (Cooke and Smith 1988;Driever 1995;Elinson 1989, 1998;Kao et al. 1986;Schneider et al. 1996;Stachel et al. 1993) and deregulates patterning in the regenerates of Hydra (Jantzen et al. 1998 teratogenesis in mammals (Nokhbatolfoghahai and Parivar 2008;Tandon et al. 2006;Tsaltas et al. 2007). ...
... This monitoring is necessary because of the high risks of toxicity associated with lithium therapy. Lithium is reasonably infamous for causing loss of glomerular function (Thomsen and Shirley, 2006;Malhi et al., 2013). Other dysfunctions caused in the body following lithium therapy include are listed in Table 2. (Muller-Oerlinghausen et al., 2012;Kibirige et al., 2013;Wright and Salehian, 2010;Edokpolo and Fyyaz, 2012;Netto and Phutane, 2012) This review will now focus only on the nephrotoxic effects caused by prolonged lithium therapy. ...
... We suggest that renal function (based on estimated GFR derived from serum creatinine levels, and proteinuria tests) and serum lithium levels should be monitored more frequently than 6 months, and certainly more than every 12 months, which some authors have suggested. 18 This is most important for patients who have received lithium for many years. Clinicians should consider stopping lithium and using other suitable mood stabilisers (eg, sodium valproate 19 ) if two consecutive readings suggest decreasing renal function, or if the estimated GFR is < 45 mL/min/1.73 ...
To analyse the annual incidence of end-stage renal disease (ESRD) associated with lithium-induced nephropathy (LiN) in Australia.
Retrospective cohort study of patients commencing renal replacement therapy (RRT) in Australia. We compared patients with LiN with all other RRT patients between 1 January 1991 and 31 December 2011, using Australia and New Zealand Dialysis and Transplant Registry data.
Numbers and characteristics of incident RRT patients, primary kidney disease (LiN or other, based on clinical diagnosis).
LiN contributed to 187 people in Australia commencing RRT between 1 January 1991 and 31 December 2011. The incidence rate increased from 0.14 cases/million population/year (95% CI, 0.06-0.22) in 1992-1996 to 0.78 (95% CI, 0.67-0.90) in 2007-2011. This increase is unlikely to be attributed solely to demographic changes in Australia. LiN patients were more likely than non-LiN patients to be women, to be white, to smoke, and to have a higher body mass index, but were less likely to have undergone renal biopsy.
Rates of ESRD attributed to LiN are increasing rapidly. Currently accepted lithium dosages and duration of treatment might induce ESRD in a large cohort of patients. We encourage clinicians to exercise discretion when prescribing lithium, check renal function regularly, stop lithium if there is a deterioration in two consecutive readings, and consider substitution with other drugs.
Zusammenfassung
Für jede der anhand der von ihnen verursachten Krankheitslast ausgewählten Krankheitsgruppen wird anhand mindestens eines Testverfahrens die Datenlage zum patientenbezogenen und gesellschaftlichen Nutzen der Laboratoriumsmedizin evaluiert. Der Beitrag der modernen Labormedizin erweist sich dabei in allen untersuchten Krankheitsgruppen als medizinisch „nutzenstiftend“ und vielfach sogar als unverzichtbar. Beispielhaft zu nennen sind der Einsatz prädiktiver Biomarker als Voraussetzung einer gezielten Krebstherapie, von Tests auf Anti-CCP-Antikörper beziehungsweise hochsensitives kardiales Troponin zur frühen Diagnose der rheumatoiden Arthritis bzw. des akuten Herzinfarkts, aber auch TSH-Tests für eine adäquate kausale Therapie von depressiven Störungen auf dem Boden einer Hypothyreose und therapeutisches Drug-Monitoring in der Neuropsychiatrie und darüber hinaus; schliesslich Erregerdiagnostik und Resistenzbestimmungen in der Infektiologie. Die untersuchten Tests erweisen sich zudem durchweg als kosteneffektiv.
Lithium is the smallest monovalent cation with many different biological effects. Although lithium is present in the pharmacotherapy of psychiatric illnesses for decades, its precise mechanism of action is still not clarified. Today lithium represents first-line therapy for bipolar disorders (because it possesses both antimanic and antidepressant properties) and the adjunctive treatment for major depression (due to its antisuicidal effects). Beside, lithium showed some protective effects in neurological diseases including acute neural injury, chronic degenerative conditions, Alzheimer's disease as well as in treating leucopenia, hepatitis and some renal diseases. Recent evidence suggested that lithium also possesses some anticancer properties due to its inhibition of Glycogen Synthase Kinase 3 beta (GSK3β) which is included in the regulation of a lot of important cellular processes such as: glycogen metabolism, inflammation, immunomodulation, apoptosis, tissue injury, regeneration etc.
Although recent evidence suggested a potential utility of lithium in different conditions, its broader use in clinical practice still trails. The reason for this is a narrow therapeutic index of lithium, numerous toxic effects in various organ systems and some clinically relevant interactions with other drugs. Additionally, it is necessary to perform more preclinical as well as clinical studies in order to a precise therapeutic range of lithium, as well as its detailed mechanism of action. The aim of this review is to summarize the current knowledge concerning the pharmacological and toxicological effects of lithium.
Epidemiological evidence suggests that people with bipolar disorder prescribed lithium exhibit a lower risk of Alzheimer's disease (AD) relative to those prescribed other mood-stabilizing medicines. Lithium chloride (LiCl) reduces brain β-amyloid (Aβ) levels, and the brain clearance of Aβ is reduced in AD. Therefore, the purpose of this study was to assess whether the cognitive benefits of LiCl are associated with enhanced brain clearance of exogenously-administered Aβ. The brain clearance of intracerebroventricularly (icv) administered125I-Aβ42was assessed in male Swiss outbred mice administered daily oral NaCl or LiCl (300 mg/kg for 21 days). LiCl exhibited a 31% increase in the brain clearance of125I-Aβ42over 10 min, which was associated with a 1.6-fold increase in brain microvascular expression of the blood-brain barrier efflux transporter low density lipoprotein receptor-related protein 1 (LRP1) and increased cerebrospinal fluid (CSF) bulk-flow. 8-month-old female wild type (WT) and APP/PS1 mice were also administered daily NaCl or LiCl for 21 days, which was followed by cognitive assessment by novel object recognition and water maze, and measurement of soluble Aβ42, plaque-associated Aβ42, and brain efflux of125I-Aβ42. LiCl treatment restored the long-term spatial memory deficit observed in APP/PS1 mice as assessed by the water maze (back to similar levels of escape latency as WT mice), but the short-term memory deficit remained unaffected by LiCl treatment. While LiCl did not affect plaque-associated Aβ42, soluble Aβ42levels were reduced by 49.9% in APP/PS1 mice receiving LiCl. The brain clearance of125I-Aβ42decreased by 27.8 % in APP/PS1 mice, relative to WT mice, however, LiCl treatment restored brain125I-Aβ42clearance in APP/PS1 mice to a rate similar to that observed in WT mice. These findings suggest that the cognitive benefits and brain Aβ42lowering effects of LiCl are associated with enhanced brain clearance of Aβ42, possibly via brain microvascular LRP1 upregulation and increased CSF bulk-flow, identifying a novel mechanism of protection by LiCl in the treatment of AD.
Background
Despite lithium being a highly effective drug, it is commonly associated with inducing nephrogenic diabetes insipidus (NDI) in a high number of patients. In this case report we describe the successful use of amiloride as an effective means to manage and minimise NDI occurring in patients while they are on lithium therapy.
Clinical details
The patient had been taking lithium for management of her bipolar disorder for approximately 5 years. While on this medication the patient suffered from acute kidney impairment, hypernatraemia, reduced urine osmolality, increased plasma osmolality, polyuria, polydipsia and severe dehydration. These clinical results were consistent with an adverse reaction known as NDI acquired from long‐term lithium use and fluid restriction.
Outcomes
Lithium was ceased on day two of admission. Intravenous fluid replacements were provided until the patient's renal function and sodium levels returned to normal. Once the patient was symptomatically stable, lithium was reintroduced at initiating dosage levels concomitantly with amiloride with aims of reversing the concentrating defect and preventing this side effect from occurring again. The patient was discharged 15 days later.
Conclusion
In most cases NDI is reversible with the cessation of lithium. However, a subset of the mental health population is resistant to other forms of therapy, leaving lithium as their only option to successfully manage their mood disorder. For patients who suffer from mental health disorders, the literature has found that amiloride can be an effective means to restore a patient's impaired urine concentrating ability.
In this chapter, we review the mechanism of action of lithium salts from a chemical perspective. A description on how lithium salts are used to treat mental illnesses, in particular bipolar disorder, and other disease states is provided. Emphasis is not placed on the genetics and the psychopharmacology of the ailments for which lithium salts have proven to be beneficial. Rather we highlight the application of chemical methodologies for the characterization of the cellular targets of lithium salts and their distribution in tissues.
Background:
Polypharmacy and inappropriate continuation of medicines can lead to a significant risk of adverse drug events and drug interactions with patient harm and escalating health care costs as a result. Thorough review of patients' medications focusing on the need for each drug can reduce the potential for harm. Limitations in performing effective medicine reviews in practice include consultation time constraints and funding for pharmacy services. We will aim to overcome these problems by designing an automatic electronic decision support tool (the medicines optimization/review and evaluation (MORE) module) that is embedded in general practice electronic records systems. The tool will focus on medicines optimization and reducing polypharmacy to aid prescribers in reviewing medicines and improve patient outcomes.
Objective:
The objectives of this study are: (1) to develop an electronic decision support tool to assist prescribers in performing clinical medication reviews with a particular focus on patients experiencing multimorbidity and polypharmacy, and (2) evaluate and assess the use of the electronic decision support tool, providing pilot data on its usefulness in supporting prescribers during consultations with patients.
Methods:
The first three study phases involve development of clinical rules outlining clinical interventions and the creation and validation of the MORE decision support tool. Phase four is a community-based, single-blind, prospective, 6-month controlled trial involving two interventions and two control general practices, matched for practice demographics. We will be measuring the number of times prescribers engage with the tool, total number of interventions suggested by the tool, and total number of times prescribers change medicines in response to recommendations. There will also be prospective follow-up of patients in the intervention group to examine whether changes to medications are upheld, and to determine the number of hospitalizations or emergency department visits within 6 months of a medicine intervention. Comparisons between control and intervention practices will measure the changes in proportions of patients with polypharmacy and inappropriately prescribed medicines before and after the introduction of the electronic decision support tool, proportions of patients receiving appropriate treatment in each practice, and changed, maintained, or improved health status, hospitalizations, and deaths in the study year. Initiation rates of inappropriately prescribed medicines will be measured as a secondary outcome. As well as external assessment of the extent of use and application of the tool, prescribers will receive monthly practice progress reports detailing the proportion of their patients experiencing polypharmacy and taking inappropriately prescribed medicines identified for review.
Results:
Phase one has now been completed and the decision support tool is under development. Final data analysis is expected to be available in December 2016.
Conclusions:
This study will establish whether the MORE decision support tool stands up to real world conditions and promotes changes in prescribing practice.
The approach taken when reviewing material for this chapter was to capture any public domain literature which related either to current practice in, or to research approaches to, the direct assessment of adherence. Patient confidentiality prevents information being released from both healthcare providers and private test laboratories. Despite these limitations, this chapter highlights investigations from many countries around the world covering a wide range of diseases. This range covers both the chronic conditions; cardiovascular diseases, diabetes, cancer, asthma, and depression; and communicable diseases such as human immunodeficiency virus, acquired immunodeficiency syndrome, malaria, and tuberculosis. Monitoring immunosuppressants and pain management drugs also constitute significant areas of investigation. The range of biosample collection techniques utilized mirrors those cited in chapter “Opportunities and Challenges for Analytical Chemistry in the Assessment of Medication Adherence” and selection appears to be based on sample transport requirements. Analyses based on tandem mass spectrometry were the most reported possibly reflecting the limitations on the data availability.
The present investigation aims to study the effect of degumming time on structural property of silk fibre obtained by silk cocoons of Bombyx mori, followed by preparation of regenerated silk fibroin (RSF) solution which can be subsequently molded into silk nanoparticles. Silk fibres degummed with different media at different time intervals were investigated for the degumming loss and were characterized using fourier transform infrared (FTIR), differential scanning calorimetry (DSC), x-ray diffraction (XRD) and scanning electron microscopy (SEM). Maximum degumming was observed when the fibres were treated with sodium carbonate for 60 min. SEM and atomic force microscopy (AFM) images of RSF solution showed aggregation of silk globules resulting in formation of solvated macrochains and giving it an appearance of island like morphology. Blank silk nanoparticles prepared from RSF solution showed smooth and spherical surface devoid of any adhesion using SEM, AFM and transmission electron microscopy (TEM). The prepared silk nanoparticles may further be explored for loading drug entities and targeting.
Background Independent prescribing of medicines by nurses is widely considered to be part of advanced nursing practice, and occurs within an episode of patient care that can be completed independently by a nurse. Nurse prescribers therefore require the competencies necessary to manage a consultation—such as history taking and diagnostic skills—and subsequently need to decide on any appropriate medicine to be prescribed. Safe prescribing should also involve an accurate, legible and comprehensive written prescription and documentation of the consultation in the patient’s records. However, the extent to which nurse independent prescribers use prescribing competencies and standards in practice had not been researched prior to this study.
Aim To describe the frequency with which nurses use a range of prescribing competencies in their prescribing consultations, in order to provide a measure of the quality and safety of nurses’ independent prescribing practices.
Design and methods Across 10 case study sites, 118 nurse independent prescribers’ prescribing consultations were analysed using non-participant observation and a structured checklist of prescribing competencies. Documentary analysis was also undertaken of a) prescriptions written ( n =132) by nurses and b) the record of the prescribing episode in patient records ( n =118).
Sample and setting 118 prescribing consultations of 14 purposively selected nurse independent prescribers working in primary and secondary care trust case study sites in England.
Findings Nurse independent prescribers were issuing a prescription every 2.82 consultations; nurses used a range of assessment and diagnosis competencies in prescribing consultations, but some were employed more consistently than others; nurses almost universally wrote full and accurate prescription scripts for their patients; nurses recorded each of their prescribing consultations, but some details of the consultation and the prescription issued were not always consistently recorded in the patient records.
Conclusion The findings from this observation study provide evidence about the quality and safety of nurses’ prescribing consultations in England.
Background Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder. Methods 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332. Findings 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death). Interpretation For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy
The effect of shortening the pulse width of the electrical stimulus when administering electroconvulsive therapy (ECT) has recently been systematically studied with promising results. This review examines reported outcomes from three randomized controlled trials which compared ultrabrief (≤0.3 ms) with brief (0.5-1.5 ms) pulse width ECT, and other recent clinical trials of ultrabrief pulse width ECT. The emerging evidence for ultrabrief pulse right unilateral (RUL) ECT suggests clinically meaningful efficacy and substantially reduced neuropsychological side effects compared with standard (brief) pulse ECT; this may represent a generational advance in the ECT technique. However, it is unclear if patients receiving ultrabrief pulse RUL ECT may have a slower speed of response and require additional treatments compared with brief pulse ECT. Therefore, until further data are available, clinicians may be well advised to use brief pulse ECT in situations requiring an urgent clinical response. The evidence base for ultrabrief bilateral ECT is limited, with findings that efficacy may be reduced compared with brief pulse width ECT. Thus ultrabrief bilateral ECT should not be used outside the research setting.
Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis.
We concluded a randomized trial involving 1088 patients with multiple sclerosis, 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years. Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks. The primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks.
Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P<0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P=0.08), and 20.2% with teriflunomide at 14 mg (P=0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI). Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase levels (≥1 times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred.
Teriflunomide significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity, as compared with placebo. (Funded by Sanofi-Aventis; TEMSO ClinicalTrials.gov number, NCT00134563.).
To update the American Society of Clinical Oncology (ASCO) guideline for antiemetics in oncology.
A systematic review of the medical literature was completed to inform this update. MEDLINE, the Cochrane Collaboration Library, and meeting materials from ASCO and the Multinational Association for Supportive Care in Cancer were all searched. Primary outcomes of interest were complete response and rates of any vomiting or nausea.
Thirty-seven trials met prespecified inclusion and exclusion criteria for this systematic review. Two systematic reviews from the Cochrane Collaboration were identified; one surveyed the pediatric literature. The other compared the relative efficacy of the 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists.
Combined anthracycline and cyclophosphamide regimens were reclassified as highly emetic. Patients who receive this combination or any highly emetic agents should receive a 5-HT(3) receptor antagonist, dexamethasone, and a neurokinin 1 (NK(1)) receptor antagonist. A large trial validated the equivalency of fosaprepitant, a single-day intravenous formulation, with aprepitant; either therapy is appropriate. Preferential use of palonosetron is recommended for moderate emetic risk regimens, combined with dexamethasone. For low-risk agents, patients can be offered dexamethasone before the first dose of chemotherapy. Patients undergoing high emetic risk radiation therapy should receive a 5-HT(3) receptor antagonist before each fraction and for 24 hours after treatment and may receive a 5-day course of dexamethasone during fractions 1 to 5. The Update Committee noted the importance of continued symptom monitoring throughout therapy. Clinicians underestimate the incidence of nausea, which is not as well controlled as emesis.
Objectives:
To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women's Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.
Design:
Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.
Results:
In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P = 0.05 for clinical myocardial infarction or stroke, P = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P = 0.04), stroke (1.20 (1.00 to 1.43), P = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P = 0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P = 0.009).
Conclusions:
Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.
Little is known about the perceived learning needs of Australian general practice (GP) registrars in relation to the quality use of medicines (QUM) or the difficulties experienced when learning to prescribe. This study aimed to address this gap.
GP registrars' perceived learning needs were investigated through an online national survey, interviews and focus groups. Medical educators' perceptions were canvassed in semi-structured interviews in order to gain a broader perspective of the registrars' needs. Qualitative data analysis was informed by a systematic framework method involving a number of stages. Survey data were analysed descriptively.
The two most commonly attended QUM educational activities took place in the workplace and through regional training providers. Outside of these structured educational activities, registrars learned to prescribe mainly through social and situated means. Difficulties encountered by GP registrars included the transition from hospital prescribing to prescribing in the GP context, judging how well they were prescribing and identifying appropriate and efficient sources of information at the point of care.
GP registrars learn to prescribe primarily and opportunistically in the workplace. Despite many resources being expended on the provision of guidelines, decision-support systems and training, GP registrars expressed difficulties related to QUM. Ways of easing the transition into GP and of managing the information 'overload' related to medicines (and prescribing) in an evidence-guided, efficient and timely manner are needed. GP registrars should be provided with explicit feedback about the process and outcomes of prescribing decisions, including the use of audits, in order to improve their ability to judge their own prescribing.
Progressive multifocal leukoencephalopathy (PML) is a rare but often fatal brain disease caused by reactivation of the polyomavirus JC. Knowledge of the characteristics of PML has substantially expanded since the introduction of combination antiretroviral therapy during the HIV epidemic and the development of immune reconstitution inflammatory syndrome (IRIS) in patients with PML. Recently, the monoclonal antibodies natalizumab, efalizumab, and rituximab--used for the treatment of multiple sclerosis, psoriasis, haematological malignancies, Crohn's disease, and rheumatic diseases--have been associated with PML. Additionally, the JC virus can also lead to novel neurological disorders such as JC virus granule cell neuronopathy and JC virus encephalopathy, and might also cause meningitis. The increasingly diverse populations at risk and the recent discovery of the presence of the JC virus in the grey matter invite us to reappraise the pathogenesis of this virus in the CNS.
OBJECTIVES: To identify participants' characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. DESIGN: Individual patient data analysis using pooled data from randomised trials. DATA SOURCES: Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). STUDY SELECTION: Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. DATA SYNTHESIS: Logistic regression analysis was used to identify significant interaction terms, followed by Cox's proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. RESULTS: Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 microg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 microg or 20 microg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. CONCLUSION: This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 microg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.
To investigate whether greater intakes of calcium, vitamin D, or milk products may protect against ischemic heart disease mortality, the authors analyzed data from a prospective cohort study of 34,486 postmenopausal Iowa women 55-69 years old and without a history of ischemic heart disease who completed a dietary questionnaire in 1986, Through 1994, 387 deaths due to ischemic heart disease were documented (International Classification of Diseases, Ninth Revision, codes 410-414, 429.2). The multivariate-adjusted relative risks for the highest versus the lowest quartiles of total calcium, vitamin D, and milk product intakes were as follows: 0.67 (95% confidence interval (CI) 0.47-0.94; p for trend = 0.09) for calcium, 1.41 (95% CI 0.93-2.15; p for trend = 0.12) for vitamin D, and 0.94 (95% CI 0.66-1.35; p for trend = 0.68) for milk products. The relative risk was 0.63 (95% CI 0.40-0.98) for high dietary calcium but no supplemental calcium intake and 0.66 (95% CI 0.36-1.23) for high supplemental calcium but low dietary calcium intake. These results suggest that a higher intake of calcium, but not of vitamin D or milk products, is associated with reduced ischemic heart disease mortality in postmenopausal women, and reduced risk may be achievable whether the higher intake of calcium is attained by diet, supplements, or both.
Background: Calcium intake is thought to have a protective effect on the risk of developing ischemic heart disease (IHD), but the existing data are inconsistent.
Objective: The objective was to assess the relation between calcium intake and risk of IHD among men.
Design: Men in the Health Professionals Follow-up Study who returned a dietary questionnaire in 1986 (n = 39 800) were followed up for 12 y. Intakes of calcium and other nutrients were assessed in 1986, 1990, and 1994. The endpoints of total IHD (nonfatal myocardial infarction and fatal IHD) incidence were ascertained by medical record review. Other IHD risk factors were recorded biennially.
Results: During 12 y of follow-up (415 965 person-years), we documented 1458 cases of IHD: 1030 of nonfatal myocardial infarction and 428 of fatal IHD. After control for standard IHD risk factors, the relative risk of developing IHD among men in the highest (median intake = 1377 mg/d) compared with the lowest (median intake = 523 mg/d) calcium intake quintile was 0.97 (95% CI: 0.81, 1.16; P for trend = 0.64), for vitamin D intake was 1.00 (95% CI: 0.80, 1.24; P for trend = 0.66), and for total dairy product intake was 1.01 (95% CI: 0.83, 1.23; P for trend = 0.57). For supplemental calcium intake, the relative risk of developing IHD in a comparison of the highest quintile with nonusers of supplements was 0.87 (95% CI: 0.64, 1.19; P for trend = 0.31).
Conclusion: The results suggest that neither dietary nor supplemental intakes of calcium are appreciably associated with the risk of IHD among men.
Osteoporotic bone fractures are becoming an increasing burden worldwide-socially and economically-as the population ages. Supplemental calcium, alone or combined with vitamin D, has been proposed as a relatively inexpensive way of preventing osteoporotic bone loss, but whether it lowers the risk of fracture remains uncertain. Meta-analyses have, up to now, yielded inconsistent results. The present meta-analysis is based on 29 randomized trials totalling 63,897 adults aged 50 years and older. Seventeen trials numbering 52,625 persons reported fracture as an outcome, while 23 trials comprising 41,419 individuals reported bone mineral density (BMD) as an outcome. All trials compared calcium, alone or combined with vitamin D supplementation, with a placebo. In trials reporting fracture as an outcome, supplementation was associated with a 12% reduction in fractures of all types (risk ratio, 0.88; 95% confidence interval, 0.83-0.95; P = 0.0004). In trials reporting BMD as an outcome, treatment correlated with a reduced rate of bone loss averaging 0.54% (0.35%-0.73%; P < 0.0001) at the hip and 1.19% (0.76%-1.61%) at the spine. The reduction in fracture risk was significantly greater (by 24%) in trials with high compliance rates. A more substantial treatment effect was noted with calcium doses of 1200 or more than with lower doses (0.80 versus 0.94; P = 0.006), and with vitamin D doses of at least 800 IU (0.84 versus 0.87; P = 0.03). Neither gender nor a history of fracture influenced observed treatment effects. Adding vitamin D to calcium also did not alter treatment effects. Subjects with relatively low serum vitamin D levels had a greater risk reduction, but the difference was not significant. Lesser risk reductions were noted in persons 50-70 years of age than in those older than 70. These findings demonstrate that supplemental calcium, alone or combined with vitamin D, can prevent osteoporotic bone fractures. Analysis of the estimated number needed to treat shows that 63 patients will have to be treated over 3.5 years to prevent a single fracture. At least 1200 mg of calcium and 800 IU of vitamin D are recommended for combined supplementation.
Mifepristone was the first antiprogestogen to be developed for clinical use. It is not only a progesterone receptor antagonist, but also acts as a glucocorticoid receptor antagonist. The fundamental importance of progesterone for human conception and throughout pregnancy has meant that mifepristone has been used in other countries for emergency contraception and medical abortion in the first and second trimester of pregnancy. It has also been used to manage fetal death in utero in the third trimester of pregnancy. There are other potential uses based on its mechanism of action, such as reducing the bleeding associated with uterine fibroids.
Background:
Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder.
Methods:
330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332.
Findings:
59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).
Interpretation:
For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy.
Funding:
Stanley Medical Research Institute; Sanofi-Aventis.
To describe the use of mifepristone in combination with buccal misoprostol in women undergoing an early medical abortion (EMA) in Australia.
Retrospective, observational study of 13,345 EMAs (gestational age ≤ 63 days) conducted at 15 Marie Stopes International Australia clinics between 1 September 2009 and 31 August 2011.
Oral mifepristone 200 mg, administered at the clinic, followed 24-48 hours later by buccal misoprostol 800 µg, self-administered at home.
Failure rate (proportion of women with an incomplete abortion requiring surgical aspiration or a continuing pregnancy).
Pregnancy termination follow-up information was available for 83.4% (11 155/13 376) of EMAs. From the patient demographic database, the EMA failure rate was 3.5% (465/13 345). Of these, most (382; 2.9% of total) were incomplete abortions requiring surgical aspiration, and 83 (0.6% of total) were continuing pregnancies. Haemorrhage (16; 0.1%) and known or suspected infection (25; 0.2%) were infrequent. One woman, who did not seek follow-up despite signs of infection, died from sepsis (< 0.01%). In 6755 EMAs with clinic follow-up from April 2010 to August 2011, 6381 women participated in a survey. Most reported medium or heavy bleeding and moderate or severe pain/cramps; most also reported that bleeding, pain/cramps and their overall experience were as expected or better than expected.
Mifepristone, with buccal misoprostol self-administered at home, for EMA up to 63 days of gestation had a low failure rate, was well accepted, and provided an effective treatment option with a favourable safety profile for women seeking an abortion in Australia.
Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium.
We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity.
We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6·22 mL/min (95% CI -14·65 to 2·20, p=0·148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158·43 mOsm/kg, 95% CI -229·78 to -87·07, p<0·0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0·5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5·78, 95% CI 2·00-16·67; p=0·001), and thyroid stimulating hormone was increased on average by 4·00 iU/mL (95% CI 3·90-4·10, p<0·0001). Lithium treatment was associated with increased blood calcium (+0·09 mmol/L, 95% CI 0·02-0·17, p=0·009), and parathyroid hormone (+7·32 pg/mL, 3·42-11·23, p<0·0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1·89, 1·27-2·82, p=0·002), but not those receiving olanzapine (0·32, 0·21-0·49, p<0·0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders.
Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment.
National Institute for Health Research Programme Grant for Applied Research.
Interest in pathogenesis of progressive multifocal leukoencephalopathy (PML) followed the observation of the high risk for the disease in HIV infection and the recent observation of an association with a variety of newer therapeutic modalities, e.g., natalizumab, an α4β1 integrin inhibitor, and efalizumab, an anti-CD11a monoclonal antibody. Any hypothesis of PML pathogenesis must account for a number of facts. Firstly, the causative agent JC virus is ubiquitously present, yet only a vanishingly small number of infected persons develop the disease. Secondly, disorders of cell-mediated immunity increase the risk of the disease, particularly HIV infection. Impaired innate immunity is not a risk for PML, and antibodies against JC virus are not protective. Thirdly, a latent period of several months appears necessary following the administration of natalizumab and efalizumab before PML develops. Fourthly, restoration of the immune system can arrest the PML. It is possible that infection with JC virus occurs with a form of the virus shed in the urine of as many as 40% of all adults and present in sewage worldwide. Once acquired, perhaps through an oropharyngeal route, it may replicate and disseminate. A neurotropic form of JC virus that replicates in glial tissues causes PML when immunosurveillance is impaired. There are many unanswered questions with respect to PML pathogenesis. How is virus acquired? What tissues are infected? What is the origin of the neurotropic form? When does virus enter brain? What is the role of central nervous system immunosurveillance? The lack of an animal model has made answering these questions challenging.
Surgical abortion by vacuum aspiration or dilatation and curettage has been the method of choice for early pregnancy termination since the 1960s. Medical abortion became an alternative method of first trimester pregnancy termination with the availability of prostaglandins in the early 1970s and anti-progesterones in the 1980s. The most widely researched drugs are prostaglandins (PGs) alone, mifepristone alone, methotrexate alone, mifepristone with prostaglandins and methotrexate with prostaglandins.
To compare different medical methods for first trimester abortion.
The Cochrane Controlled Trials Register, MEDLINE and Popline were systematically searched. Reference lists of retrieved papers were also searched. Experts in WHO/HRP were contacted.
Types of studies Randomised controlled trials comparing different medical methods for abortion during first trimester (e.g. single drug, combination) were considered. Trials were assessed and included if they had adequate concealment of allocation, randomisation procedure and follow-up. Women, pregnant during the first trimester, undergoing medical abortion were the participants. The outcomes were mortality, failure to achieve complete abortion, surgical evacuation, ongoing pregnancy at follow-up, time until passing of conceptus, blood transfusion, side effects and women's dissatisfaction with the procedure.
Two reviewers independently selected trials for inclusion from the results of the search strategy described previously.The selection of trials for inclusion in the review was performed independently by two reviewers after employing the search strategy described previously. Trials under consideration were evaluated for appropriateness for inclusion and methodological quality without consideration of their results. Data were processed using Revman software.
Fifty-eight trials were included in the review. The effectiveness outcomes below refer to 'failure to achieve complete abortion' with the intended method unless otherwise stated. 1) Combined regimen mifepristone/prostaglandin: Mifepristone 600 mg compared to 200 mg shows similar effectiveness in achieving complete abortion (4 trials, RR 1.07, 95% CI 0.87 to 1.32). Misoprostol administered orally is less effective (more failures) than the vaginal route (RR 3.00, 95% CI 1.44 to 6.24) and may be associated with more frequent side effects such as nausea and diarrhoea. Sublingual and buccal routes were similarly effective compared to the vaginal route, but had higher rates of side effects. 2) Mifepristone alone is less effective when compared to the combined regimen mifepristone/prostaglandin (RR 3.76 95% CI 2.30 to 6.15). 3) Five trials compared prostaglandin alone to the combined regimen (mifepristone/prostaglandin). All but one reported higher effectiveness with the combined regimen. The results of these studies could not be combined but the RR of failure with prostaglandin alone is reportedly between 1.4 to 3.75 with the 95% confidence intervals indicating statistical significance. 4) In one trial comparing gemeprost 0.5 mg with misoprostol 800 mcg, misoprostol was more effective (failure with gemeprost: RR 2.86, 95% CI 1.14 to 7.18). 5) There was no difference in effectiveness with use of a divided dose compared to a single dose of prostaglandin. 6) Combined regimen methotrexate/prostaglandin demonstrates similar rates of failure to complete abortion when comparing intramuscular to oral methotrexate administration (RR 2.04, 95% CI 0.51 to 8.07). Similarly, day 3 vs. day 5 administration of prostaglandin following methotrexate administration showed no significant differences (RR 0.72, 95% CI 0.36 to 1.43). One trial compared the effect of tamoxifen vs. methotrexate and no statistically significant differences were observed in effectiveness between the groups.
Safe and effective medical abortion methods are available. Combined regimens are more effective than single agents. In the combined regimen, the dose of mifepristone can be lowered to 200 mg without significantly decreasing the method effectiveness. Vaginal misoprostol is more effective than oral administration, and has less side effects than sublingual or buccal. Some results are limited by the small numbers of participants on which they are based. Almost all trials were conducted in settings with good access to emergency services, which may limit the generalizability of these results.
Close family and friends are often a primary source of support for a person with bipolar disorder. However, there is a lack of information for caregivers about ways to provide helpful support and take care of themselves. Rates of caregiver burden are high and increase the risk of caregiver depression and health problems. This study aimed to develop guidelines to assist caregivers of adults with bipolar disorder to be informed about bipolar disorder and to support the person without neglecting their own wellbeing.
The Delphi method was used to assess consensus between international expert panels of 45 caregivers, 47 consumers, and 51 clinicians about what information to include in the caregiver guidelines. Initial online survey items were based on the existing literature. Subsequent surveys included new or reworded items suggested by panel members and items that needed re-rating. Items endorsed by at least 80% of all three panels formed the content of the guidelines.
Nearly 86% of the 626 survey items were endorsed. The items covered information on the illness, treatment, and suggestions on ways caregivers can provide support and take care of themselves in the different phases of illness and wellness, and information on dealing with specific real-life challenges. Although consensus rates were high, meaningful areas of difference between panels were found (e.g., collaboration issues).
The guidelines provide comprehensive introductory information, suggestions, and resources for caregivers. Access to relevant information may help caregivers to cope constructively with the person's bipolar disorder and their caregiving situation. The content of the guidelines could be used to help formulate a stepped-care approach to supporting caregivers, ranging from basic information and pamphlets to brief training courses and specialized family or caregiver interventions based on need and accessibility.
Electroconvulsive therapy (ECT) is a highly effective treatment for severe depressive disorder. Efficacy and cognitive outcomes have been shown to depend on variations in electrode placement and other stimulus parameters, presumably because of differences in the pattern of neuronal activation. This latter effect, however, is poorly understood.
In this study, we present an anatomically accurate human head computational model to stimulate neuronal excitation during ECT, to better understand the effects of varying electrode placement and stimulus parameters.
Electric field and current density throughout the head, as well as direct neural activation within the brain, were computed using the finite element method. Regions representing passive volume conductors (skin, skull, cerebrospinal fluid) were extracellularly coupled to an excitable neural continuum region representing the brain. The skull was modeled with anistropic electrical conductivity.
Simulation results indicated that direct activation of the brain occurred immediately beneath the electrodes on the scalp, consistent with existing imaging studies. In addition, we found that the brainstem was also activated using a right unilateral electrode configuration. Simulation also demonstrated that a reduction in stimulus amplitude or pulse width led to a reduction in the spatial extent of brain activation.
The novel model described in this study was able to simulate direct excitation of the brain during ECT, was useful in characterizing differences in neuronal activation as electrode placement, pulse width, and amplitude were altered, and is proposed as a tool for further exploring the effects of variations in ECT stimulation approaches. Results from the simulations assist in understanding recently described clinical phenomena, in particular, the reduction in cognitive side effects with ultrabrief pulse width stimulation, and greater effects of the ECT stimulus on cardiovascular function with unilateral electrode placement.
Drug-induced diabetes insipidus is always of the nephrogenic type, i.e. unresponsiveness of the kidneys to the action of antidiuretic hormone. This condition is easily diagnosed by measuring urinary concentrating capacity during a thirst test (e.g. 12 hours of water deprivation) or by administration of a modified antidiuretic hormone, desmopressin, to demonstrate the renal unresponsiveness. Drug-induced nephrogenic diabetes insipidus is not a common disorder except in patients receiving treatment with lithium salts for affective disorders where it may affect about 10% of patients treated long term (15 years). Drug-induced nephrogenic diabetes insipidus caused by other drugs usually occurs in critically ill patients in intensive care units receiving a multitude of drugs dominated by antimicrobials and cytostatics. A search of the World Health Organization's adverse effect database revealed 359 reports of drug-induced diabetes insipidus. Lithium was the most common cause (159 reports) followed by foscarnet (15) and clozapine (10). Treatment is symptomatic in most patients and the offending drug should be stopped. If urine volumes exceed 4 L/day, treatment with thiazides and amiloride has been advocated, and nonsteroidal anti-inflammatory drugs, such as indomethacin, may be tried in severe cases. Prevention of lithium-induced nephrogenic diabetes insipidus is an important aspect of the treatment of affective disorders. In patients treated long term it appears to be only partly reversible upon lithium discontinuation. Close monitoring of the treatment aiming at 12-hour trough value of 0.4 to 0.6 mmol/L is recommended. Yearly measurement of the urinary volume/day is effective in making both the patient and the physician aware of the development of the drug-induced nephrogenic diabetes insipidus. The condition is a serious adverse effect because of the risk of developing dehydration and aggravation of drug intoxications.
Lithium has long been recognised for its mood-stabilizing effects in the management of bipolar disorder (BD) but in practice its use has been limited because of real and 'imagined' concerns. This article addresses the need for lithium to be measured with respect to its clinical and functional effects. It introduces a visual scale, termed lithiumeter, which captures the optimal lithium plasma levels for the treatment of BD.
Key words pertaining to lithium's administration, dosing, and side effects as well as its efficacy in acute and long-term treatment of BD were used to conduct an electronic search of the literature. Relevant articles were identified by the authors and reviewed.
This paper outlines the considerations necessary prior to initiating lithium therapy and provides a guide to monitoring lithium plasma levels. Current recommendations for optimal plasma lithium levels in the management of BD are then discussed with respect to indications for use in the acute phases of the illness and maintenance therapy. The risks associated with lithium treatment are also discussed.
The lithiumeter provides a practical guide of optimal lithium levels for the clinical management of BD.
Calcium supplementation has been widely accepted as a key strategy in the prevention and treatment of osteoporosis. Its role has been undermined, to some extent, by its disappointing effects on fracture in randomised controlled trials, but its use has continued to be encouraged on the grounds that it is physiologically appealing, and is unlikely to cause harm. The latter assumption is now under threat from accumulating evidence that calcium supplement use is associated with an increased risk of myocardial infarction and, possibly, stroke. The latest data, based on meta-analysis of trials involving 29,000 participants, indicate that this risk is not mitigated by co-administration of vitamin D, and that the number of cardiovascular events caused is likely to be greater than the number of fractures prevented. These findings indicate that calcium supplementation probably does not have a role as a routine preventative agent and that dietary advice is the appropriate way to attain an adequate calcium intake in most situations. Patients at high risk of fracture need to take interventions of proven anti-fracture efficacy. Available evidence suggests that this efficacy is not dependent on the co-administration of calcium supplements.
Natalizumab, a therapy for multiple sclerosis (MS), has been associated with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS associated with the JC virus. We assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated PML.
Physicians provided Karnofsky scores and narrative descriptions of clinical status. Data were supplemented by the natalizumab global safety database.
At the time of analysis, 25 patients (71%) had survived. Survivors were younger (median 40 vs 54 years) and had lower pre-PML Expanded Disability Status Scale scores (median 3.5 vs 5.5) and a shorter time from symptom onset to diagnosis (mean 44 vs 63 days) compared with individuals with fatal cases. Of patients with nonfatal cases, 86% had unilobar or multilobar disease on brain MRI at diagnosis, whereas 70% of those with fatal cases had widespread disease. Gender, MS duration, natalizumab exposure, prior immunosuppressant use, and CSF JC viral load at diagnosis were comparable. Most patients were treated with rapid removal of natalizumab from the circulation. The majority of patients developed immune reconstitution inflammatory syndrome and were treated with corticosteroids. Among survivors with at least 6 months follow-up, disability levels were evenly distributed among mild, moderate, and severe, based on physician-reported Karnofsky scores.
Natalizumab-associated PML has improved survival compared with PML in other populations. Disability in survivors ranged from mild to severe. A shorter time from symptom onset to diagnosis and localized disease on MRI at diagnosis were associated with improved survival. These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive management may improve outcomes.
Oral chemotherapies represent an emerging risk area in ambulatory oncology practice. To examine the hazards associated with five oral chemotherapies, we performed a proactive risk assessment.
WE CONVENED INTERDISCIPLINARY TEAMS AND CONDUCTED FAILURE MODE AND EFFECTS ANALYSES (FMEAS) FOR FIVE ORAL CHEMOTHERAPY AGENTS: capecitabine, imatinib, temozolomide, 6-mercaptopurine, and an investigational agent. This involved the creation of process maps for each medication, identification of failure modes, selection of high-risk failure modes, and development of recommendations to mitigate these risks. We analyzed the number of steps and types of failure modes and compared this information across the study drugs.
Key vulnerabilities include patient education about drug handling and adverse effects, prescription writing, patient self-administration and medication adherence, and failure to monitor and manage toxicities. Many of these failure modes were common across the five oral chemotherapies, suggesting the presence of common targets for improvement. Streamlining the FMEA itself may promote the dissemination of this method.
Each stage of the medication process poses risks to the safe use of oral chemotherapies. FMEAs may identify opportunities to improve medication safety and reduce the risk of patient harm.
What is known and objectives: Intoxication with oral low-dose methotrexate (MTX) is a well-known and frequent problem, which is often discovered accidently. The major reason is error in the frequency of dosing, mostly of daily instead of weekly intake. We report a case where the critical error was discovered by the community pharmacist during the routine implementation of the Pharmaceutical Care process SOAP while dispensing a new prescription for the patient.
Details of the case: A 78-year-old widow went to her regular community pharmacy to pick up a prescription for oral mucositis. The evaluation of the case by the pharmacist using the SOAP (an acronym for Subjective, Objective, Assessment and Plan) note method revealed the underlying oral low-dose MTX intoxication which led to hospitalization a few days later. The incorrect interpretation of the required dose had arisen from the written instructions for use and led to the erroneous intake of MTX daily (instead of weekly). We interviewed the patient at her home 2 months after discharge. She explained that her continued intake of MTX in spite of manifest adverse effects was because of a profound conviction that she was doing right. Her confidence in physicians remained unchanged after the incident, but she would now refuse to take MTX.
What is new and conclusion: The reasons for the intoxication were not discovered accidently but by the routine use of the Pharmaceutical Care process SOAP by the community pharmacist. We describe three main errors that might have been avoided and provide solutions for physicians, pharmacists, manufacturers and patients, to reduce such risks. Our case highlights the dangers of teleconsultation, the crucial role of Pharmaceutical Care provided by community pharmacists and the continued need to supply advice to patients being prescribed low-dose MTX. The fact that a patient has had a previous and successful experience with a similar treatment should not deter health professionals from verifying a patient’s understanding via questions and feedback.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Prescribing errors are common and are caused by multiple factors. Standard medication charts have been recommended by British and Australian Health services. A study of a standard medication chart in five hospitals in one state of Australia significantly reduced prescribing errors.
WHAT THIS STUDY ADDS
• A standard medication chart developed in one area can be adopted through a collaborative process and successfully implemented across a diverse country resulting in similar reductions in prescribing errors. Three of the four stages of the prescribing process (information gathering, decision making and communication of instructions) can be improved by the use of an improved standard medication chart. The introduction of a standard medication chart has enabled development of standard prescribing education programmes.
AIMS To establish whether a standard national inpatient medication chart (NIMC) could be implemented across a range of sites in Australia and reduce frequency of prescribing errors and improve the completion of adverse drug reaction (ADR) and warfarin documentation.
METHODS A medication chart, which had previously been implemented in one state, was piloted in 22 public hospitals across Australia. Prospective before and after observational audits of prescribing errors were undertaken by trained nurse and pharmacist teams. The introduction of the chart was accompanied by local education of prescribers and presentation of baseline audit findings.
RESULTS After the introduction of the NIMC, prescribing errors decreased by almost one-third, from 6383 errors in 15 557 orders, a median (range) of 3 (0–48) per patient to 4293 in 15 416 orders, 2 (0–45) per patient (Wilcoxon Rank Sum test, P < 0.001). The documentation of drugs causing previous ADRs increased significantly from 81.9% to 88.9% of drugs (χ2 test, P < 0.001). The documentation of the indication for warfarin increased from 12.1 to 34.3% (χ2 test, P= 0.001) and the documentation of target INR increased from 10.8 to 70.0% (χ2 test, P < 0.001) after implementation of the chart.
CONCLUSIONS National implementation of a standard medication chart is possible. Similar reduction in the rate of prescribing errors can be achieved in multiple sites across one country. The consequent benefits for patient care and training of staff could be significant.
Trials in normal older women and in patients with renal impairment suggest that calcium supplements increase the risk of cardiovascular disease. To further assess their safety, we recently conducted a meta-analysis of trials of calcium supplements, and found a 27-31% increase in risk of myocardial infarction and a 12-20% increase in risk of stroke. These findings are robust because they are based on pre-specified analyses of randomized, placebo-controlled trials and show consistent risk across the trials. The fact that cardiovascular events were not primary endpoints of any of these studies will introduce noise but not bias into the data. A recent re-analysis of the Women's Health Initiative suggests that co-administration of vitamin D with calcium does not lessen these adverse effects. The increased cardiovascular risk with calcium supplements is consistent with epidemiological data relating higher circulating calcium concentrations to cardiovascular disease in normal populations. There are several possible pathophysiological mechanisms for these effects, including effects on vascular calcification, on the function of vascular cells, and on blood coagulation. Calcium-sensing receptors might mediate some of these effects. Because calcium supplements produce small reductions in fracture risk and a small increase in cardiovascular risk, there may be no net benefit from their use. Food sources of calcium appear to produce similar benefits on bone density, although their effects on fracture are unclear. Since food sources have not been associated with adverse cardiovascular effects, they may be preferable. Available evidence suggests that other osteoporosis treatments are still effective without calcium co-administration.
Sunlight exposure by improving vitamin D status could be a simple public health strategy in reducing falls among frail elder people. In a randomised controlled trial, adherence to sunlight exposure was low (median adherence, 26%) and no effect of increased UV exposure on falls risk was observed (incidence rate ratio (IRR) 1.06, P = 0.73).
This study aimed to determine whether increased sunlight exposure was effective to improve vitamin D status and reduce falls in the elderly.
In a cluster randomised controlled trial (NCT00322166 at ClinicalTrials.gov), 602 residents aged 70 or more (mean age, 86.4 years; 71% female) were recruited from 51 aged care facilities in Northern Sydney, Australia. Participants were randomised by facility to receive either increased sunlight exposure (additional 30-40 min/day in the early morning) with (UV+) or without (UV) calcium supplementation (600 mg/day) or neither (control) for a year. The co-primary endpoints were change in serum 25 hydroxy vitamin D (25OHD) and falls incidence after 12 months.
Adherence to sunlight exposure was low (median adherence, 26%; IQR, 7%-45%). Serum 25OHD levels were low at baseline (median, 32.9 nmol/L) and increased only slightly depending on the number of sunlight sessions attended over 12 months (P = 0.04). During the study, 327 falls occurred in 111 (54%) subjects in the control group, 326 falls in 111 (58%) subjects in the UV only group and 335 falls in 108 (52%) subjects in the UV+ group. By intention-to-treat analysis, there was no significant effect of increased UV exposure on falls risk (IRR, 1.06; 95% CI, 0.76-1.48; P = 0.73). However, in 66 participants who attended ≥130 sessions per year (adherence, ≥50% of 260 sessions-five per week), falls were significantly reduced (IRR, 0.52; 95% CI, 0.31-0.88; P = 0.01) compared with the control group.
Increased sunlight exposure did not reduce vitamin D deficiency or falls risk in frail older people. This public health strategy was not effective most likely due to poor adherence to the intervention.
Background:
With the improvement of ultrasound technology, the likelihood of detection of major fetal structural anomalies in mid-pregnancy has increased considerably. Upon the detection of serious anomalies, women typically are offered the option of pregnancy termination. Additionally, there are still many reasons other than fetal anomalies why women seek abortion in the mid-trimester.
Objectives:
To compare different methods of second trimester medical termination of pregnancy for their efficacy and side-effects.
Search strategy:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, Popline and reference lists of retrieved papers and other sources.
Selection criteria:
All randomised controlled trials (RCTs) examining medical regimens for termination of pregnancy of a singleton living fetus between 12-28 weeks' gestation were analysed. The outcome measures were the induction to abortion interval, abortion rate within 24 hours, need for surgical evacuation, blood loss, uterine rupture, pain, and side-effects.Trials including >20% fetal death, multiple pregnancies, previous uterine scars and regimens which involved cervical preparation were excluded.
Data collection and analysis:
Two authors selected the trials and three authors extracted data.
Main results:
Fourty RCTs were included, addressing various agents for pregnancy termination and methods of administration. When used alone, misoprostol was an effective inductive agent, though it appeared to be more effective in combination with mifepristone. However, the evidence from RCTs is limited.Misoprostol was preferably administered vaginally, although among multiparous women sublingual administration appeared equally effective. A range of doses of vaginally administered misoprostol has been used. No randomised trials comparing doses of misoprostol were identified; however low doses of misoprostol appear to be associated with fewer side-effects while moderate doses appear to be more efficient in completing abortion. Four RCTs showed that the induction to abortion interval with 3-hourly vaginal administration of prostaglandins is shorter than 6-hourly administration without an increase in side-effects.Many studies reported the need for surgical evacuation. Indications for surgical evacuation include retained products of the placenta and heavy vaginal bleeding. Fewer women required surgical evacuation when misoprostol was administrated vaginally compared with women receiving intra-amniotical PGF(2a) . Mild, self-limiting diarrhoea was more common among women who received misoprostol compared to other agents.
Authors' conclusions:
Medical abortion in the second trimester using the combination of mifepristone and misoprostol appeared to have the highest efficacy and shortest abortion time interval. Where mifepristone is not available, misoprostol alone is a reasonable alternative. The optimal route for administering misoprostol is vaginally, preferably using tablets at 3-hourly intervals. Apart from pain, the side-effects of vaginal misoprostol are usually mild and self limiting. Conclusions from this review are limited by the gestational age ranges and variable medical regimens, including dosing, administrative routes and intervals of medication, of the included trials.
To clarify advantages of unilateral electrode placement as an optimisation technique for electroconvulsive therapy (ECT) for depression, aims were to meta-analyse unilateral ECT effects on cognitive performance relative to: (1) bitemporal electrode placement, (2) electrical dosage, and (3) time interval between final treatment and cognitive reassessment. Relevant electronic databases were systematically searched through May 2009, using the terms: "electroconvulsive therapy" and ["cogniti∗", "neuropsycholog∗", "memory", "attention", "executive", "spatial", or "intellectual"]. Inclusion criteria were: independent study of depressed patients receiving unilateral or bitemporal brief-pulse ECT; within-subjects design; use of objective cognitive assessments; available mean electrical dosage for unilateral samples. Standardized pre-post ECT weighted effect sizes were computed and pooled within 16 cognitive domains by a mixed-effects model. Thirty-nine studies (1415 patients) were meta-analysed. Up to three days after final treatment, unilateral ECT was associated with significantly smaller decreases in global cognition, delayed verbal memory retrieval, and autobiographical memory, compared to bitemporal ECT. Significant publication bias was found for autobiographical memory, favouring reporting of larger percentage loss. Higher unilateral ECT electrical dosage predicted larger decreases in verbal learning, delayed verbal memory retrieval, visual recognition, and semantic memory retrieval. When retested more than three days after completing ECT, no significant differences remained between the two electrode placements; for unilateral ECT, electrical dosage no longer predicted cognitive performance whereas increasing interval between final treatment and retesting predicted growing improvement in some variables. This interval is a more useful long-term predictor of cognitive function than electrode placement or electrical dosage following unilateral ECT.
The issue of medication safety is highly significant when anti-cancer therapy is used as a treatment modality due to the high potential for harm from these agents and the disease context in which they are being used.
These guidelines provide recommendations on the safe prescribing, dispensing and administration of chemotherapy and related agents used in the treatment of cancer. The guidelines represent a multidisciplinary collaboration to standardise the complex process of providing chemotherapy for cancer and to enhance patient safety. These are consensus guidelines based on the best available evidence and expert opinion of professionals working in cancer care. The aim of these guidelines is to assist in the prevention of medication errors and to improve patient safety with respect to the treatment of cancer.
This guidance is intended for a multi-disciplinary audience and will have most relevance for medical, nursing and pharmacy staff involved in the complex processes of delivering chemotherapy and associated treatment. The scope of the guidelines includes; all patients and age groups receiving chemotherapy and targeted therapy for the treatment of cancer and cancer therapy administered by any route in both the hospital and home setting. These guidelines should be seen as point of reference for practitioners providing cancer chemotherapy services.
To compare the psychological impact, acceptability and clinical effectiveness of medical versus surgical termination of pregnancy (TOP) at 13-20 weeks of gestation.
Randomised trial.
Large UK tertiary centre.
Women accepted for TOP at 13-20 weeks of gestation.
Medical TOP (MTOP) using mifepristone and misoprostol or surgical TOP (STOP) by vacuum aspiration at <15 weeks of gestation, and by dilatation and evacuation at 15 or more weeks of gestation.
Distress 2 weeks after TOP, measured by the impact of events scale (IES), and acceptability, measured by the proportion of women who would opt for the same procedure again.
One hundred and twenty two women were randomised: 60 to the MTOP group and 62 to the STOP group. Twelve women opted to continue their pregnancy. Follow-up rates were low (n=66/110; 60%). At 2 weeks post-procedure there was no difference in total IES score between groups. However, compared with women undergoing STOP, women undergoing MTOP had a higher score on the IES intrusion subscale (mean difference 6.6; 95% CI 1.4-11.8), and a higher score on the general health questionnaire (GHQ) (P=0.033). Women found STOP more acceptable: compared with MTOP, more women would opt for the same procedure again (100% versus 53%, P≤0.001), and fewer women found the experience to be worse than expected (0% versus 53%, P=0.001). Women who had MTOP experienced more bleeding (P=0.003), more pain on the day of the procedure (P=0.008), and more days of pain (P=0.020). Of the 107 women who declined to participate, 58 (67%) preferred a STOP.
Randomised trials of women requesting midtrimester TOP are challenging. Women found STOP less painful and more acceptable than MTOP.
Annual intravenous administration of 5 mg of zoledronate decreases fracture risk over 3 years. The optimal dosing interval of 5 mg of zoledronate is not known. In order to determine the duration of the antiresorptive action of a single 5-mg dose of intravenous zoledronate, we conducted a 3-year double-blind, randomized, placebo-controlled trial in a volunteer sample of 50 postmenopausal women with osteopenia. The coprimary endpoints were the bone turnover markers β-C-terminal telopeptide of type I collagen (β-CTX) and serum procollagen type-I N-terminal propeptide (P1NP). Secondary endpoints were bone mineral density (BMD) at the lumbar spine, total hip, and total body. After 3 years, mean (95% confidence interval) levels of serum β-CTX and P1NP were 44% (27-60) and 40% (24%-56%) lower in the zoledronate group (p < .001 versus placebo for each marker). BMD was higher in the zoledronate group than in the placebo group by an average of 6.8% (4.6%-9.1%) at the lumbar spine, 4.0% (1.8%-6.3%) at the total hip, and 2.0% (0.9%-3.0%) at the total body (p < .001 for each skeletal site). Between-group differences in markers of bone turnover and BMD were stable from 12 to 36 months. These data demonstrate that the antiresorptive effects of a single 5-mg dose of zoledronate are sustained for 3 years; clinical trials to investigate the antifracture efficacy of dosing intervals longer than 1 year are justified.
Although people with bipolar disorder spend more time in a depressed than manic state, little evidence is available to guide the treatment of acute bipolar depression.
To compare the efficacy, acceptability and safety of mood stabiliser monotherapy with combination and antidepressant treatment in adults with acute bipolar depression.
Systematic review and meta-analysis of randomised, double-blind controlled trials.
Eighteen studies with a total 4105 participants were analysed. Mood stabiliser monotherapy was associated with increased rates of response (relative risk (RR) = 1.30, 95% CI 1.16-1.44, number needed to treat (NNT) = 10, 95% CI 7-18) and remission (RR = 1.51, 95% CI 1.27-1.79, NNT = 8, 95% CI 5-14) relative to placebo. Combination therapy was not statistically superior to monotherapy. Weight gain, switching and suicide rates did not differ between groups. No differences were found between individual medications or drug classes for any outcome.
Mood stabilisers are moderately efficacious for acute bipolar depression. Extant studies are few and limited by high rates of discontinuation and short duration. Further study of existing and novel agents is required.
To evaluate the efficacy of zoledronic acid in the prevention of bone loss in postmenopausal women with low bone mass.
In this 2-year, randomized, multicenter, double-blind, placebo-controlled study, postmenopausal women with low bone mass were selected randomly to receive either zoledronic acid 5 mg intravenously at randomization and at month 12 (zoledronic acid 2 x 5 mg), zoledronic acid 5 mg intravenously only at randomization and placebo at month 12 (zoledronic acid 1 x 5 mg), or placebo at randomization and at month 12 (placebo). The primary efficacy endpoint was the percentage change in lumbar spine bone mineral density (BMD) (lumbar spine BMD) at month 24 relative to baseline.
Both zoledronic acid 2 x 5 mg and zoledronic acid 1 x 5 mg regimens significantly increased mean lumbar spine BMD compared with placebo at month 24 (5.18% and 4.42% compared with -1.32%, respectively, both P<.001). Similarly, significantly greater increases for both zoledronic acid regimens relative to placebo were observed for lumbar spine BMD at month 12 and for BMD at the proximal femur sites (total hip, femoral neck, trochanter) at month 12 and 24 (all P<.001). Both zoledronic acid regimens significantly reduced bone turnover markers over time relative to placebo (all P<.001), although changes with zoledronic acid 2 x 5 mg regimen were sustained greater during the second year relative to zoledronic acid 1 x 5 mg. The overall incidence of adverse events and serious adverse events were similar across all treatment groups.
Both once-yearly dosing and a single dose of intravenous zoledronic acid 5 mg prevented bone loss for 2 years and were well-tolerated in postmenopausal women with low bone mass.
ClinicalTrials.gov, www.clinicaltrials.gov, NCT00132808.
I.
In preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy.
Sixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants.
There were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P = 0.13). The rate was similar to the 3-4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomide-exposed and non-leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non-leflunomide-exposed RA groups.
Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.
Medication adherence contributes to the efficacy-effectiveness gap of treatment in patients with bipolar disorder. This paper aims to examine the challenges involved in improving medication adherence in bipolar disorder, and to extract some suggestions for future directions from the core psychosocial studies that have targeted adherence as a primary or secondary outcome.
A search was conducted for articles that focused on medication adherence in bipolar disorder, with emphasis on publications from 1996 to 2008 using Medline, Web of Science, CINAHL PLUS, and PsychINFO. The following key words were used: adherence, compliance, alliance, adherence assessment, adherence measurement, risk factors, psychosocial interventions, and psycho-education.
There are a number of challenges to understanding non-adherence including the difficulty in defining and measuring it and the various risk factors that need to be considered when aiming to enhance adherence. Nevertheless, the importance of addressing adherence is evidenced by the connection between adherence problems and poor outcome. Despite these challenges, a number of small psychosocial studies targeting adherence as a primary outcome point to the potential usefulness of psycho-education aimed at improving knowledge, attitudes, and adherence behavior, but more large scale randomized controlled trials are needed in this area. Evidence of improved outcomes from larger randomized controlled trials of psychosocial interventions that target medication adherence as a secondary outcome suggests that tackling other factors besides medication adherence may also be an advantage. While some of these larger studies demonstrate an improvement in medication adherence, the translation of these interventions into real life settings may not always be practical. A person centered approach that considers risk factors for non-adherence and barriers to other health behaviors may assist with the development of more targeted briefer interventions. Integral to improving medication adherence is the delivery of psycho-education, and attention needs to be paid to the implementation, and timing of psycho-education. Progress in the understanding of how medicines work may add to the credibility of psycho-education in the future.
Enhancement of treatment adherence in bipolar patients is a necessary and promising management component as an adjunct to pharmacotherapy. The current literature on psychosocial interventions that target medication adherence in bipolar disorder points to the possibility of refining the concept of non-adherence and adapting psycho-education to the needs of certain subgroups of people with bipolar disorder. Large scale randomized controlled trials of briefer or more condensed interventions are needed that can inform clinical practice.