Add-on Regimen Research Articles

Cost-effectiveness analysis of denosumab versus alendronate for improving bone mineral density in renal transplant recipients: a comparative study

BackgroundDenosumab and alendronate had a positive impact on bone mineral density (BMD) preservation after kidney transplantation. However, the cost-effectiveness of these agents in the context of kidney transplantation remains largely unexplored. We have conducted a cost-effectiveness analysis to compare the cost and the clinical outcomes of adding subcutaneous (SC) 60 mg denosumab every 6 months vs. oral weekly 70 mg Alendronate, to the standard care therapy (vitamin D and calcium) in renal transplant recipients (RTRs). The impact of both drugs on BMD t-score improvement and fracture prevention was investigated. A decision-analysis model from a health care payer perspective was applied.ResultsThe cost-effectiveness analysis has shown that alendronate add-on to the standard therapy was the most cost-effective regimen, in terms of BMD improvement and fracture prevention with an incremental cost-effectiveness ratio (ICER) of $154/patient/year. The one-way sensitivity analyses have delineated the change in cost-effectiveness when alendronate retail unit price was increased by 25% and 50%, or when denosumab retail unit price was decreased by 25% and 50%. The model was sensitive to the uncertainties (95% confidence interval) in the probabilities of fracture prevention and the probabilities of attaining the desired outcome.ConclusionThe model suggests that oral once weekly alendronate add-on regimen to standard therapy seems to be substantially more cost effective than twice yearly SC denosumab in terms of BMD improvement and fracture prevention in RTRs. Longer time horizon models with longer follow-up periods for fracture risks and adverse events are warranted to validate these data.

Evaluation of safety and efficacy of Unani Add-on regimen in preventing the progression of severity of the disease in hospitalized SARS-CoV2 tested positive asymptomatic /mild to moderate symptomatic COVID-19 cases- A Randomised Controlled Clinical Trial

Objectives: The study aimed to establish the effectiveness of Unani add-on regimen by comparing theduration required for change in disease status from COVID-19 positive asymptomatic / mildto moderate symptomatic patients to asymptomatic negative. Methods: This single-centric, randomized, twin arm, controlled, clinical trial was carried out on a totalnumber of 62 RT-PCR confirmed COVID-19 patients. The Intervention group (IG) receivedUnani Regimen (Khameera Marwareed and Unani Joshanda) in addition to the conventional management, while the Control group (CG) received only conventional management. Results: It was observed that 16 (51.6%) patients in Intervention Group and 3 (9.4%) patients incontrol group became negative for COVID-19 at day 7 and remaining 13 out of 15 (93.5%) patients in Intervention Group and 20 out of 28 (74.1%) patients in control group becamenegative for COVID-19 at day 14 .This effect of the Unani Regimen in comparison to thecontrol group was statistically significant (p =0.003). Conclusions: It can be concluded that the change of COVID-19 positive asymptomatic / mild to moderate symptomatic patients to RT-PCR negative was much earlier in the add-on Unani regimen group as compared to control group. Bangladesh Journal of Medical Science Vol. 21 No. 04 October’22 Page : 901-911

Lacosamide as first add-on or conversion monotherapy: A retrospective real-life study

PurposeLacosamide (LCM), the R-enantiomer of 2-acetamido-N-benzyl-3-methoxypropionamide, is a newer approved antiseizure medication characterized by a novel pharmacodynamic and favorable pharmacokinetic profile that was approved as adjunctive treatment for adults with focal onset and focal to bilateral tonic-clonic seizures in 2008, and recently also for monotherapy. The aim of this study was to evaluate the effectiveness and tolerability of LCM as first add-on or conversion monotherapy in adult subjects with focal epilepsy. MethodsWe retrospectively included all adult patients who received LCM as first add-on regimen or as substitution monotherapy at least 12 months before starting the chart review, with a historical baseline of 6 months prior to day of the first administration of LCM. The choice of treatment was made independently by the epilepstologists, according to routine clinical practice. Clinical data were obtained at 3, 6, and 12 months after subjects started LCM and then analyzed to assess retention rate, seizure freedom, and adverse events (AE). ResultsA total of 101 patients (58 men) with a mean age of 44 years and a median epilepsy duration of 6.6 years (range 1–53) were included in the study. At 12 months 72 patients retained LCM, 54 (75%) of them were seizure free, 44 (81.5%) in monotherapy and 10 (18.5%) in add-on LCM treatment. Among all subjects, 31 (57.4%) were free from seizure under LCM monotherapy throughout the entire observation period. Thirty one out of 72 (43%) PwE who retained LCM at 12 months, were free from seizures throughout the entire observation period. The maintenance median dosage of LCM was 200 mg/day. Ten (10%) subjects reported mild to moderate AE, most commonly drowsiness and dizziness. No serious AE were documented. ConclusionsThis real-life study confirms that LCM is an effective and well tolerated treatment option as first add-on or conversion monotherapy for focal seizures.

Add-On Chinese Medicine for Coronavirus Disease 2019 (ACCORD): A Retrospective Cohort Study of Hospital Registries.

Chinese medicine (CM) was extensively used to treat COVID-19 in China. We aimed to evaluate the real-world effectiveness of add-on semi-individualized CM during the outbreak. A retrospective cohort of 1788 adult confirmed COVID-19 patients were recruited from 2235 consecutive linked records retrieved from five hospitals in Wuhan during 15 January to 13 March 2020. The mortality of add-on semi-individualized CM users and non-users was compared by inverse probability weighted hazard ratio (HR) and by propensity score matching. Change of biomarkers was compared between groups, and the frequency of CMs used was analyzed. Subgroup analysis was performed to stratify disease severity and dose of CM exposure. The crude mortality was 3.8% in the semi-individualized CM user group and 17.0% among the non-users. Add-on CM was associated with a mortality reduction of 58% (HR = 0.42, 95% CI: 0.23 to 0.77, [Formula: see text] = 0.005) among all COVID-19 cases and 66% (HR = 0.34, 95% CI: 0.15 to 0.76, [Formula: see text] = 0.009) among severe/critical COVID-19 cases demonstrating dose-dependent response, after inversely weighted with propensity score. The result was robust in various stratified, weighted, matched, adjusted and sensitivity analyses. Severe/critical patients that received add-on CM had a trend of stabilized D-dimer level after 3-7 days of admission when compared to baseline. Immunomodulating and anti-asthmatic CMs were most used. Add-on semi-individualized CM was associated with significantly reduced mortality, especially among severe/critical cases. Chinese medicine could be considered as an add-on regimen for trial use.

Add-On Semi-Individualized Chinese Medicine for Coronavirus Disease 2019 (ACCORD): A Retrospective Cohort Study of Hospital Registries

Background: Previous studies showed that the effect of antivirals for COVID-19 was promising but varied across patient population, and was modest among severe cases. Chinese Medicine (CM) was extensively used and reported effective in China, awaiting further evidence support. We aimed to evaluate the real-world effectiveness of add-on semi-individualized.Methods: A retrospective total sampling cohort of 1788 adult confirmed COVID-19 patients were recruited from all 2235 consecutive records retrieved from 5 hospitals in Wuhan during15 January to 13 March 2020. Consultation notes, laboratory/imaging investigations, pharmacy and prognosis records were linked by an electronic medical record system and verified by at least 2 researchers independently. The mortality of add-on semi-individualized CM users and non-users was compared by weighted hazard ratios of multivariable Cox regression and by propensity score matching. Change of biomarkers was compared between groups and the frequency of CMs used was analysed. Subgroup analysis was performed to stratify disease severity and dose of CM exposure. Sensitivity analyses were conducted to test the robustness.Findings: The crude mortality was 3.8% in the semi-individualized CM user group and 17.0% among the non-users. Add-on CM was associated with a significant mortality reduction of 58% (HR=0.42, 95%CI: 0.23 to 0.77, p=0.005) and 66% (HR=0.34, 95%CI: 0.15 to 0.76, p=0.009) among all and severe/critical COVID-19 cases with dose-dependent response, after inversely weighted with propensity score calculated by age, gender, history of hypertension, diabetes, coronary artery disease and disease severity. The result was robust in various stratified, weighted, matched, adjusted and sensitivity analyses. Severe/critical patients received add-on CM had a trend of stabilized D-dimer level after 3-7 days of admission compared to baseline.Interpretation: Add-on semi-individualized CM was associated with reduced mortality demonstrating dose-dependent response, especially among severe/critical COVID-19 patients. Chinese medicine could be considered as an add-on regimen for trial use.Funding Statement: This work is partially supported by the National Key Research and Development Program (2017YFC1703506 and 2020YFC0841600). Declaration of Interests: No financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.Ethics Approval Statement: This study was approved by the ethics review board of Hubei Provincial Hospital of Traditional Chinese Medicine (HBZY2020-C01-01). Written consent was waived due to the retrospective nature.

The Promotoer, a brain-computer interface-assisted intervention to promote upper limb functional motor recovery after stroke: a study protocol for a randomized controlled trial to test early and long-term efficacy and to identify determinants of response

BackgroundStroke is a leading cause of long-term disability. Cost-effective post-stroke rehabilitation programs for upper limb are critically needed. Brain-Computer Interfaces (BCIs) which enable the modulation of Electroencephalography (EEG) sensorimotor rhythms are promising tools to promote post-stroke recovery of upper limb motor function. The “Promotoer” study intends to boost the application of the EEG-based BCIs in clinical practice providing evidence for a short/long-term efficacy in enhancing post-stroke hand functional motor recovery and quantifiable indices of the participants response to a BCI-based intervention. To these aims, a longitudinal study will be performed in which subacute stroke participants will undergo a hand motor imagery (MI) training assisted by the Promotoer system, an EEG-based BCI system fully compliant with rehabilitation requirements.MethodsThis longitudinal 2-arm randomized controlled superiority trial will include 48 first ever, unilateral, subacute stroke participants, randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and a hand MI training not supported by BCI. Both interventions are delivered (3 weekly session; 6 weeks) as add-on regimen to standard intensive rehabilitation. A multidimensional assessment will be performed at: randomization/pre-intervention, 48 h post-intervention, and at 1, 3 and 6 month/s after end of intervention. Primary outcome measure is the Fugl-Meyer Assessment (FMA, upper extremity) at 48 h post-intervention. Secondary outcome measures include: the upper extremity FMA at follow-up, the Modified Ashworth Scale, the Numeric Rating Scale for pain, the Action Research Arm Test, the National Institute of Health Stroke Scale, the Manual Muscle Test, all collected at the different timepoints as well as neurophysiological and neuroimaging measures.DiscussionWe expect the BCI-based rewarding of hand MI practice to promote long-lasting retention of the early induced improvement in hand motor outcome and also, this clinical improvement to be sustained by a long-lasting neuroplasticity changes harnessed by the BCI-based intervention. Furthermore, the longitudinal multidimensional assessment will address the selection of those stroke participants who best benefit of a BCI-assisted therapy, consistently advancing the transfer of BCIs to a best clinical practice.Trial registrationName of registry: BCI-assisted MI Intervention in Subacute Stroke (Promotoer).Trial registration number: NCT04353297; registration date on the ClinicalTrial.gov platform: April, 15/2020.

Effectiveness of Quinacrine (Mepacrine) in Photosensitive Autoimmune Diseases, Lupus Erythematosus, and Dermatomyositis: Report on 38 Cases and Literature Review

Objectives This study aims to report our experience with photosensitive autoimmune diseases including lupus erythematosus and dermatomyositis (DM) treated with quinacrine (Qn) as either monotherapy or combination with other antimalarials, steroids, and immunosuppressive therapy in an add-on regimen in light of a review of the relevant literature.

Bismuth supplements as the first-line regimen for Helicobacter pylori eradication therapy: Systemic review and meta-analysis.

An increase in the use of antibiotics leads to increased antibiotic resistance of Helicobacter pylori (Hpylori). Consequently, it has been considered that the first-line standard regimen should be changed. The main purpose of this study was to evaluate the efficacy of nonantibiotic (bismuth) supplements as a first-line regimen for Hpylori eradication. We searched PubMed, EMBASE, CINAHL, and the Cochrane Library databases for randomized controlled trials (RCTs) reported in English and undertaken up until August 2018. A meta-analysis of all randomized controlled trials comparing bismuth supplements with non-bismuth-containing regimens in Hpylori eradication was performed. RCTs of classic bismuth-containing quadruple therapy as a first-line regimen were excluded. We identified twenty-five randomized trials (3990 patients), and the total Hpylori eradication rate, according to per protocol analyzed, was 85.8%. The odds ratio was 1.83 (95% confidence interval (CI). 1.57-2.13). Among these RCTs, there were 7 RCTs for bismuth add-on therapy, and the odds ratio was 2.81 (95% CI. 2.03-3.89). When the studies were performed in a high clarithromycin resistance area (≥15%) or included patients with clarithromycin resistance, bismuth-containing regimens were superior to non-bismuth regimens. Moreover, the incidence of total side effects was insignificant. Bismuth supplements as a first-line regimen could be effective, with bismuth add-on regimens being the most effective. Particularly, bismuth supplements showed the potential efficacy for clarithromycin-resistant strains and would be the most viable alternative in clinical practice.

Characteristics of Dapagliflozin Responders: A Longitudinal, Prospective, Nationwide Dapagliflozin Surveillance Study in Korea.

IntroductionSodium glucose co-transporter 2 (SGLT2) inhibitors, such as dapagliflozin, have demonstrated favorable effects in patients with type 2 diabetes (T2D). However, there are limited reports in the literature regarding the glucose-lowering effects of SGLT2 inhibitors in actual clinical settings.MethodsThe post-marketing surveillance data from a longitudinal prospective study of 2007 patients with T2D who were prescribed dapagliflozin (10 mg/day) were analyzed (ClinicalTrials.gov, NCT02252224).ResultsAfter 12 weeks of dapagliflozin treatment, glycated hemoglobin (HbA1c) and body mass index were significantly decreased (P < 0.001) from 8.1 ± 1.3% to 7.5 ± 1.2% and from 28.1 ± 4.4 to 27.6 ± 4.2 kg/m2, respectively. Both body weight and HbA1c were reduced in 67.7% of patients, and HbA1c was lowered in 75.1%. Younger age, male sex, shorter diabetes duration, higher baseline HbA1c and estimated glomerular filtration rate (eGFR), and having dapagliflozin as add-on therapy were associated with stronger HbA1c reductions after dapagliflozin use (all P < 0.05). Moreover, subgroup analysis of eGFR of subjects with renal hyperfiltration (eGFR ≥ 120 ml/min/1.73 m2) showed the largest reduction in glucose level (% change, − 9.5; 95% CI − 6.8 to − 12.3 for HbA1c; P < 0.001). Multivariable logistic regression analysis showed that recent T2D diagnosis and higher HbA1c at baseline in patients who received an add-on regimen of dapagliflozin were statistically significantly associated with a dapagliflozin response (all P < 0.05).ConclusionsDapagliflozin provides benefits for glycemic control and body weight. Patients in a relatively early stage of the course of diabetes with renal hyperfiltration might be more suitable for and gain maximal benefit from dapagliflozin treatment.Trial RegistrationClinicalTrials.gov identifier, NCT02252224.FundingAstraZeneca.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0470-9) contains supplementary material, which is available to authorized users.

Patterns of antiepileptic drug prescription in Sweden: Aregister-based approach.

To determine drug utilization pathways from the incident healthcare visit due to epilepsy and three years onward. Anti-epileptic drug utilization was calculated using individual information on inpatient- and outpatient care utilization and drug sales. Throughout, we used national register information pertaining to pharmaceutical sales linked to diagnosis-related healthcare utilization. Information on pharmaceutical sales was collected for the 2007-2013 period. For the entire studied period, a majority of new patients with epilepsy were initiated on anti-epileptic drug treatment with a monotherapy (98%); most of these patients remained on that first treatment (64%). The three most frequently prescribed drugs accounted for 72% of the initiated AED treatments. Patients with epilepsy (ICD-10: G40/41) were most commonly prescribed carbamazepine, lamotrigine and valproate. The most common second-line monotherapy was levetiracetam. About 12% of new patients with epilepsy who were initiated on AED treatment during the period eventually switched to an add-on therapy. The proportion of patients who were initiated on treatment with carbamazepine or valproate decreased, and the proportion of patients who remained on their initial monotherapy increased between 2007 and 2013. A limited number of anti-epileptic drugs accounted for the treatment of a majority of new patients with epilepsy (carbamazepine, lamotrigine and valproate accounted for more than 70%). Add-on therapies showed the same pattern, as the most frequently prescribed add-on regimens were the same ones that accounted for most of the monotherapies. There was a tendency towards fewer patients being initiated on AED treatment with either carbamazepine or valproate.

Dual Therapy for Refractory Overactive Bladder in Children: A Prospective Open-Label Study

Mirabegron (β3 adrenoreceptor agonist) is a new molecule with a mechanism of action distinct from antimuscarinics. Combination therapy with solifenacin was recently studied in an adult population. We evaluated the efficacy and safety of mirabegron as add-on therapy to treat urinary incontinence in children with idiopathic overactive bladder refractory/intolerant to antimuscarinics. A prospective off-label study using add-on regimens of mirabegron was conducted in pediatric patients presenting with no symptom improvement while undergoing intensive behavioral and medical therapies and/or significant side effects while undergoing antimuscarinic dose escalation. Our primary outcome was better reported efficacy than with the use of prior antimuscarinic monotherapy. Secondary end points were tolerability, safety and satisfaction. Efficacy and tolerability were assessed based on voiding diaries, post-void residuals, urine cultures, electrocardiograms and vital signs. Families were questioned regarding continence, side effects and compliance. Wilcoxon signed-rank test was used for statistical analysis. A total of 35 patients were recruited at a median age of 10.3 years and were administered add-on mirabegron for a median of 16.4 months. Median bladder capacity improved from 50% to 74% expected bladder capacity (p<0.001). Continence improved in all patients, with 12 being completely dry. Post-void residual was increased in 2 patients and 1 urinary tract infection was reported. Seven patients reported mild or moderate side effects, with 2 withdrawals because of side effects (1 patient) and post-void residual (1). Add-on mirabegron appears to be a safe alternative for children with refractory overactive bladder. Dual therapy is well tolerated and adjusted dose regimen appears safe in this first pediatric study.

The role of zonisamide in the management of pediatric partial epilepsy

In our review we discuss the group of approved antiepileptic drugs for children in Hungary. We cite the results of the review conducted by the International League Against Epilepsy on antiepileptic drug efficacy and effectiveness as initial monotherapy for newly diagnosed epileptic seizures and syndromes in pediatric age group. 25% of pediatric epilepsy is therapy resistant, so we further need new drugs, which must be investigated according to the rules of the European Medicine Agency. The ethical dilemmas of childhood drug studies lead to the situation that the new antiepileptic drugs, approved as monotherapy in adult epilepsies, are in the majority just in add-on regimen tested in pediatric patients. As clinicians we appreciate open label extension safety studies. An old-new antiepileptic drug in Europe is zonisamide. Though it was approved for first line monotherapy in pediatric and adult patients with partial and generalised epilepsy in 1989 in Japan, the European Medicine Agency licensed its use as adjunctive therapy in children aged 6 years or older with partial seizures (with or without secondary generalisation) just in 2013. The results of the openlabel extension study appeared in 2014. The mean dose received was 7.5 mg/kg/day. During the open label phase 11% of the patients achieved seizure freedom and it was maintained throughout the study. The drug was generally well tolerated. The most frequently reported treatment-related adverse events were decreased weight (6%), decreased appetite (4%), and headache (2%). No new or unexpected side effects emerged. In conclusion oral zonisamide as adjunctive therapy in pediatric patients aged 6-17 years with partial seizures demonstrated an acceptable safety and tolerability profile and efficacy over a period at least 1 year. So it is a good treatment option in this population.

Does zafirlukast reduce future risk of asthma exacerbations in adults? Systematic review and meta-analysis

&#x0D; &#x0D; &#x0D; &#x0D; Background and objective: The purpose of asthma management is to achieve a total asthma control that involves current control and future risk. It has proven efficacy in reducing asthma exacerbations, but the effect size of zafirlukast for asthma exacerbations of various severity is not systematically explored.&#x0D; Methods: Randomized controlled trials were searched in PubMed Central, Web of Science, and Embase, where zafirlukast prevented asthma exacerbations in adults. The primary outcome was asthma exacerbations, the secondary outcomes were asthma exacerbations requiring systemic corticosteroids and emergency visits, respectively. Odds ratio (OR) with 95% confidence intervals (CI) were pooled.&#x0D; Results: Twelve trials were identified. As first-line therapy, compared to those having placebo, the patients with chronic asthma receiving zafirlukast experienced statistically lower asthma exacerbations (OR = 0.68, 95% CI = [0.45, 1.00]), but it was not found that zafirlukast was superior to placebo in asthma exacerbations requiring systemic corticosteroids (OR = 0.76, 95% CI = [0.45, 1.29]). Furthermore, zafirlukast was inferior to ICs in asthma exacerbations (OR = 2.11, 95% CI = [1.35, 3.30]) and requiring systemic corticosteroids (OR = 3.71, 95% CI = [1.82, 7.59]). As add-on therapy, zafirlukast was not superior to placebo in asthma exacerbations (OR =0.99, 95% CI = [0.54, 1.81] and requiring emergency visits (OR = 0.72, 95% CI = [0.18, 2.99]). Intriguingly, there was not a significant difference in asthma exacerbations between zafirlukast and ICs (OR = 1.12, 95% CI = [0.53, 2.34]).&#x0D; Conclusions: Our study suggests that zafirlukast, as the first-line therapy, significantly reduces mild to moderate but not severe asthma exacerbations. In the add-on regimen, zafirlukast could not reduce asthma exacerbations, which would perhaps result from small sample size and needs to be further studied.&#x0D; &#x0D; &#x0D; &#x0D;

Does zafirlukast reduce future risk of asthma exacerbations in adults? Systematic review and meta-analysis.

Background and objectiveThe purpose of asthma management is to achieve a total asthma control that involves current control and future risk. It has proven efficacy in reducing asthma exacerbations, but the effect size of zafirlukast for asthma exacerbations of various severity is not systematically explored.MethodsRandomized controlled trials were searched in PubMed Central, Web of Science, and Embase, where zafirlukast prevented asthma exacerbations in adults. The primary outcome was asthma exacerbations, the secondary outcomes were asthma exacerbations requiring systemic corticosteroids and emergency visits, respectively. Odds ratio (OR) with 95% confidence intervals (CI) were pooled.ResultsTwelve trials were identified. As first-line therapy, compared to those having placebo, the patients with chronic asthma receiving zafirlukast experienced statistically lower asthma exacerbations (OR = 0.68, 95% CI = [0.45, 1.00]), but it was not found that zafirlukast was superior to placebo in asthma exacerbations requiring systemic corticosteroids (OR = 0.76, 95% CI = [0.45, 1.29]). Furthermore, zafirlukast was inferior to ICs in asthma exacerbations (OR = 2.11, 95% CI = [1.35, 3.30]) and requiring systemic corticosteroids (OR = 3.71, 95% CI = [1.82, 7.59]). As add-on therapy, zafirlukast was not superior to placebo in asthma exacerbations (OR =0.99, 95% CI = [0.54, 1.81] and requiring emergency visits (OR = 0.72, 95% CI = [0.18, 2.99]). Intriguingly, there was not a significant difference in asthma exacerbations between zafirlukast and ICs (OR = 1.12, 95% CI = [0.53, 2.34]).ConclusionsOur study suggests that zafirlukast, as the first-line therapy, significantly reduces mild to moderate but not severe asthma exacerbations. In the add-on regimen, zafirlukast could not reduce asthma exacerbations, which would perhaps result from small sample size and needs to be further studied.

Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor α2 chain in recurrent malignant glioma patients with HLA-A*24/A*02 allele

Dendritic cell (DC)-based vaccination targeting tumor-associated antigens is an attractive approach to overcoming the limitations of current treatments for malignant gliomas (MG). Interleukin-13 receptor α2 chain (IL-13Rα2) is a promising target because of its abundant and specific expression in MG. We conducted a phase I trial of DC vaccination in patients with recurrent MG using two IL-13Rα2-derived peptides restricted to HLA-A*0201 and -A*2402. The objective was to evaluate the safety and clinical and immunologic responses. Eight recurrent MG patients were enrolled. DC were generated from peripheral blood and pulsed with HLA-matched peptide; 1 × 10(7) DC were administered every 2 weeks for a maximum of six immunizations. The T-cell response in peripheral blood was evaluated by tetramer and ELISPOT assays in HLA-A*2402 patients. All enrolled patients except one completed at least four DC vaccinations. No severe adverse events were observed. A positive T-cell response was detected in two out of three evaluable HLA-A*2402 patients. One patient achieved stable disease for 16 months and another patient showed a dramatic regression for one lesion for 4 months. The regimen was feasible and safe, and the HLA-A*24-restricted peptide exhibited a capacity to induce immune responses. These results warrant further studies to evaluate whether add-on regimens to post-operative chemoradiotherapy delays recurrence in newly diagnosed MG patients.

Use of moxonidine in elderly patients with resistant hypertension

Treatment of hypertension in the elderly people reduces the risk of cardiovascular and cerebrovascular events. Effective treatment often will require the use of two or more antihypertensive agents. Elderly people are at increased risk of adverse events from medication because of physiological changes in pharmacokinetics and pharmacodynamics, polypharmacy and drug interactions. They might not tolerate conventional add-on regimens of antihypertensives as a result. To investigate the use of the I1-imidazoline receptor agonist moxonidine as an 'add-on' agent in elderly patients with resistant hypertension. We investigated the safety and efficacy of moxonidine (200-400 microg) in a group of elderly patients whose blood pressure (BP) control remained poor despite treatment with two or more antihypertensives. BP was assessed by ambulatory BP monitoring with Spacelabs oscillometric equipment (Model 90207) before and after 6 weeks of treatment with moxonidine used as an 'add-on' agent with the patients normal medication. Following treatment with moxonidine, the mean daytime systolic BP fell from 169.2 to 153.8 mmHg, a significant reduction of 15.4 +/- 8.9 mmHg (P = 0.003). The mean daytime diastolic BP fell from 91.6 to 84.2 mmHg, a reduction of 7.4 +/- 5.8 mmHg (P = 0.017). For the night-time readings, the systolic BP fell from 151.1 to 141.2 mmHg, a reduction of 9.3 +/- 9.3 mmHg (P = 0.05). The corresponding diastolic fall in BP was not significant (77.9-74.7 mmHg). The 24 h-readings showed a significant reduction in the mean systolic BP from 163.0 to 148.6 mmHg (P = 0.004). The mean diastolic BP also fell significantly from 87.2 to 80.2 mmHg (P = 0.013). Clinical BP readings also showed a significant reduction from 195.9 +/- 19.6 to 174 +/- 17.8 mmHg (P = 0.002) and 103.6 +/- 9.5 to 99.0 +/- 12.4 mmHg (P = 0.013) for systolic and diastolic readings respectively. Moxonidine was well tolerated in 11 of the14 patients. These results suggest that moxonidine might have a place as an 'add-on' treatment in elderly patients whose hypertension is poorly controlled despite treatment with two or more antihypertensive agents.

Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing l-Thyroxine plus Liothyronine with l-Thyroxine Alone

Substituting part of the dose of l-thyroxine with small but supraphysiologic doses of liothyronine in hypothyroid patients has yielded conflicting results. To evaluate combinations of L-thyroxine plus liothyronine in hypothyroid patients that match the proportions present in normal secretions of the human thyroid gland. Randomized, double-blind, crossover trial. Academic research hospital. 28 women with overt primary hypothyroidism. Crossover trial comparing treatment with l-thyroxine, 100 microg/d (standard treatment), versus treatment with L-thyroxine, 75 microg/d, plus liothyronine, 5 microg/d (combination treatment), for 8-week periods. All patients also received L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d (add-on combination treatment), for a final 8-week add-on period. Primary outcomes included serum thyroid hormone levels, results of quality-of-life and psychometric tests, and patients' preference. Multiple biological thyroid hormone end points were studied as secondary outcomes. Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels. No improvement was observed in the other primary and secondary end points after combination treatment, with the exception of the Digit Span Test, in which the mean backward score and the mean total score increased slightly (0.6 digit [CI, 0.1 to 1.0 digit] and 0.8 digit [CI, 0.2 to 1.4 digits], respectively). The add-on combination treatment resulted in overreplacement. Levels of thyroid-stimulating hormone decreased by 0.85 mU/L (CI, 0.27 to 1.43 mU/L) and serum free triiodothyronine levels increased by 0.8 pmol/L (CI, 0.1 to 1.5 pmol/L) compared with standard treatment; 10 patients had levels of thyroid-stimulating hormone that were below the normal range. Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015). Treatment with L-thyroxine, 87.5 microg/d, plus liothyronine, 7.5 microg/d, was an add-on regimen and was not randomized. Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over l-thyroxine alone, yet patients prefer combination treatment.

Add-on combination and maintenance treatment: case series of five obese patients with different eating behavior.

Obesity is a general medical condition associated with an increase in morbidity and mortality. Although it would be desirable to use efficacious prevention programs, the success rates reported to date have been rather disappointing. In this observational study, a new drug treatment regimen was evaluated in five obese patients with a mean age of 39.6 +/- 4.2 years and an initial body mass index between 34.5 and 38.3 kg/m for a period of 96 weeks. The patients showed restrained and unrestrained eating patterns according to a German version of the Three-Factor Eating Questionnaire and were treated in an add-on regimen with the combination of three drugs with different anorectic properties that were consecutively introduced in an interval of 16 weeks. First, orlistat (120 mg three times a day) was given as a monotherapy. Sibutramine (15 mg in the morning) and then topiramate (in a dose dependent on appetite suppression and side effects) were added for a total duration of 48 weeks. A 48-week maintenance and relapse prevention treatment period with topiramate monotherapy followed the discontinuation of orlistat and sibutramine. This outpatient treatment procedure was tolerated well, although side effects occurred in all patients depending on the phase of the treatment regimen. After 96 weeks, the mean body mass index was 25.7 +/- 1.2 kg/m. Moreover, a normalization of eating patterns according to the Three-Factor Eating Questionnaire could be noticed. Factor 3, hunger, was significantly reduced. This treatment plan may be highly effective and safe in a subpopulation of obese patients.

Topiramate in the treatment of severe myoclonic epilepsy in infancy

The aim of this study was to assess the effectiveness of topiramate (TPM) as an add-on regimen in reducing seizure rate in a population sample of patients diagnosed with severe myoclonic epilepsy in infancy (SME). Eighteen patients were evaluated. The mean observation time was 10.5 months (range, 6–18 months). Seizure frequency and type were recorded. Topiramate was administered as an add-on regimen at a starting dose of 1 mg kg−1and titrated to a maximum of 6–8 mg per kg per day. Different escalation rates were used, mainly weekly or fortnightly increments of dose. Three patients (16.6%) became seizure free, and 10 (55.6%) had a >50% reduction in seizure frequency: six of them (22.2%) achieved a reduction greater than 75%. Side-effects were observed in nine patients , eight with a weekly titration schedule and one with a fortnightly schedule. TPM is effective as adjunctive therapy for SME. Side-effects were mild and transient, generally related to rapid dosage titration.