Successful Clozapine Re-Challenge After Suspected Clozapine-Induced Myocarditis.

BACKGROUND Clozapine plays a unique role in the management of treatment-resistant schizophrenia (TRS). Clozapine re-challenge following an episode of myocarditis is controversial, with a very limited literature, although it may be crucial in the recovery of certain patients. To date and to the best of our knowledge, only 10 of 22 studied cases reported successful clozapine retrial after myocarditis. CASE REPORT We present the case of a 22-year-old Hispanic man with treatment-resistant schizophrenia and polysubstance use disorder (methamphetamine, cannabis, and alcohol) initiated on aggressive clozapine titration after lack of response to several other therapies. Approximately 16 days after clozapine trial, the patient developed cardiac function impairment, presenting with chest pain, notable elevation in several biomarkers (troponin: 0.72 ng/ml, ESR >100 mm/h, CRP: 20.8 mg/dl, and BNP: 999 ng/ml), and a depressed ejection fraction at 25%. Further assessments also showed positive hepatitis A serology. Following discontinuation of clozapine and providing supportive care, the patient's physical symptoms resolved. He had a relapse of psychotic symptoms, which were refractory to treatment with other antipsychotic agents. Subsequently, the patient underwent a second clozapine trial under close monitoring, with resolution of his psychosis. Repeated echocardiography demonstrated improved EF to 50%, transaminitis was resolved, repeat blood test results were normalized, and the patient was discharged while he was stabilized and asymptomatic. CONCLUSIONS This case adds to the previous case reports and suggests that clinicians may consider clozapine re-challenge following an episode of myocarditis based on clinical judgment, on a case-by-case basis, and under close monitoring. We highlight the need for development of clinical guidelines for clozapine re-challenge.

Cost-Effectiveness Analysis of Tocilizumab in Comparison with Infliximab in Iranian Rheumatoid Arthritis Patients with Inadequate Response to tDMARDs: A Multistage Markov Model.

OBJECTIVES: To analyze the cost-effectiveness of two common treatment strategies in Iran, comparing infliximab plus methotrexate with tocilizumab plus methotrexate in patients with rheumatoid arthritis with inadequate response to traditional disease-modifying antirheumatic drugs. METHODS: A multistage Markov decision model was applied to assess the incremental cost-effectiveness ratio (ICER) of a tocilizumab-containing regimen versus an infliximab-containing regimen over a 5-year time period. In the case of no response, we assumed that patients switched to the next treatment (adalimumab, rituximab, or supportive care) in sequence for each strategy. We considered major cost items, such as direct medical costs and direct nonmedical costs, from a payer (patients and third-party payers) perspective. A deterministic sensitivity analysis was conducted to assess the robustness of the model results over the uncertainty of key parameters. RESULTS: In the base-case analysis, the ICER of the tocilizumab-containing regimen was US $60,800 per quality-adjusted life-year as compared to the infliximab-containing regimen. In the sensitivity analysis, changes in the price of the drugs by generic substitution, in utility scores, and in discount rate did not change our overall conclusions. Among all inputs to the primary study and the sensitivity analyses, however, the price of tocilizumab had the most impact on the ICER. CONCLUSIONS: Although tocilizumab and methotrexate provide a larger gain in quality-adjusted life-years, their current price is quite high as compared with those of our other interventions. Therefore, a regimen containing tocilizumab is not cost-effective as compared with an infliximab-containing regimen for patients with rheumatoid arthritis in Iran.

Degarelix for the treatment of advanced prostate cancer compared with GnRh-Agonists: a systematic review and meta-analysis.

BACKGROUND: Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer. We performed a systematic review to compare safety, efficacy and effectiveness of degarelix, a new gonadotropin-releasing hormone (GnRH) antagonist (blocker), versus gonadotropin-releasing hormone (GnRH) agonists. METHODS: MEDLINE, Web of Science and the Cochrane library were searched to identify all of the published Randomized Controlled Trials (RCTs) that used degarelix versus gonadotropin-releasing hormone agonists with or without anti-androgen therapy for the treatment of prostate cancer. We performed meta-analysis of extracted data on safety and efficacy of the target medication. RESULTS: Six studies were included. They involved a total of 2296 patients which were used in the meta-analysis. Follow-up times after treatment were between 12 weeks and 12 months. Three of six RCTs compared degarelix with goserelin and the others compared it with leuprolide. Meta-analysis on safety outcomes revealed that the only statistically significant difference between the degarelix treated group and GnRH agonists treated group was complication in the injection site which was higher in degarelix-treated group (OR= 46.34, 95% CI: 15.79 to 136, p<0.001). Although general mortality rate was lower in degarelix-treated group (OR= 2.06, 95% CI: 1.08 to 3.93, p=0.03); mortality due to the drug side effects was not different. Meta-analysis of efficacy data also showed that International Prostate Symptom Score (IPSS) reduction at week 12, (MD=-1.85, 95% CI: -2.97 to - 0.72, p=0.001) and Testosterone reduction between day 1-28, (OR=11.58, 95% CI: 5.77 to 23.22, p<0.001) was statistically higher in degarelix-treated group. Testosterone reduction after day 28 and prostate volume reduction did not have significant difference. CONCLUSION: Our meta-analysis indicates that, compared with GnRH agonists, degarelix has significantly more effects on lower urinary tract symptoms and also Prostate Specific Antigen (PSA) and testosterone reduction in the first month of the treatment. Except minor complications in the injection site like pain, erythema and swelling, there is no increase in major side effects and mortality due to degarelix. This is while the effect on testosterone and PSA after the first month of treatment is not statistically different between the two groups.

Comparative efficacy of methylphenidate and atomoxetine in the treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: The aim of this study was to directly compare efficacy of atomoxetine and methylphenidate in treatment of children and adolescents 6- 18 years. METHODS: All published, randomized, open label or double blind trials, comparing the efficacy of methylphenidate with atomoxetine in treatment of children diagnosed with ADHD, using DSM-IV criteria were included in this study; ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS) scores was used. The standardized mean difference (SMD) was used as a measure of effect size. RESULTS: Eleven studies were included with a total of 2,772 participants. The meta-analysis did not find a significant difference in the efficacy between methylphenidate and atomoxetine (SMD= 0.09, 95% CI -0.06, 0.25) (Z= 1.18, p= 0.24). Sub group analysis showed a significant standardized mean difference favoring OROS methylphenidate (SMD= 0.31, 95% CI 0.16, 0.47 (Z= 3.91, p< 0.0001); immediate release methylphenidate was not superior to atomoxetine (SMD= -0.05, 95% CI -0.20, 0.10) (Z= 0.68, p= 0.49). Open label trials did not make a difference in the standardized mean difference (SMD= 0.10, 95% CI -0.02, 0.23) (Z= 1.17, p= 0.09). There was significant heterogeneity among the studies (p= 0.003, I2= 63%). Subgroup analysis demonstrated that heterogeneity was because of the open label trials (p= 0.009, I2= 79%). CONCLUSION: Atomoxetine and methylphenidate showed comparable efficacy in the treatment of children and adolescents with ADHD. However, Osmotic (Controlled) Release Oral (Delivery) System (OROS) methylphenidate is more effective than atomoxetine in treatment of ADHD in children and adolescents that is suggested as a first-line treatment in ADHD. Moreover, comparing the immediate release (IR) methylphenidate to atomoxetine did not lead to the benefit of IR methylphenidate.

The safety and effectiveness of the current treatment regimen with or without roflumilast in advanced COPD patients: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease, which reduces the lung function and causes respiratory symptoms over time, and it is primarily associated with shortness of breath, cough and sputum production. Roflumilast, which is a long-acting selective inhibitor, reduces the anti-inflammatory effect of the main symptoms of COPD. The aim of this study was to compare the clinical effectiveness of adding roflumilast to the current treatment regimen of patients with severe COPD. METHODS: To retrieve the marker studies, medical databases were searched up to February 2014. We included studies, which compared the clinical effectiveness and safety of roflumilast as concomitant to Long-acting ß2-agonist/Long-acting muscarinic antagonist (LABA/LAMA) regimen, in adult patients with severe COPD. The number of exacerbations, changes in the lung function FEV1, FEV1/FVC and quality of life were the major predefined outcomes. Meta-analysis of outcomes was performed by the RevMan software, with I(2)> 50%, representing considerable heterogeneity. RESULTS: Seven randomized controlled trials and two systematic reviews were included. In terms of safety, participants were likely to experience more side effects from roflumilast compared to placebo, particularly gastrointestinal effects (diarrhea, nausea, vomiting), headache and weight loss. There was no significant difference in the risk of cardiac complications or flu-like symptoms or upper respiratory tract infection in the two groups. In terms of effectiveness, only a small improvement was observed in SGRQ (St George's Respiratory Questionnaire) index. Roflumilast reduced moderate to severe attacks, and caused significant improvements in the lung function regardless of the severity of the disease and the concurrent use of other standard COPD therapies. CONCLUSION: Roflumilast anti-inflammatory therapy reduces the chronic bronchitis symptoms in patients with moderate to severe COPD, and it can be safely used with other drugs simultaneously.

Comparison of the effectiveness and safety of formoterol versus salmeterol in the treatment of patients with asthma: A systematic review and meta-analysis.

BACKGROUND: Formoterol and salmeterol are two long-acting ß2-agonists given by inhalation, with bronchodilating effects lasting for at least 12 h after a single administration. Formoterol has a faster onset of action compared with salmeterol. The aim of this study was to perform a systematic review and meta-analysis on the data published from previous review in order to calculate pooled estimates of effectiveness and safety assessment of formoterol and salmeterol in treatment of patients with asthma. MATERIALS AND METHODS: In this study, we conducted an electronic search for medical citation databases including Cochrane, PubMed, Scopus, PsycInfo, and IranMedex. Besides manual search of the databases that record randomized clinical trials, conference proceedings, and journals related to asthma were included. Studies were evaluated by two independent people based on inclusion and exclusion criteria, and the common outcomes of studies were entered into the RevMan 5.0.1 software, after evaluation of studies and extraction of data from them; and in cases where there were homogeneous studies, meta-analysis was performed, and for heterogeneous studies, the results were reported qualitatively. RESULTS: Of the 1539 studies initially found, 13 were included in the study. According to the meta-analysis conducted, no significant difference was found between the inhalation of formoterol 12 µg and salmeterol 50 µg in the two outcomes of mean forced expiratory volume 1 s (FEV1), 12 h after inhalation of medication and Borg score (A frequently used scale for quantifying breathlessness) after inhalation of medication. In addition, salmeterol was more effective than formoterol in the two outcomes of percent decrease in FEV1 after inhalation of methacholine and the number of days without an attack. Since the two outcomes of FEV1 30-60 min after inhalation of medication and morning peak expiratory flow after inhalation of medication were heterogeneous, they had no meta-analysis capabilities, and its results were reported qualitatively. CONCLUSION: The data from included studies shows that, more efficacy has been achieved with Salmeterol, especially in some outcomes such as the percent decrease in FEV1 after inhalation of Methacholine, and the number of days without an attack; and therefore, the administration of Salmeterol seems to be beneficial for patients, compared with Formoterol.

Impact of sanctions on procurement of medicine and medical devices in Iran; a technical response.

Following recent sanctions on foreign trade, financial and banking services, Iran has faced major difficulties for importing medicines (both finished products and pharmaceutical raw materials) and medical devices. Problems with money transfer have made it extremely lengthy in time to import medicine and medical devices and these have negatively affected access to and affordability of medicines. Quality of pharmaceuticals and treatment of patients have also been affected due to changing the sources of imported medicines and raw materials for locally produced pharmaceuticals. Several interventions have been employed during the past few months in Iran to overcome the effects imposed by recent sanctions and drug shortages have been managed to some extent with attempts made by Iran Food and Drug Organization (IRI FDO). As recommended by the experts, a specific Society for Worldwide Interbank Financial Telecommunication line should be allocated for transferring money for medicines and medical devices and certain financial institutions are assigned for this purpose. It is also suggested that defining a white list of Iranian pharmaceuticals and medical device companies together with their foreign counterparts would facilitate this process. It appears that, in a public health prospective, ordinary people and patients are hurt and paying the cost for current sanctions. It remains the responsibility of the public health and international communities to separate public health from politics and to ease the pain of public from sanctions.

Pediatric multiple sclerosis with primary progressive course--report of a retrospective cohort study in Iran.

The aims of this study were to suggest the rate of primary progressive (PP) subtype of pediatric onset multiple sclerosis (MS) in Isfahan, Iran, and describe its clinical and paraclinical features. The data of patients were retrieved from Isfahan MS Society (IMSS) database from April 2003 to August 2011. Among 3,843 MS patients of Isfahan who have been registered in IMSS, 260 patients had onset symptom when younger than the age of 18 years, of whom, 11 patients had a PP course (4.23%). The mean age at onset in pediatric primary progressive multiple sclerosis (PPMS) was 16 years (range: 13 to 17) with female preponderance (2.66:1) and disease duration of 4.73 ± 3.03 years. Ataxia was the most frequent initial symptom (7/11). Additionally, the mean Expanded Disability Status Scale and progression index was 4.31 ± 0.60 and 1.50 ± 1.21, respectively. Cerebrospinal fluid analysis showed oligoclonal immunoglobulin G bands in seven patients. Magnetic resonance imaging (MRI) demonstrated periventricular lesions in all 11 patients and spinal lesions in 9 patients. Exposure to parental smoking was recorded in seven individuals. In conclusion, PPMS is an uncommon subtype of pediatric onset MS. Cerebral lesions are more common MRI findings in pediatric PPMS patients than that in adults. The course of PPMS seems to be more progressive in the pediatric population than in adults.