Modafinil for people with schizophrenia or related disorders.

BACKGROUND: People with schizophrenia have a range of different symptoms, including positive symptoms (hallucinations and delusions), negative symptoms (such as social withdrawal and lack of affect), and cognitive impairment. The standard medication for people with schizophrenia is antipsychotics. However, these medications may not be effective for all symptoms of schizophrenia, as cognitive and negative symptoms are usually hard to treat. Additional therapies or medications are available for the management of these symptoms. Modafinil, a wakefulness-promoting agent most frequently used in narcolepsy or shift work sleep disorder, is one intervention that is theorised to have an effect of these symptoms. OBJECTIVES: The primary objective of this review was to assess the effects of modafinil for people with schizophrenia or related disorders. SEARCH METHODS: On 27 April 2015, 24 May 2017, and 31 October 2019, we searched the Cochrane Schizophrenia Group's register of trials, which is based on regular searches of CENTRAL, MEDLINE, Embase, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials. There are no language, time, document type, or publication status limitations for the inclusion of records in the register. SELECTION CRITERIA: We selected all randomised controlled trials comparing modafinil with placebo or other treatments for people with schizophrenia or schizophrenia-spectrum disorders. DATA COLLECTION AND ANALYSIS: We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CI. We used a random-effects model for the meta-analysis. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for the included studies. MAIN RESULTS: Eleven studies including a total of 422 participants contributed to data analyses. Most studies had a small population size (average 38 people per study) and were of short duration. We also detected a high risk of bias for selective outcome reporting in just under 50% of the trials. We therefore rated the overall methodological quality of the included studies as low. We considered seven main outcomes of interest: clinically important change in overall mental state, clinically important change in cognitive functioning, incidence of a clinically important adverse effect/event, clinically important change in global state, leaving the study early for any reason, clinically important change in quality of life, and hospital admission. All studies assessed the effects of adding modafinil to participants' usual antipsychotic treatment compared to adding placebo to usual antipsychotic treatment. Six studies found that adding modafinil to antipsychotic treatment may have little or no effect on overall mental state of people with schizophrenia, specifically the risk of worsening psychosis (RR 0.91, 95% CI 0.28 to 2.98; participants = 209; studies = 6, low-quality evidence). Regarding the effect of modafinil on cognitive function, the trials did not report clinically important change data, but one study reported endpoint scores on the MATRICS Consensus Cognitive Battery (MCCB): in this study we found no clear difference in scores between modafinil and placebo treatment groups (MD -3.10, 95% CI -10.9 to 4.7; participants = 48; studies = 1, very low-quality evidence). Only one study (N = 35) reported adverse effect/event data. In this study one serious adverse event occurred in each group (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). One study measured change in global state using the Clinical Global Impression - Improvement Scale. This study found that adding modafinil to antipsychotic treatment may have little or no effect on global state (RR 6.36, 95% CI 0.94 to 43.07, participants = 21; studies = 1, very low-quality evidence). Nine studies found that modafinil has no effect on numbers of participants leaving the study early (RR 1.26, 95% CI 0.63 to 2.52 participants = 357; studies = 9, moderate-quality evidence). None of the trials reported clinically important change in quality of life, but one study did report quality of life using endpoint scores on the Quality of Life Inventory, finding no clear difference between treatment groups (MD -0.2, 95% CI -1.18 to 0.78; participants = 20; studies = 1, very low-quality evidence). Finally, one study reported data for number of participants needing hospitalisation: one participant in each group was hospitalised (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). AUTHORS' CONCLUSIONS: Due to methodological issues, low sample size, and short duration of the clinical trials as well as high risk of bias for outcome reporting, most of the evidence available for this review is of very low or low quality. For results where quality is low or very low, we are uncertain or very uncertain if the effect estimates are true effects, limiting our conclusions. Specifically, we found that modafinil is no better or worse than placebo at preventing worsening of psychosis; however, we are uncertain about this result. We have more confidence that participants receiving modafinil are no more likely to leave a trial early than participants receiving placebo. However, we are very uncertain about the remaining equivocal results between modafinil and placebo for outcomes such as improvement in global state or cognitive function, incidence of adverse events, and changes in quality of life. More high-quality data are needed before firm conclusions regarding the effects of modafinil for people with schizophrenia or related disorders can be made.

A Drug Safety Surveillance Study of a Ciprofloxacin/Dexamethasone Ophthalmic Fixed Combination in Peruvian Population.

(1) Background: drugs provide a significant benefit for patients who require medical treatment; however, their use implies an intrinsic potential danger, with the possibility of causing unwanted effects. These effects are known as adverse drug reactions (ADRs). Post-marketing drug safety surveillance detects unknown risks that have not been identified in clinical trials, and it is necessary to monitor marketed medications under real-life practice. Due to the scarce information about fixed combination of ciprofloxacin 0.3%/dexamethasone 0.1% (SDO), we performed a drug safety surveillance study. (2) Methods: A prospective non-controlled drug safety surveillance study was conducted in Peruvian population. A total of 236 patients prescribed SDO were included derived from 12 sites. Patients' standardized information was collected through two phone calls, including demographics, medical history, prescribing patterns of SDO, concomitant medication, and ADRs in detail. The ADRs were classified by causality and severity, followed by outcome measures to identify new risk. (3) Results: 236 patients prescribed with SDO participated in the study and 220 were included. A total of 82 ADRs/220 patients were reported after the use of SDO, presenting a ratio 0.37 ADR/patient. The most frequent ADR with SDO administration was eye irritation (30%). All ADRs were classified as non-serious, and 97.5% (n = 80) were classified as mild while 2.5% as moderate (n = 2). No cases under the severe category were identified. (4) Conclusion: No new risks were found in the population where this study was conducted.

Active Pharmacovigilance in Peruvian Population: Surveillance of a Timolol/Brimonidine/Dorzolamide Ophthalmic Fixed Combination.

PURPOSE: In this study active pharmacovigilance was used in an uncontrolled population to enrich the safety profile and canvass the Adverse Drug Reactions (ADRs) associated with the use of a fixed combination of 0.5% timolol + 0.2% brimonidine + 2.0% dorzolamide (TBD). METHODS: Active pharmacovigilance consisting of 3 follow-up calls within 60 days was used to monitor the product's safety and identify new risks by searching for unexpected ADRs and increased incidence, tolerability, drug interactions and special population-related ADRs. RESULTS: Ninety-four ADRs were reported by a total of 246 patients (0.38 ADRs/patient); all of them were classified as "mild". We found an increased risk of ADRs with a Relative Risk (RR) for simultaneous use of TBD + ophthalmic ciprofloxacin and TBD + oral atorvastatin; 2.0309 (95% CI, 1.2467-3.3083) and 1.8864 (95% CI, 1.0543-3.3754), respectively. Two unexpected ADRs were discovered, both of which presented belonged to the System Organ Class (SOC) of "infections and infestations" and the preferred term (PT) of "nasopharyngitis.". CONCLUSION: Three safety signals were identified, two of them corresponded to an increase in the incidence of ADRs and the last one is associated with 2 unexpected ADR. Nevertheless, we found a good tolerability profile for TBD in the study population.

Methodological assessment of Mexican Clinical Practice Guidelines: GRADE framework adherence and critical appraisal.

BACKGROUND AND OBJECTIVE: Clinical Practice Guidelines (CPGs) provide evidence-based recommendations to healthcare professionals, policy makers, patients and other stakeholders. Mexico is the biggest producer of CPGs in Latin America and Caribbean countries. The National Healthcare Technology Excellence Center (acronym in Spanish: CENETEC) is responsible for the CPG development, adaptation and update. The aim of this study was to assess the adherence to the GRADE framework and to critically appraise the Mexican CPGs with the AGREE-II tool. STUDY DESIGN: We conducted a descriptive cross-sectional study with a random sample of 86 CPGs produced by CENETEC between 2015 and 2017 and published in an online database called "Catalogo Maestro". We assessed the adherence to the GRADE framework and performed a critical appraisal with the AGREE II tool. RESULTS: Of the 86 CPGs, 34 were published in 2015, 21 in 2016 and 31 in 2017. Of the 86 CPGs, 25 (29%) used the GRADE framework; adherence to GRADE standards was, however, inconsistent and generally poor. The overall methodological quality by AGREE II proved a median of 16.6% (Min 16.6%, Max 50%). CONCLUSION: CPGs produced by CENETEC during this period had a poor adherence to the GRADE framework and low score by AGREE II standards. A concerted initiative could rapidly improve CENETEC guidelines.

Aminoguanidine reduces diabetes-associated cardiac fibrosis.

Aminoguanidine (AG) inhibits advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP) accumulated as a result of excessive oxidative stress in diabetes. However, the molecular mechanism by which AG reduces AGE-associated damage in diabetes is not well understood. Thus, we investigated whether AG supplementation mitigates oxidative-associated cardiac fibrosis in rats with type 2 diabetes mellitus (T2DM). Forty-five male Wistar rats were divided into three groups: Control, T2DM and T2DM+AG. Rats were fed with a high-fat, high-carbohydrate diet (HFCD) for 2 weeks and rendered diabetic using low-dose streptozotocin (STZ) (20 mg/kg), and one group was treated with AG (20 mg/kg) up to 25 weeks. In vitro experiments were performed in primary rat myofibroblasts to confirm the antioxidant and antifibrotic effects of AG and to determine if blocking the receptor for AGEs (RAGE) prevents the fibrogenic response in myofibroblasts. Diabetic rats exhibited an increase in cardiac fibrosis resulting from HFCD and STZ injections. By contrast, AG treatment significantly reduced cardiac fibrosis, α-smooth muscle actin (αSMA) and oxidative-associated Nox4 and Nos2 mRNA expression. In vitro challenge of myofibroblasts with AG under T2DM conditions reduced intra- and extracellular collagen type I expression and Pdgfb, Tgfß1 and Col1a1 mRNAs, albeit with similar expression of Tnfα and Il6 mRNAs. This was accompanied by reduced phosphorylation of ERK1/2 and SMAD2/3 but not of AKT1/2/3 and STAT pathways. RAGE blockade further attenuated collagen type I expression in AG-treated myofibroblasts. Thus, AG reduces oxidative stress-associated cardiac fibrosis by reducing pERK1/2, pSMAD2/3 and collagen type I expression via AGE/RAGE signaling in T2DM.