Strengthening research networks: Insights from a clinical research network in Brazil.

Clinical Research Networks (CRNs) are means to improve healthcare delivery, quality of care and patient outcomes. The Oswaldo Cruz Foundation (Fiocruz), Latin America's leading health research organization, has established a CRN to promote interaction and collaboration among its clinical research experts. After a decade of operation, a revitalization process was undertaken out of the need to improve its functionality. This study aimed to describe the evaluation process of the Fiocruz Clinical Research Network (RFPC) by gathering the opinions and perspectives of its members and identifying the network structure. The goal was to improve scientific collaboration and member engagement, thereby increasing the integration, effectiveness, and impact of clinical research conducted at the institution. Clinical research professionals at Fiocruz were invited to participate in an online questionnaire to collect information about their professional experience, the benefits and constraints of participating in research networks, relevant discussion topics, and the challenges of complying with Good Clinical Practices (GCP). With the help of social network analysis, a deeper understanding of the dynamics and structure of professional communication networks was obtained. The questionnaire was completed by 122 professionals (response rate 50.4%), with most respondents being principal investigators (PIs) with more than 10 years of professional experience (24.6%). Participation in research networks was considered beneficial, particularly in working groups (48.4%), and as an opportunity to exchange experiences with other professionals (44.3%). Almost half of the participants (48.4%) did not identify any barriers to participating in a network. Topics that required further discussion included data management, biorepositories and biobanks, and ethical and regulatory issues. Challenges to conducting clinical research with GCP standards included strategic support and funding, staffing and training, data management, infrastructure, quality management, and collaboration. Communication within the research network was loosely structured, with the most experienced professionals holding central positions. This analysis provided valuable insights to support the management of the RFPC. It highlighted the internal community's interests and expectations, identified key areas for improvement in GCP implementation, and influential professionals who could improve information sharing and national integration. The findings have far-reaching implications that can be applied in different contexts. They contribute to the ongoing discussion on the establishment and management of research networks.

Monoamine oxidase-A (MAO-A) low-expression variants and increased risk of Plasmodium vivax malaria relapses.

OBJECTIVES: Primaquine is essential for the radical cure of Plasmodium vivax malaria and must be metabolized into its bioactive metabolites. Accordingly, polymorphisms in primaquine-metabolizing enzymes can impact the treatment efficacy. This pioneering study explores the influence of monoamine oxidase-A (MAO-A) on primaquine metabolism and its impact on malaria relapses. METHODS: Samples from 205 patients with P. vivax malaria were retrospectively analysed by genotyping polymorphisms in MAO-A and cytochrome P450 2D6 (CYP2D6) genes. We measured the primaquine and carboxyprimaquine blood levels in 100 subjects for whom blood samples were available on the third day of treatment. We also examined the relationship between the enzyme variants and P. vivax malaria relapses in a group of subjects with well-documented relapses. RESULTS: The median carboxyprimaquine level was significantly reduced in individuals carrying low-expression MAO-A alleles plus impaired CYP2D6. In addition, this group experienced significantly more P. vivax relapses. The low-expression MAO-A status was not associated with malaria relapses when CYP2D6 had normal activity. This suggests that the putative carboxyprimaquine contribution is irrelevant when the CYP2D6 pathway is fully active. CONCLUSIONS: We found evidence that the low-expression MAO-A variants can potentiate the negative impact of impaired CYP2D6 activity, resulting in lower levels of carboxyprimaquine metabolite and multiple relapses. The findings support the hypothesis that carboxyprimaquine may be further metabolized through CYP-mediated pathways generating bioactive metabolites that act against the parasite.

Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study

The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration “time t” was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients’ adherence to the treatment and quality of life.

Poor response to azithromycin in cutaneous leishmaniasis leading to a premature interruption of a multicentric phase III clinical trial in Brazil

Introduction Parenteral antimony-based compounds are still the standard of care for cutaneous leishmaniasis (CL) treatment in many countries, despite their high toxicity. Previous studies showed that oral azithromycin could be an option for CL treatment. The aim of this study was to evaluate efficacy and safety of oral azithromycin (AZ) for CL treatment compared with injectable meglumine antimoniate (MA). Methods This was a randomized, open-label, 2-arm, non-inferiority clinical trial. Treatment-naïve patients with localized CL were treated with MA (15mg/kg/day up to 1,215mg) or AZ (500mg/day) during 20 consecutive days. The primary efficacy end point was a CL cure 90 days after treatment completion. The analysis was performed with intention-to-treat (ITT) and per protocol (PP) analyses. After an anticipated interim analysis, the study was interrupted due to the high failure rate in the azithromycin group. Results Twenty-four volunteers were included in each group. The MA group had a higher cure rate than the AZ group with the ITT and PP analyses, which were 54.2% versus 20.8% [relative risk (RR) 1.97; 95% confidence intervals (95%CI) 1.13-3.42] and 72.2% versus 23.8% (RR 3.03; 95%CI 1.34-6.87), respectively. No unexpected adverse events were observed. Conclusions ...