Delayed gametocyte clearance in Plasmodium vivax malaria is associated with polymorphisms in the cytochrome P450 reductase (CPR).

Primaquine (PQ) is the main drug used to eliminate dormant liver stages and prevent relapses in Plasmodium vivax malaria. It also has an effect on the gametocytes of Plasmodium falciparum; however, it is unclear to what extent PQ affects P. vivax gametocytes. PQ metabolism involves multiple enzymes, including the highly polymorphic CYP2D6 and the cytochrome P450 reductase (CPR). Since genetic variability can impact drug metabolism, we conducted an evaluation of the effect of CYP2D6 and CPR variants on PQ gametocytocidal activity in 100 subjects with P. vivax malaria. To determine gametocyte density, we measured the levels of pvs25 transcripts in samples taken before treatment (D0) and 72 hours after treatment (D3). Generalized estimating equations (GEEs) were used to examine the effects of enzyme variants on gametocyte densities, adjusting for potential confounding factors. Linear regression models were adjusted to explore the predictors of PQ blood levels measured on D3. Individuals with the CPR mutation showed a smaller decrease in gametocyte transcript levels on D3 compared to those without the mutation (P = 0.02, by GEE). Consistent with this, higher PQ blood levels on D3 were associated with a lower reduction in pvs25 transcripts. Based on our findings, the CPR variant plays a role in the persistence of gametocyte density in P. vivax malaria. Conceptually, our work points to pharmacogenetics as a non-negligible factor to define potential host reservoirs with the propensity to contribute to transmission in the first days of CQ-PQ treatment, particularly in settings and seasons of high Anopheles human-biting rates.

Spatial analysis of a case of reverse logistics of medicines in community pharmacies in Brazil - a preliminary study

Background: The reverse logistics of medicines consists of the logistical procedure of collection, transport, storage, treatment and final disposal of post-consumer or expired waste. Medicines can be toxic to the environment and affect the health of citizens of the territory. Community pharmacies, as a health facility, play a key role in this process. Objectives: Define the spatial analysis and cases of reverse logistics of medicines in community pharmacies in Brazil. Methods: This is a cross-sectional study, and the research covered the medicines collected by 400 community pharmacies in the period from 2020 to 2022. To obtain the data, the medicines were collected, weighed, segregated and the weight released on a dedicated waste management platform. All regions of Brazil subject to georeferencing were processed using the free software Geographic Information System (QGIS). Data were expressed as median and range or as frequency of occurrence. Chi-square t-test and Fisher's exact test were used to compare variables. The accepted significance level was 5%. Results: Of the five existing regions in Brazil, only three had records of reverse medication logistics. 4,519.74 Kg of products were collected, and the North region of Brazil was responsible for 69.1% of the collection. In the spatial analysis, it was possible to perceive a difference between the areas of concentration of the RDL, that is, locations where collections were carried out in the period from 2020 to 2022. Conclusion: The present study preliminarily analyzed the reverse logistics of medicines in Brazil. The data obtained can contribute to the knowledge of this area and to the strengthening of the process. Thus, these places must exercise a task force for the educational process of the population about the risks of incorrect disposal of medicines and that this could harm the environment, economic aspects of society, food and the entire context that involves health and well-being. of citizens (AU)

Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis.

Isoniazid is a key component of tuberculosis treatment. Adequate exposure is a determinant for therapeutic success; however, considerable inter- and intraindividual variations in drug plasma levels can lead to unfavorable outcomes. While some predictors of isoniazid levels are well-known, others, such as sex, yield controversial results, requiring further investigation to optimize exposure. This study investigates whether the sex of patients influences the dose administered and the concentrations of isoniazid in plasma. Levels of isoniazid were associated with the N-acetyltransferase 2 phenotypes. A total of 76 male and 58 female patients were included. Isoniazid was measured by high-performance liquid chromatography, and N-acetyltransferase 2 phenotypes were assessed using molecular techniques. The results show that the dose administered, expressed in mg/kg, was higher in females, but the plasma levels were similar between both sexes. Among patients, 46.2%, 38.8%, and 15% were slow, intermediate, and fast acetylators, respectively. As expected, isoniazid levels were associated with the acetylation phenotypes, with higher concentrations in the slow acetylators. Thus, sex-related difference in isoniazid levels is due to the body weight of patients, and the optimized dose regimen based on patient weight and acetylator phenotypes can improve the treatment outcomes.

Performing rapid metabolite tests (IgG-IgM) for SARS-CoV-2 infection in community pharmacies: A cross sectional-study from Brazil

Background: Immunochromatographic rapid tests in pharmacies allow the discovery of specific antibodies against SARS-CoV-2 or viral antigens and provide a broader and more effective screening of the virus. However, in many countries, this process is still not well defined. In this sense, the perception of pharmacists about these screening practices presents an overview of how the service is being carried out in the country. Objective: This study was to evaluate the performance of rapid immunochromatographic tests and their clinical results in community pharmacies in northern Brazil. Method: A retrospective study was carried out between May 2020 and December 2021 in community pharmacies in the northern region of Brazil. Participants were 18 years of age or older, of both sexes, who spontaneously sought the SARS-CoV-2 rapid testing service at pharmacies located in the municipality of Belem and who had had close contact with the virus or symptoms infection-related. Data were expressed as median and range or as frequency of occurrence. Chi-square t-test and Fisher’s exact test were used to compare variables. The accepted significance level was 5%. This study was approved by the Research Ethics Committee (number: 4,865,206). Results: A total of 78,849 patients were recruited into the study. Most patients, 37,847 (48%), were tested antibody positive for SARS-CoV-2. There were no severe signs and symptoms of the disease. The results showed the great demand for carrying out the rapid test in pharmacies and these places could contribute to the understanding of this health establishment, to curb the speed of SARS-CoV-2 dissemination. (AU)

Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis

ABSTRACT Isoniazid is a key component of tuberculosis treatment. Adequate exposure is a determinant for therapeutic success; however, considerable inter- and intraindividual variations in drug plasma levels can lead to unfavorable outcomes. While some predictors of isoniazid levels are well-known, others, such as sex, yield controversial results, requiring further investigation to optimize exposure. This study investigates whether the sex of patients influences the dose administered and the concentrations of isoniazid in plasma. Levels of isoniazid were associated with the N-acetyltransferase 2 phenotypes. A total of 76 male and 58 female patients were included. Isoniazid was measured by high-performance liquid chromatography, and N-acetyltransferase 2 phenotypes were assessed using molecular techniques. The results show that the dose administered, expressed in mg/kg, was higher in females, but the plasma levels were similar between both sexes. Among patients, 46.2%, 38.8%, and 15% were slow, intermediate, and fast acetylators, respectively. As expected, isoniazid levels were associated with the acetylation phenotypes, with higher concentrations in the slow acetylators. Thus, sex-related difference in isoniazid levels is due to the body weight of patients, and the optimized dose regimen based on patient weight and acetylator phenotypes can improve the treatment outcomes.

Pharmacokinetics of chloroquine in patients with malaria by P. vivax from the Western Brazilian Amazon basin.

The western Amazon basin is an important endemic area for malaria by P. vivax. In recent years, several reports showed the treatment failure with chloroquine, which can be related to resistance. The assessment of chloroquine resistance requires the evaluation of drug exposure, and when possible, the estimation of the pharmacokinetic parameters. However, there is no data on the pharmacokinetics of chloroquine in this endemic area. Moreover, the influence of the early reappearance of parasites in blood on the exposure to the drug was low exploited in the literature. The present study described the pharmacokinetic parameters of chloroquine in whole blood of adult patients with P. vivax malaria from the western Brazilian Amazon basin and compared the area under the curve (AUC) with the parasitological outcome at day 28. A total of 19 patients with parasite recurrence within 28 days and 20 patients with no recurrence were included in the study. Chloroquine was measured by high-performance liquid chromatography (HPLC). The pharmacokinetic parameters were estimated by non-compartmental modeling. The maximum concentration ranged from 1285 to 2030 ng/mL. The terminal half-life varied from 5.3 to 12.8 days. The volume of distribution from 1090 to 2340 L/kg, and the area under the curve to the last measurable concentration from 247 to 432 ng/mL.h. The pharmacokinetic parameters were similar in both groups, which suggests the lack of influence of early reappearance of parasites on chloroquine pharmacokinetics.

A preliminary study on the association of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids in patients with breast cancer.

The long-term treatment with tamoxifen can alter the lipid profile of patients with breast cancer. Only a few studies associated the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids, which is relevant as the distribution of these compounds for the tissues can be changed, negatively affecting the treatment. The variations in lipids also can account for the high interindividual variation in plasma concentrations of these compounds. The aim of this preliminary study was to associate the plasma levels of tamoxifen and the active metabolites with the lipid levels. An observational study of cases was conducted in patients with breast cancer using tamoxifen in a daily dose of 20 mg. The lipids were measured by spectrophotometric methods and the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen by high-performance liquid chromatography. A total of 20 patients were included in the study. The median plasma concentrations of tamoxifen, 4-hydroxytamoxifen and endoxifen were 62 ng/mL, 1.04 ng/mL and 8.79 ng/mL. Triglycerides levels ranged from 59 to 352 mg/dL, total cholesterol from 157 to 321 mg/dL, LDL-c from 72 mg/dL to 176 mg/dL and HDL-C from 25.1 mg/dL to 62.8 mg/dL. There were no significant associations between the plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen with the levels of triglycerides and total cholesterol. The multivariate analysis revealed a weak association between plasma concentrations of tamoxifen and the active metabolites with HDL-c, LDL-c and VLDL-c. This finding provides preliminary evidence of the low impact of lipoproteins levels in the exposure to tamoxifen, 4-hydroxytamoxifen and endoxifen.

Nutritional determinants as potential contributors to anemia in children and adolescents with malaria by P. vivax / Determinantes nutricionais como potenciais contribuintes para anemia em crianças e adolescentes com malária por P. vivax / Determinantes nutricionales como posibles contribuyentes para la anemia en niños y adolescentes con malaria por P. Vivax

Background and Objectives: Nutrition, in addition to its physiological function, plays an important role in the recovery of individuals with malaria, a disease that still represents a serious public health problem in the world. The objective of this study was to assess nutritional determinants in the frequency of food intake and the occurrence of anemia in children and adolescents with P. vivax malaria. Methods: A cross-sectional analytical study was carried out between 2014 and 2015 in the Marajo Island. The hemoglobin level was measured by the colorimetric enzymatic reaction and a questionnaire of food intake frequency was used to assess the consumption of different types of food. Results: A total of 67 patients met the inclusion criteria, from which 62.7% were children and 37.3% were adolescents. There was a high consumption of ultra-processed foods in both age groups. Anemia occurred in 52.2% of patients, and in most of them it was moderate. There was no significant association between anemia and sex, age group or parasitemia at admission. However a significant association was found between anemia and the ingestion of ultra-processed foods. Conclusion: The ingestion of ultra-processed foods contributes to anemia in children and adolescent with malaria by P. vivax.(AU)

Justificativa e Objetivos: A nutrição, além de sua função fisiológica, desempenha um papel importante na recuperação de indivíduos com malária, uma doença que ainda representa um grave problema de saúde pública no mundo. O objetivo deste estudo é avaliar os determinantes nutricionais na frequência da ingestão alimentar e a ocorrência de anemia em crianças e adolescentes com malária por P. vivax. Métodos: Estudo transversal analítico, realizado entre 2014 e 2015 na ilha do Marajó. O nível de hemoglobina foi medido pela reação enzimática colorimétrica e um questionário de frequência de ingestão alimentar foi utilizado para avaliar o consumo de alimentos. Resultados: Um total de 67 pacientes atendeu aos critérios de inclusão do estudo, dos quais 62,7% eram crianças e 37,3% adolescentes. Houve alto consumo de alimentos ultraprocessados em ambas as faixas etárias. A anemia foi detectada em 52,2% dos pacientes e, na maioria deles, foi moderada. Não houve associação significativa entre anemia e sexo, faixa etária ou parasitemia na admissão. No entanto, encontramos uma associação significativa entre presença de anemia e ingestão de alimentos ultraprocessados. Conclusão: A ingestão de alimentos ultraprocessados contribui para a anemia em crianças e adolescentes com malária por P. vivax.(AU)

Justificación y objetivos: La nutrición, además de su función fisiológica, juega un papel importante en la recuperación de las personas con malaria, una enfermedad que todavía representa un importante problema de salud pública en el mundo. El objetivo de este estudio es evaluar los determinantes nutricionales en la frecuencia del consumo de alimentos y la ocurrencia de anemia en niños y adolescentes con malaria por P. vivax. Métodos: se realizó un estudio analítico transversal entre 2014 y 2015, en la Isla de Marajó. El nivel de hemoglobina fue evaluado por ensayos enzimáticos colorimétricos y se utilizó un cuestionario de frecuencia de consumo de alimentos para evaluar el consumo. Resultados: Un total de 67 pacientes cumplió los criterios de inclusión en el estudio, de los cuales el 62,7% eran niños y el 37,3% adolescentes. Se registró un alto consumo de alimentos ultraprocesados en niños y adolescentes. La anemia se detectó en el 52,2% de los pacientes, de carácter moderada principalmente. No se encontró una asociación significativa entre anemia y sexo, grupo de edad o parasitemia al ingreso. Sin embargo, se encontró una asociación significativa entre la anemia y la ingestión de alimentos ultraprocesados. Conclusión: La ingesta de alimentos ultraprocesados se asocia con la presencia de anemia en niños y adolescentes con malaria por P. vivax.(AU)

Exposure to chloroquine in male adults and children aged 9-11 years with malaria due to Plasmodium vivax.

BACKGROUND: Chloroquine is effective against the asexual blood stage of Plasmodium vivax. A high proportion of children are underdosed with the drug, but there are no studies comparing chloroquine exposure in adults and children aged 8-11 years old. The present study intends to compare these populations using the area under the curve (AUC) derived from the plasma concentration-time profile in patients with P. vivax. METHODS: A prospective study of cases was performed on male children (aged 9-11 years) and adults with vivax malaria. Blood samples were collected after several days of treatment. Chloroquine was measured by high-performance liquid chromatography. A non-compartmental pharmacokinetic model was used to calculate the pharmacokinetic parameters of the drug. RESULTS: A total of 20 children and 25 adults were included in the study. Plasma concentrations of chloroquine in older children ranged from 67 to 1112 ng/ml, and in adults the value ranged from 74 to 1147 ng/ml. The AUC to the last measurable concentration and to infinite was significantly lower in children than in adults, indicating a lower exposure to the drug. CONCLUSION: These data demonstrate lower exposure to chloroquine in children, which corroborates the importance of optimising the doses of chloroquine in the study age band to ensure adequate exposure to the drug.

Absence of gender influence on the pharmacokinetics of chloroquine combined with primaquine in malaria vivax patients.

Chloroquine is the first-line therapy against the asexual stages of Plasmodium vivax . There is a high variation of chloroquine plasma levels after therapeutic doses, which can lead to inadequate exposure to the drug. The gender influence was low regarding the disposition of the drug, which is relevant as there are significant physiological variations between male and female patients. The objective of the study was to investigate whether gender modifies the pharmacokinetics parameters of chloroquine in patients with malaria vivax. A prospective study was performed in male and female adult patients using chloroquine (total dose of 25 mg/kg for three days) combined with primaquine. Serial blood samples were collected at admission and up to 672 h post-administration of the drugs. Chloroquine was measured in plasma samples by high-performance liquid chromatography with fluorescence detection. A non-compartmental analysis was used for modeling the data. A total of 26 male and 25 female patients were enrolled in the study. The pharmacokinetic parameters of chloroquine were similar between male and female patients: a half-life of 9.5 days and 10.2 days, maximum concentration (Cmax) of 1295 ng/ml and 1220 ng/ml, area-under-the-curve (AUC 0-28) of 241 µg/mL h and 237 µg/mL h, observed clearance (CL/f) of 5.8 and 5.5 L/h and the volume of distribution (V/f) of 1869 L and 1936 L. The study results suggest that a similar dose regimen of chloroquine combined with primaquine provides a comparable pattern of exposure in male and female patients.

Can diabetes mellitus modify the plasma concentrations of rifampicin in patients under treatment for tuberculosis?

Abstract Rifampicin is a key component of treatment for tuberculosis and its efficacy is determined by the blood levels attained after therapeutic doses. However, there is a high variability of rifampicin blood levels that is related to both the patient and the formulation used. To date, the effect of diabetes mellitus on the plasma levels of rifampicin was low exploited, which could be relevant either by the significant increase of the comorbidity worldwide as by the probable influence of diabetes on the rifampicin exposure. The study aims to evaluate whether diabetes mellitus contribute to the variation of the maximum concentration of rifampicin in patients with tuberculosis treated with a daily dose of 10 mg/kg. Rifampicin and glycated hemoglobin were measured by high-performance liquid chromatography, and blood glucose by spectrophotometry. A total of 62 male patients were included in the study, and 26 presented diabetes mellitus. Rifampicin plasma levels in 2-h plasma samples collected at day 61 ranged from 3 µg/mL to 14.2 µg/mL. Drugs levels were similar between diabetic and non-diabetic patients and were not correlated with blood glucose and glycated hemoglobin. Moreover, a high percentage of patients in both groups presented low levels of rifampicin.

Doses of primaquine administered to children with Plasmodium vivax according to an age-based dose regimen.

Primaquine is still the first-line drug to eliminate hypnozoites of Plasmodium vivax. The therapeutic efficacy is related to the total dose administered. In several endemic areas, the drug is administered for children in an age-based regimen, which can lead to inadequate exposure, increasing the rates of recurrence of the infection. The present study aims to describe the mg/kg total dose of primaquine administered to children for treatment for vivax malaria when an age-based regimen is used and to measure the plasma concentrations of primaquine and carboxyprimaquine. A total of 85 children were included in the study. The total dose of primaquine administered based on mg/kg had a median value of 3.22 mg/kg. The percentage of patients with a total dose below the required dose of 3.5 mg/kg was 55.75%. The median primaquine maximum concentration was 94 ng/ml. For carboxy-primaquine, the median maximum concentration was 375 ng/ml. The results suggest that age-based dosing regimens likely lead to substantial under-dosing of primaquine, which is evident in the youngest children and is reflected in decreased levels of primaquine and carboxy-primaquine in plasma samples 13.

Can diabetes mellitus modify the plasma concentrations of rifampicin in patients under treatment for tuberculosis?

Rifampicin is a key component of treatment for tuberculosis and its efficacy is determined by the blood levels attained after therapeutic doses. However, there is a high variability of rifampicin blood levels that is related to both the patient and the formulation used. To date, the effect of diabetes mellitus on the plasma levels of rifampicin was low exploited, which could be relevant either by the significant increase of the comorbidity worldwide as by the probable influence of diabetes on the rifampicin exposure. The study aims to evaluate whether diabetes mellitus contribute to the variation of the maximum concentration of rifampicin in patients with tuberculosis treated with a daily dose of 10mg/kg. Rifampicin and glycated hemoglobin were measured by high-performance liquid chromatography, and blood glucose by spectrophotometry. A total of 62 male patients were included in the study, and 26 presented diabetes mellitus. Rifampicin plasma levels in 2-h plasma samples collected at day 61 ranged from 3µg/mL to 14.2µg/mL. Drugs levels were similar between diabetic and non-diabetic patients and were not correlated with blood glucose and glycated hemoglobin. Moreover, a high percentage of patients in both groups presented low levels of rifampicin.

An Ultra-Sensitive Technique: Using Pv-mtCOX1 qPCR to Detect Early Recurrences of Plasmodium vivax in Patients in the Brazilian Amazon.

BACKGROUND: Early recurrence of Plasmodium vivax is a challenge for malaria control in the field, particularly because this species is associated with lower parasitemia, which hinders diagnosis and monitoring through blood smear testing. Early recurrences, defined as the persistence of parasites in the peripheral blood despite adequate drug dosages, may arise from resistance to chloroquine. The objective of the study was to estimate early recurrence of P. vivax in the Brazilian Amazon by using a highly-sensitive detection method, in this case, PCR. METHODS: An ultra-sensitive qPCR that targeted mitochondrial DNA was used to compare a standard qPCR that targeted 18S rDNA to detect early recurrence of P. vivax in very low densities in samples from patients treated with chloroquine. RESULTS: Out of a total of 312 cases, 29 samples (9.3%) were characterized as recurrences, from which 3.2% (10/312) were only detected through ultra-sensitive qPCR testing. CONCLUSIONS: Studies that report the detection of P. vivax early recurrences using light microscopy may severely underestimate their true incidence.

Association of Lipid Levels with Mefloquine and Carboxy-Mefloquine Concentrations in Patients with Uncomplicated Falciparum Malaria.

Mefloquine shows a high capacity to bind plasma proteins, which influences the amount of drug in erythrocytes. The study investigated the association of lipids levels with plasma concentrations of mefloquine and carboxy-mefloquine in 85 Brazilian patients with uncomplicated falciparum malaria. There were no significant associations between the total cholesterol or triglycerides with plasma concentrations of mefloquine and of carboxy-mefloquine. Lipoprotein levels explained 25.68% and 18.31% of mefloquine and carboxy-mefloquine plasma concentrations, respectively.

Doses of chloroquine in the treatment of malaria by Plasmodium vivax in patients between 2 and 14 years of age from the Brazilian Amazon basin.

BACKGROUND: A total dose of chloroquine of 25 mg/kg is recommended by the World Health Organization (WHO) to treat malaria by Plasmodium vivax. In several endemic areas, including the Brazilian Amazon basin, anti-malarial drugs are dispensed in small plastic bags at a dosing regimen based on age. This practice can lead to suboptimal dosing of the drug, which can impact treatment outcomes. The aim of the present study was to estimate the extent of sub-dosing of chloroquine in children and adolescents with vivax malaria using an age-based dose regimen, in addition to investigating the influence of age on the plasma concentrations of chloroquine and desethylchloroquine. METHODS: A study of cases was conducted with male patients with a confirmed infection by P. vivax, ages 2 to 14 years, using a combined regimen of chloroquine and primaquine. Height, weight and body surface area were determined at admission on the study. The total dose of chloroquine administered was estimated based on the weight and on the body surface area of the study patients. Chloroquine and desethylchloroquine were measured on Day 7 in each patient included in the study by a high-performance liquid chromatographic method with fluorescence detection. RESULTS: A total of 81 patients were enrolled and completed the study. The median age was 9 years (2-14 years). All patients presented negative blood smears at 42 days follow-up. The total dose of chloroquine ranged from 13.1 to 38.1 mg/kg. The percentage of patients with a total dose of the drug below 25 mg/kg ranged from 29.4 to 63.6%. The total dose of chloroquine administered based on BSA ranged from 387 to 1079 mg/m2, increasing with age. Plasma chloroquine concentrations ranged from 107 to 420 ng/ml, increasing with age. For desethylchloroquine, the plasma concentrations ranged from 167 to 390 ng/ml, with similar values among age-groups. CONCLUSION: The data demonstrated the widespread exposure of children and adolescents to suboptimal doses of chloroquine in the endemic area investigated.

Concentrations of rifampicin in pre-dose samples in patients with pulmonary tuberculosis.

Rifampicin is used in both phases of treatment for tuberculosis. In chronic use, the short half-life and the self-induction of metabolism can decrease the levels of the drug below the minimal inhibitory concentration. The aim of the study was to investigate whether plasma concentrations of rifampicin are sustained above 0.5µg/mL in patients with tuberculosis using 600mg/day. Rifampicin was measured in plasma by high-performance liquid chromatography and a sputum smear microscopy was performed in all days of the study. A total of 44 male patients completed the study. On days 31, 61 and 91, the mean plasma concentrations of rifampicin were 0.6 (0.5)µg/mL, 0.55 (0.5)µg/mL and 0.46 (0.4)µg/mL. There was a high variation of rifampicin levels leading to a high percentage of samples with concentrations below 0.5µg/mL. There was no significant association between the frequency of samples with drug levels below 0.5µg/mL with the conversion of the sputum microscopy. These data suggest that pre-doses samples offer limited information on the exposure of M. tuberculosis to rifampicin.