Single Low Dose Primaquine (0.25mg/kg) Does Not Cause Clinically Significant Haemolysis in G6PD Deficient Subjects

Background

Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75mg/kg (adult dose 45mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15–20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25mg/kg (adult dose 15mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%.

Methods and Findings

The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic.

Conclusions

The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01872702","term_id":"NCT01872702"}}NCT01872702     

Effects of oral contraceptive use on body mass index and blood pressure among female villagers in north-east Thailand

The use of contraceptives has become prevalent among females in Thailand in the past 20 years, and oral contraceptive use has been suggested to trigger changes in fat intake, energy expenditure, fat metabolism and blood pressure. Based on field investigations of 391 married women aged 20 years or over in Yasothon Province, North-east Thailand, this study aims to elucidate the effects of oral contraceptive use on body mass index (BMI: kg/m2) and blood pressure, taking into account reproductive histories and socioeconomic conditions. The proportion of obese (BMI > or = 25) subjects was high in the age groups 30-39, 40-49 and 50-59, accounting for, respectively, 39.4%, 51.1% and 48.5% of these populations. The proportion of women with hypertension (90/140 mmHg) was 23.7%, 18.5% and 26.2% in the 40-49, 50-59 and 60-69 age groups. Current contraceptive practices in the studied population included sterilization by operation, oral contraception and injection. These methods accounted for 43.0%, 12.8% and 8.2% of the population, respectively. Sociodemographic factors such as reproductive history, years of education and household income were not significantly related to BMI or to blood pressure (ANOVA with age adjustment). In contrast, oral contraceptive users had significantly higher BMIs and diastolic blood pressures (p<0.01, ANOVA with age adjustment). Multiple regression analysis also revealed that oral contraceptive use was a weak but significant contributing factor to both high BMI and blood pressure when sociodemographic factors were taken into account and controlled for statistically. It can thus be concluded that the use of contraceptive pills, which contain oestrogen and progestin and are provided free of charge to Thai women, tend to increase BMI and to elevate blood pressure.     

Long-term persistence of cytomegalovirus genome in cultured human cells of prostatic origin.

Cells from prostatic tissue obtained from a 3-year-old male donor exhibited scattered foci of cytopathology on primary culture. A virus was isolated and shown by serological analysis to be cytomegalovirus (CMV). After a number of cell culture passages, a cell line (disignated CMV-Mj-P) was obtained in which foci of infection could no longer be demonstrated, nor could virus be rescued. On continued passage the doubling time of the cells decreased markedly, and the fibroblastoid cells ceased to demonstrate contact inhibition. CMV-specific antigen(s) was detected on the surface of the cells by indirect immunofluorescence techniques after exposure of the cultures to iododeoxyuridine. Microcytotoxocity tests established that CMV-Mj-P cells, but not control human prostate cells or human embryonic lung cells, share a membrane antigen with hamster cells transformed by CMV. Nucleic acid hybridization studies revealed that virus genetic information was carried by the human prostate cells and that the cells contained an average of about 10 to 15 genome equivalents of CMV DNA. Karyotypic analysis confirmed that the CMV-Mj-P cells were of human male origin. These results indicate that the cells either have been transformed by CMV or are chronically infected with CMV and releasing virus at levels below detection.     

Effects of Combining 2 Weeks of Passive Sensory Stimulation with Active Hand Motor Training in Healthy Adults

The gold standard to acquire motor skills is through intensive training and practicing. Recent studies have demonstrated that behavioral gains can also be acquired by mere exposure to repetitive sensory stimulation to drive the plasticity processes. Single application of repetitive electric stimulation (rES) of the fingers has been shown to improve tactile perception in young adults as well as sensorimotor performance in healthy elderly individuals. The combination of repetitive motor training with a preceding rES has not been reported yet. In addition, the impact of such a training on somatosensory tactile and spatial sensitivity as well as on somatosensory cortical activation remains elusive. Therefore, we tested 15 right-handed participants who underwent repetitive electric stimulation of all finger tips of the left hand for 20 minutes prior to one hour of motor training of the left hand over the period of two weeks. Overall, participants substantially improved the motor performance of the left trained hand by 34%, but also showed a relevant transfer to the untrained right hand by 24%. Baseline ipsilateral activation fMRI-magnitude in BA 1 to sensory index finger stimulation predicted training outcome for somatosensory guided movements: those who showed higher ipsilateral activation were those who did profit less from training. Improvement of spatial tactile discrimination was positively associated with gains in pinch grip velocity. Overall, a combination of priming rES and repetitive motor training is capable to induce motor and somatosensory performance increase and representation changes in BA1 in healthy young subjects.     

Scanning electron microscopic examination of a pellet formulation of Bacillus megaterium and B. pumilus,antagonists of Rhizoctonia solani,and survival during storage

Bacterial formulations, produced using both Bacillus megaterium and B. pumilus individually with pharmaceutical technology, were formulated using a wet granular method. Viability testing in the laboratory revealed that bacterial populations rapidly declined during storage at room temperature (26–30 °C) for 6 months. The scanning electron microscope (SEM) was used to observe bacterial formulations. Both endospores and vegetative cells of B. megaterium and B. pumilus were detected on the formulation surfaces. This revised version was published online in July 2006 with corrections to the Cover Date.     

Greenhouse and field trials of the bacterial antagonists in pelletformulations to suppress sheath blight of rice caused by Rhizoctoniasolani

Bacterial formulations, produced using both Bacillus megaterium andB. pumilus individually with pharmaceutical technology, were testedunder both greenhouse and field conditions. In the greenhouse testing,some bacterial formulations, for instance For 7 minus Lac and For 16 minusLac, performed as well as freshly prepared bacterial antagonists insuppress sheath blight disease. In the field testing, For 16 minus Lac wasnot effective in suppressing sheath blight development. Failure of the For16 minus Lac to suppress sheath blight disease in the field trial may be dueto the dilution and inactivation of antibiotics produced by B.megaterium in the aquatic environment in the rice field and climaticconditions during the formulation application.     

Radioreceptor assay for epidermal growth factor.

An established cell line of human lung fibroblasts with a high number of surface receptorsfor mouse epidermal growth factor (mEGF) was used to develop a simple and highly sensitive radioreceptor assay for EGF. ¹²⁵I-Labeled mEGF competed mole for mole with unlabeled mEGF for specific receptors. Optimal range for discriminating EGF concentrations in body fluids and tissue extracts by a competitive binding assay was between 5 and 100 ng/ml. Interassay correlation of variation was 8.47% and the recovery of highly purified mEGF added to serum and urine samples was greater than 95%. Human serum and amniotic fluids contained about 24 and 4 ng/ml, respectively, of mEGF equivalents. Concentrations of mEGF in mouse urine and serum were highly variable and were 2- to 10-fold greater than that previously detected by radioimmune assay. Hypophysectomy nearly abolished submaxillary mEGF content in both male and female mice, but testosterone treatment of hypophysectomized animals restored normal concentrations of mEGF to the glands. mEGF added to culture medium disappeared with time as a function of the number of cellular EGF receptors indicating cellular degradation of the growth factor. The radioreceptor assay for EGF is based on the close biologic relationship between the cell receptor site and the native hormone and should prove to be a useful complementary tool to characterize the physiological role of EGF.     

Correlation between phosphatidylcholine labeling and hormone receptor levels in alveolar type II epithelial cells: effects of dexamethasone and epidermal growth factor

Phosphatidylcholine labeling was studied in freshly isolated adult rat alveolar type II epithelial cells exposed to dexamethasone and epidermal growth factor. Dexamethasone at a medium concentration of 10^?8m, enhanced phosphatidylcholine labeling in type II cells by about 25%. In lung fibroblast controls, dexamethasone had no effect. Phosphatidylcholine secretion into the culture medium was not observed in either cell type. Quantitation of dexamethasone receptors revealed a twofold greater number of receptors in type II cells than in control fibroblasts. In contrast, the addition of epidermal growth factor to the medium of type II cells or lung fibroblasts had no effect on phosphatidylcholine labeling or secretion into culture medium. Lung fibroblasts were found to have 11-fold more surface receptors for epidermal growth factor than isolated type II cells. These results indicate that dexamethasone significantly increases phosphatidylcholine synthesis in type II cells and thus, may also effect the production of surfactant by these cells.