Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation

Aim

The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.

Methods

Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.

Results

Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.

Conclusions

The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.     

New insights on IgA vasculitis with underlying solid tumor: a nationwide French study of 30 patients

Clinical Rheumatology - IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the...     

Plasmodium vivax resistance to chloroquine in Dawei, southern Myanmar

Objective  To assess the efficacy of chloroquine in the treatment of Plasmodium vivax malaria in in Dawei District, southern Myanmar.
Methods  Enrolled patients at Sonsinphya clinic >6 months of age were assessed clinically and parasitologically every week for 28 days. To differentiate new infections from recrudescence, we genotyped pre- and post-treatment parasitaemia. Blood chloroquine was measured to confirm resistant strains.
Results  Between December 2002 and April 2003, 2661 patients were screened, of whom 252 were included and 235 analysed. Thirty-four per cent (95% CI: 28.1–40.6) of patients had recurrent parasitaemia and were considered treatment failures. 59.4% of these recurrences were with a different parasite strain. Two (0.8%) patients with recurrences on day 14 had chloroquine concentrations above the threshold of 100 ng/ml and were considered infected with chloroquine resistant parasites. 21% of failures occurred during the first 3 weeks of follow-up: early recurrence and median levels of blood chloroquine comparable to those of controls suggested P. vivax resistance.
Conclusions  Plasmodium vivax resistance to chloroquine seems to be emerging in Dawei, near the Thai-Burmese border. While chloroquine remains the first-line drug for P. vivax infections in this area of Myanmar, regular monitoring is needed to detect further development of parasite resistance.     

Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee

OBJECTIVE: To assess the efficacy and safety of topical diclofenac diethylamine gel, 1.16%, 4 g applied qid for 3 weeks to relieve the symptoms of osteoarthritis (OA) of the knee. METHODS: Patients with OA of the knee washed out their OA medications for at least 5 drug half-lives. Patients with adequately high baseline pain scores were randomized to apply either double-blind active or placebo gel for 3 weeks. Acetaminophen (up to 2 g/day) was supplied as rescue medication. In a diary, patients recorded compliance to dosing and use of rescue medication and assessed daily pain on movement, spontaneous pain, and pain relief. At weekly site visits, patients completed the Western Ontario and McMaster (WOMAC) Osteoarthritis Index Questionnaire, which includes assessment of pain, stiffness, and physical function, and assessed pain intensity "right now." At the final visit, a global assessment of treatment efficacy was completed. RESULTS: Of 238 randomized patients, 237 were included in the intent to treat efficacy analysis. Treatments differed significantly for daily pain on movement at Day 5, and continued on most days through end of study. Peak differences were achieved in the second week. On the primary outcome, average pain on movement over Days 1-14, diclofenac gel was significantly superior to placebo gel. Scores for all 3 WOMAC indices for diclofenac gel treatment were significantly superior to placebo at Weeks 2 and 3. A significant difference was achieved on pain intensity "right now" at all 3 weeks. At the end of the study, patients rated diclofenac gel as significantly more effective in treating the pain of OA of the knee (p = 0.03) compared to placebo. There were no safety issues concerning adverse events or laboratory values. CONCLUSION: Diclofenac gel was effective and safe for relief of symptoms of OA of the knee over 3 weeks of dosing.     

Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection disturbs glucose and lipid metabolism contributing to the development of liver steatosis, insulin resistance and type 2 diabetes mellitus. On the other hand, insulin resistance and steatosis have been found to be associated with increased rates of fibrosis progression and lower rates of response to interferon therapy in chronic hepatitis C (CHC). The molecular mechanisms contributing to insulin resistance in CHC are not well understood. We have shown previously that protein phosphatase 2A (PP2A) is over-expressed in biopsies from patients with CHC. In this study, we tested if PP2A over-expression leads to insulin resistance. METHODS: We studied insulin signalling in cell lines that allow the regulated over-expression of HCV proteins and of the PP2A catalytic subunit (PP2Ac). Insulin signalling and PP2Ac expression were also studied in HCV transgenic mice and in liver biopsies from patients with CHC. RESULTS: Over-expression of PP2Ac in cells inhibited insulin signalling by dephosphorylation of PKB/Akt. PP2Ac over-expression and impaired insulin signalling were found in the liver of HCV transgenic mice and in liver biopsies of patients with CHC. CONCLUSIONS: HCV-induced over-expression of PP2A in the liver contributes to the pathogenesis of insulin resistance in patients with CHC.     

Mutation analysis in families with discordant phenotypes of phenylalanine hydroxylase deficiency. Inheritance and expression of the hyperphenylalaninaemias

Summary Neonatal hyperphenylalaninaemia caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) represents a wide spectrum of metabolic phenotypes, ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). The marked interindividual heterogeneity is due to the expression of multiple PAH mutations in genetic compounds. We have investigated four unusual families in which both PKU and MHP were present. In each family three different mutations in the PAH gene were identified, including two associated with PKU and one associated with MHP. The unexpected outcome of discordant phenotypes within the families described is explained by previously unrecognized parental MHP. By mutation analysis we have also predicted the phenotypical outcome in a hyperphenylalaninaemic infant born to a mother who before pregnancy had been diagnosed as having MHP. Our results demonstrate the utility of nucleic acid analysis in follow-up in PKU screening programmes.     

Constitutional thinness: unusual human phenotype of low bone quality

CONTEXT: Low fat mass and hormonal or nutritional deficiencies are often incriminated in bone loss related to thinness. Constitutional thinness has been described in young women with low body mass index (BMI) but close-to-normal body composition, physiological menstruation, no hormonal abnormalities, and no anorexia nervosa (AN) psychological profile. OBJECTIVE: Our objective was to determine whether constitutional thinness is associated with impaired bone quality. DESIGN, SETTING, AND PARTICIPANTS: This was an observational, cross-sectional study on 25 constitutionally thin and 44 AN young women with similar low BMI (<16.5 kg/m2) and 28 age-matched controls. MAIN OUTCOME MEASURES: Femoral and lumbar spine bone mineral density by dual-energy x-ray absorptiometry, distal tibia and radius bone architecture and breaking strength by three-dimensional peripheral quantitative computed tomography, and bone turnover markers were determined. RESULTS: Constitutionally thin subjects displayed a higher percentage of fat mass than AN subjects but had similar lumbar and femoral bone mineral density, which were significantly lower than in controls (P < 0.001). Constitutionally thin subjects displayed more markedly impaired trabecular and cortical bone parameters in the distal tibia than in the radius. AN bone structure was impaired only in subjects with a long history of disease. Calculated breaking strength was decreased in constitutional thinness and long-standing AN in both the radius and the tibia. Bone markers in constitutionally thin subjects were similar to those of controls. Osteoprotegerin to receptor activator of nuclear factor kappa B ligand ratio was higher in constitutionally thin subjects than in controls or AN women. CONCLUSIONS: Young women with constitutional thinness present an unexpectedly high prevalence of low bone mass (44%) associated with small bone size, overall diminished breaking strength, but normal bone turnover. Mechanisms related to insufficient skeletal load and/or genetics are proposed to explain this new phenotype of impaired bone quality.     

Translocation t(5;12)(q31-q33;p12-p13): a non-random translocation associated with a myeloid disorder with eosinophilia

SUMMARY. To investigate the clinical significance of determination of plasma tissue factor (TF) antigen, we have developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) for plasma TF, using two different monoclonal antibodies against TF apoprotein, 6B4 (catching antibody) and 5G9 (detecting antibody), and tetramethyl benzidine/H₂O₂ as substrates. Titration curves of recombinant human TF in buffer containing Triton X-100 were linear within the range from 50 to 2000pg/ml. The total assay time was 3h. Ultracentrifugation and immunoblot analysis indicated that human plasma and urine contained 50 000 g sedimentable and non-sedimentable forms of TF, both of which were detected by our ELISA method.
Plasma and urine concentrations of TF in healthy subjects and patients with various diseases were measured by the ELISA method. In healthy subjects, plasma and urinary TF levels were found to be 149± 72pg/ml (n = 30) and 175±60pg TF/urine creatinine mg (n = 95). respectively. TF was increased in plasma of patients with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura, vasculitis associated with collagen diseases, diabetic microangiopathy and chronic renal failure receiving haemodialysis, but not in the plasma of endotoxaemic patients without DIC. The plasma TF/serum creatinine ratio did not show a positive correlation. Measurement of TF antigen in plasma may be useful for evaluating the endothelial damage and cell destruction in TF-containing tissues.     

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.     

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.