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.     

Antinuclear antibody positive pleural effusion in a patient with tuberculosis

A patient with tuberculosis presented with a pleural effusion that was highly positive for antinuclear antibody (ANA). The pleural fluid autoimmune profile was positive for ANA IgG at a titre of 1 : 1280. Antibodies to double-stranded DNA were not detected in the pleural fluid or in serum.The serum autoimmune profile was positive for ANA IgG at 1 : 160 and IgM at 1 : 40. Pleural fluid was positive on culture for Mycobacterium tuberculosis after 8 weeks. Pleural biopsy for histology showed chronic inflammation and culture revealed no growth. The pleural fluid resolved with the anti-tuberculous treatment, and signs and symptoms of systemic lupus erythematosus or malignancy did not occur, which suggests that tuberculous pleural effusion is one of the causes of high ANA in pleural fluid.     

The anti-leukaemic activity of novel synthetic naphthoquinones against acute myeloid leukaemia: induction of cell death via the triggering of multiple signalling pathways

Naphthoquinones, such as menadione, display lower toxicity than anthracyclins used in cancer chemotherapy. Novel anti-leukaemic compounds comprised of chloro-amino-phenyl naphthoquinones with substitutions on the benzoic ring were developed. Structure–activity relationship studies indicated that the analogue with both methyl and amine substitutions (named TW-92) was the most efficient in killing leukaemic cells. Treatment of U-937 promonocytic cells with TW-92 induced apoptotic or necrotic cell death, dependent on incubation and dose conditions. TW-92 induced rapid phosphorylation of p38 mitogen-activated protein kinase (p38^MAPK) and of extracellular signal-regulated protein kinases (ERK1/2). The generation of apoptosis was preceded by intracellular H₂O₂ accumulation accompanied by glutathione depletion, the former inhibited by di-phenyl-iodonium (DPI), an inhibitor of NADPH oxidase. TW-92 induced swelling of isolated rat liver mitochondria, indicative of a direct effect on mitochondria. Apoptosis in intact cells was accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase activation. In addition, the level of Mcl-1, an anti-apoptotic regulatory protein, was down-regulated, whereas the expression of the pro-apoptotic BAX was elevated. Finally, TW-92 exerted strong pro-apoptotic and necrotic effects in primary acute myeloid leukaemia samples when given in submicromolar concentrations. Together, these findings demonstrate that TW-92 may provide an effective anti-leukaemic strategy.     

Pitfalls in estimating piperaquine elimination

By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a healthy volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs.     

The role of transbronchial needle aspiration in the diagnosis of bronchogenic carcinoma

BACKGROUND: For many years in the United States transbronchial needle aspiration (TBNA) has been used with flexible bronchoscopy to diagnosis bronchogenic carcinoma, but very few data are available from the United Kingdom. METHODS: All bronchoscopies performed for suspected bronchial carcinoma at Papworth Hospital, Cambridge, United Kingdom, over the last 3 years were reviewed retrospectively. Patients with peribronchial disease, as evidenced by submucosal infiltration or extrinsic compression on bronchoscopy, were selected for TBNA. Patients with computed tomography evidence of subcarinal lymphadenopathy were also included. In total we identified 78 patients: 67 with peribronchial disease and 21 with subcarinal lymphadenopathy. All 78 patients underwent TBNA, and in 8 of these TBNA was performed in 2 sites. RESULTS: Malignancy was confirmed in 66 of the 78 patients. TBNA was positive in 31/66 (47%) of the patients who had proven bronchogenic carcinoma. Additional staging information was obtained in 9/21 patients (42.8%) who underwent subcarinal lymph node aspiration. We also found that TBNA was diagnostic in 1 patient with tuberculosis and 1 with sarcoidosis. There was only 1 important TBNA complication, which was a small pneumothorax. CONCLUSION: In our preliminary experience with selected patients suspected to have bronchogenic carcinoma (based on peribronchial disease or subcarinal lymphadenopathy), we found TBNA a safe and useful tool.     

Cardiopulmonary exercise tests and lung cancer surgical outcome

STUDY OBJECTIVES: Surgical resection remains the treatment of choice for anatomically resectable non-small cell lung cancer. However, the presence of associated comorbid conditions increases the risk of death and surgical complications. Several studies have evaluated the usefulness of preoperative exercise testing for predicting postoperative morbidity and mortality. The aim of this study was to establish whether exercise testing could predict poor surgical outcome in lung cancer surgery and whether the absolute value or percentage of predicted value is the better predictor of the surgical outcome. DESIGN: The study was designed as a prospective study. PATIENTS AND SETTING: One hundred thirty patients with potentially operable lung cancer at Papworth Hospital over 2 years were recruited; of these, 101 underwent curative surgery. INTERVENTIONS: Spirometry and cardiopulmonary exercise tests were performed for every patient (n = 99), except for two patients with back problems. We also recorded the outcome of surgery, in particular, complications and mortality. MEASUREMENTS AND RESULTS: Mean maximum oxygen transport at peak exercise (Vo(2)peak) was 18.3 mL/kg/min (SD, 4.7 mL/kg/min), and mean percentage of predicted Vo(2)peak value was 84.4% (SD, 30%). Poor surgical outcome was significantly related to Vo(2)peak percentage of predicted (p < 0.01) but not to the actual oxygen uptake value. CONCLUSIONS: The use of the percentage of predicted Vo(2)peak value would be a better indicator of surgical outcome, since it predicts the surgical outcome better, and corrects for normal physiologic ranges. The threshold of Vo(2)peak for surgical intervention could be set between 50% and 60% of predicted without excess surgical mortality.