Joint modelling of multivariate longitudinal clinical laboratory safety outcomes, concomitant medication and clinical adverse events: Application to artemisinin-based treatment during pregnancy clinical trial
Noel PatsonMavuto MukakaUmberto D’AlessandroGertrude ChapoteraVictor MwapasaDon P. MathangaLawrence KazembeMiriam K. LauferTobias Chirwa
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Abstract Background In drug trials, clinical adverse events (AEs), concomitant medication and laboratory safety outcomes are repeatedly collected to support drug safety evidence. Despite the potential correlation of these outcomes, they are typically analysed separately, potentially leading to misinformation and inefficient estimates due to partial assessment of safety data. Using joint modelling, we investigated whether clinical AEs vary by treatment and how laboratory outcomes (alanine amino-transferase, total bilirubin) and concomitant medication are associated with clinical AEs over time following artemisinin-based antimalarial therapy. Methods We used data from a trial of artemisinin-based treatments for malaria during pregnancy that randomized 870 women to receive artemether–lumefantrine (AL), amodiaquine–artesunate (ASAQ) and dihydroartemisinin–piperaquine (DHAPQ). We fitted a joint model containing four sub-models from four outcomes: longitudinal sub-model for alanine aminotransferase, longitudinal sub-model for total bilirubin, Poisson sub-model for concomitant medication and Poisson sub-model for clinical AEs. Since the clinical AEs was our primary outcome, the longitudinal sub-models and concomitant medication sub-model were linked to the clinical AEs sub-model via current value and random effects association structures respectively. We fitted a conventional Poisson model for clinical AEs to assess if the effect of treatment on clinical AEs (i.e. incidence rate ratio (IRR)) estimates differed between the conventional Poisson and the joint models, where AL was reference treatment. Results Out of the 870 women, 564 (65%) experienced at least one AE. Using joint model, AEs were associated with the concomitant medication (log IRR 1.7487; 95% CI: 1.5471, 1.9503; p<0.001) but not the total bilirubin (log IRR: -0.0288; 95% CI: -0.5045, 0.4469; p=0.906) and alanine aminotransferase (log IRR: 0.1153; 95% CI: -0.0889, 0.3194; p=0.269). The Poisson model underestimated the effects of treatment on AE incidence such that log IRR for ASAQ was 0.2118 (95% CI: 0.0082, 0.4154; p=0.041) for joint model compared to 0.1838 (95% CI: 0.0574, 0.3102; p=0.004) for Poisson model. Conclusion We demonstrated that although the AEs did not vary across the treatments, the joint model yielded efficient AE incidence estimates compared to the Poisson model. The joint model showed a positive relationship between the AEs and concomitant medication but not with laboratory outcomes. Trial registration ClinicalTrials.gov: NCT00852423.Keywords:
Concomitant
Dihydroartemisinin
Lumefantrine
Artemisinin (qinghaosu), extracted from the Chinese herb Artemisia annua L. in 1972, and its three major derivatives--artemether, artesunate and dihydroartemisinin--were firstly identified as antimalarials and found active against all species of the malaria parasite. Since the early 1980s, artemisinin and its derivatives have been found efficacious against Schistosoma spp., notably larval parasites, and artemisinin derivatives have played a critical role in the prevention and treatment of human schistosomiasis in China. Currently, China is moving towards the progress of schistosomiasis elimination. However, the potential development of praziquantel resistance may pose a great threat to the progress of elimination of schistosomiasis japonica in China. Fortunately, these three major artemisinin derivatives also exhibit actions against adult parasites, and reduced sensitivity to artemether, artesunate and dihydroartemisinin has been detected in praziquantel-resistant S. japonicum. In this review, we describe the application of artemisinin derivatives in the prevention and treatment of schistosomiasis japonica in China, so as to provide tools for the global agenda of schistosomiasis elimination. In addition to antimalarial and antischistosomal actions, they also show activities against other parasites and multiple cancers. Artemisinin derivatives, as old drugs identified firstly as antimalarials, continue to create new stories.
SCHISTOSOMIASIS JAPONICA
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The declining efficacy of artemisinin derivatives against Plasmodium falciparum in western Cambodia is a major concern. The knowledge gap in the understanding of the mechanisms involved hampers designing monitoring tools. Here, we culture-adapted 20 isolates from Pailin and Ratanakiri (areas of artemisinin resistance and susceptibility in western and eastern Cambodia, respectively) and studied their in vitro response to dihydroartemisinin. No significant difference between the two sets of isolates was observed in the classical isotopic test. However, a 6-h pulse exposure to 700 nM dihydroartemisinin (ring-stage survival assay -RSA]) revealed a clear-cut geographic dichotomy. The survival rate of exposed ring-stage parasites (ring stages) was 17-fold higher in isolates from Pailin (median, 13.5%) than in those from Ratanakiri (median, 0.8%), while exposed mature stages were equally and highly susceptible (0.6% and 0.7%, respectively). Ring stages survived drug exposure by cell cycle arrest and resumed growth upon drug withdrawal. The reduced susceptibility to artemisinin in Pailin appears to be associated with an altered in vitro phenotype of ring stages from Pailin in the RSA.
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Piperaquine
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Artemisinin is famous for its effectiveness of treating malaria for years. Potential of artemisinin in treating cancer has been recently recognized. In this study, the anticancer potential of artemisinin and its derivative dihydroartemisinin (DHA) is comprehensively illustrated, including brief introduction of background and clinical applications. Artemisinin derivatives, especially dihydroartemisinin, of which the anticancer mechanism such as induction of apoptosis, inhibition of peripheral blood vessels has also been depicted. Cases of clinical study of cervical cancer and breast cancer are also reported to further proof the anticancer efficiency of dihydroartemisinin. Finally, summary of perspectives and significance of artemisinin and DHA is also provided.
Dihydroartemisinin
Artemisia annua
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We have produced monoclonal antibodies against artelinic acid and investigated the reactivity with artemisinin drugs and metabolites. Antibody F170-10 is fairly specific for artelinic acid but does bind artemisinin and artemether (3-5% cross-reactivity). Dihydroartemisinin, artesunate, and metabolites of artemisinin showed less reactivity. With this antibody, an inhibition ELISA has been set up to detect artemisinin compounds in urine. In healthy subjects who received a single oral dose of artemisinin, artemether, artesunate or dihydroartemisinin, ELISA reactivity in urine was found. This reactivity in urine paralleled the plasma concentrations of artemether and dihydroartemisinin. The results show that this immunoassay for artelinic acid can be used to detect artemisinin compounds in urine for about 8 hr after intake. With a more sensitive test, this simple method as a urine dipstick may be become useful for drug use and compliance studies in malaria-endemic areas where the artemisinin derivatives are increasingly used.
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Artemether
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Ten bisdihydroartemisinin ethers and five monodihydroartemisinin ethers were prepared from dihydroartemisinin. The bioactivities of the synthetic componds, artemisinin and dihydroartemisinin against Pieris rapae larvae were examined by using the conventional no-choice leaf-disk method at 1.0 g/L. The result showed the bis-ethers exhibited higher antifeedant activity, their antifeedant rates were 85.4-96.9% and 90.9-98.6% after 24 and 48 h, the mono-ethers were 45.5-60.6% and 50.9-68.2%, dihydroartemisinin was 36.6% and 42.4%, artemisinin was 40.1 and 47.0%. The bis-ethers also exhibited higher insecticidal activity, their rectified mortality rates were 72.7-95.5% after 96 h, the mono-ethers were 45.4-54.6%, dihydroartemisinin was 49.9%, artemisinin was not noticeable. Based on the activity data, the preliminary structure-activity relationship was also discussed.
Dihydroartemisinin
Pieris rapae
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Objective: To observe the inhibitory effect of artemisinin and its derivatives on non-small cell lung cancer A549 cells.Methods: The TC50(concentration required to cause 50% toxicity compared with controls)of artemisinin,dihydroartemisinin,and artesunate on A549 cells was detemined by MTT assay.The TC10 was selected as the experimental dosage in the proliferation inhibition of A549 assay.Results: The TC50 of artemisinin,dihydroartemisinin,and artesunate were 1.77 mmol/L,58.24 μmol/L,64.33 μmol/L,respectively.Artemisinin had no direct inhibition effect on the proliferation of A549,but dihydroartemisinin and artesunate prolonged the the cell cycle progression by delaying the double proliferation time.Conclusion: Dihydroartemisinin and artesunate may have direct inhibitory effect on the proliferation of A549 cells.
Dihydroartemisinin
Artesunate
IC50
MTT assay
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Dihydroartemisinin
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The area cultivated with Artemisia annua for the extraction of the antimalarial compound artemisinin is increasing, but the environmental impact of this cultivation has not yet been studied. A sensitive and robust method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the determination of artemisinin in soil. Dihydroartemisinin and artemether were included in the method, and performance on analytical columns of both traditional C(18) phenyl-hexyl and porous shell particles-based Kinetex types was characterized. The versatility of the method was demonstrated on surface water and groundwater samples and plant extracts. The limit of detection was 55, 30 (25 ng/g soil), and 4 ng/mL for dihydroartemisinin, artemisinin, and artemether, respectively. Method performance was demonstrated using naturally contaminated soil samples from A. annua fields in Kenya. The highest observed concentrations were above EC(10) for lettuce growth. Monitoring of artemisinin in soil with A. annua crop production seems necessary to further understand the impact in the environment.
Dihydroartemisinin
Artemisia annua
Artemether
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A monoclonal antibody (MAb) 1C1 against artemisinin was prepared by a cell fusion with splenocytes and aminopterin-sensitive myeloma cells, SP2/0. An artesunate-BSA conjugate was used as immunogen to raise antibodies specific to artemisinin. The prepared anti-artemisinin MAb-1C1 have a novel characteristic which shows a specificity to compounds that are structurally related to artemisinin such as artesunate (630 %) and dihydroartemisinin (29.9 %). By using MAb-1C1, a specific and reliable ELISA was developed for the detection of compounds structurally related to artemisinin. The system shows a full measuring range from 2 to 20 μg/mL in the case of artemisinin and from 4 to 125 ng/mL in the case of artesunate in the competitive ELISA, and was validated to be of use for surveying and breeding of Artemisia annua containing a high amount of artemisinin as well as for the characterization of the pharmacokinetics of artemisinin and its derivatives.
Artesunate
Dihydroartemisinin
Artemisia annua
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Dihydroartemisinin
Artemisia annua
Artemether
Artesunate
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