The pharmacokinetics and drug-drug interactions of ivermectin in Aedes aegypti mosquitoes

Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. FemaleAedes aegyptimosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01–1 μg/ml ivermectin without showing saturation (R2: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI90%: 17.0–19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI90%: 5.1–5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI90%: 8.7–14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in anAe.aegyptianimal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods.

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Larvicidal activity of phytoextracts against dengue fever vector, Aedes aegypti - A review

Plant Science Today ◽

10.14719/pst.2018.5.4.407 ◽

2018 ◽

Vol 5 (4) ◽

pp. 167-174 ◽

Cited By ~ 1

Author(s):

Kalarikkal Venugopalan Lakshmi ◽

Ambalaparambil Vasu Sudhikumar ◽

Embalil Mathachan Aneesh

Keyword(s):

Life Cycle ◽

Aedes Aegypti ◽

Vector Control ◽

Dengue Fever ◽

Inhibitory Action ◽

Control Measures ◽

Mosquito Vectors ◽

Chemical Insecticide ◽

Insecticide Application ◽

Efficient Control

Since Aedes aegypti is considered as the major vector of dengue fever, development of strategies to accomplish improved vector control without much interference in the environment composition are more common. As phytochemicals are now in the run for achieving this goal, this review is a humble attempt to recognize the plant species and their larvicidal efficacy with their inhibitory action on the life cycle of the species of interest, that has been documented through various studies conducted till date. Here we also discuss the synergistic impact of a number of phytoextracts which will provide more efficient control measures for mosquito vectors. All these studies are an exploration for a risk-free vector control tactic to replace the current chemical insecticide application for the betterment of our nature.

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Pharmacokinetics and Monte Carlo Simulations of Doripenem in Patients with Febrile Neutropenia

Annals of Pharmacotherapy ◽

10.1345/aph.1r097 ◽

2012 ◽

Vol 46 (10) ◽

pp. 1281-1286 ◽

Cited By ~ 10

Author(s):

Gary E Stein ◽

Grace Kulhanek ◽

Curtis L Smith ◽

Joseph L Kuti ◽

David P Nicolau ◽

...

Keyword(s):

Monte Carlo ◽

Febrile Neutropenia ◽

Drug Exposure ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Gram Negative Bacteria ◽

Time Curve ◽

Gram Negative ◽

Probability Estimates ◽

Drug Concentrations

Background: Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia. Objective: To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens. Methods: We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every B hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT>MIC). Results: The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h-1, a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg·h/L. An optimal probability of target attainment (40% fT>MIC) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed. Conclusions: The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.

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Vector control measures failed to affect genetic structure of Aedes aegypti in a sentinel metropolitan area of Brazil

Acta Tropica ◽

10.1016/j.actatropica.2013.09.002 ◽

2013 ◽

Vol 128 (3) ◽

pp. 598-605

Author(s):

Kathleen R. Souza ◽

Gilmar Ribeiro ◽

Carlos Gustavo Silva dos Santos ◽

Eliaci Couto de Lima ◽

Paulo R.S. Melo ◽

...

Keyword(s):

Genetic Structure ◽

Aedes Aegypti ◽

Vector Control ◽

Metropolitan Area ◽

Control Measures

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Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02605-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2965-2971 ◽

Cited By ~ 18

Author(s):

Amit Khatri ◽

Sandeep Dutta ◽

Martin Dunbar ◽

Thomas Podsadecki ◽

Roger Trinh ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Drug Interactions ◽

Healthy Volunteers ◽

Antiretroviral Drugs ◽

Pharmacokinetic Parameters ◽

Direct Acting Antiviral ◽

Drug Concentrations ◽

Tenofovir Df ◽

Direct Acting

ABSTRACTThe three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n= 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (≤32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen.

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Population Pharmacokinetics of Pyrimethamine and Sulfadoxine in Children Treated for Congenital Toxoplasmosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.10.3794-3800.2004 ◽

2004 ◽

Vol 48 (10) ◽

pp. 3794-3800 ◽

Cited By ~ 20

Author(s):

Stéphane Corvaisier ◽

Bruno Charpiat ◽

Cyril Mounier ◽

Martine Wallon ◽

Gilles Leboucher ◽

...

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Rate Constants ◽

High Performance ◽

Structural Model ◽

Elimination Rate ◽

Congenital Toxoplasmosis ◽

Compartment Model ◽

Pharmacokinetic Parameters ◽

Drug Concentrations

ABSTRACT The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis. A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling. PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months. Drug concentrations were measured by high-performance liquid chromatography. A total of 101 measurements in serum were available for both drugs. Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h−1, 4.379 liters/kg, 0.00839 h−1, and 5.5 days for PYR and 1.659 h−1, 0.392 liters/kg, 0.00526 h−1, and 6.6 days for SDX, respectively. Wide interindividual variability was observed. The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively. Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children. Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight. The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established. A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children.

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Abundance and Updated Distribution of Aedes aegypti (Diptera: Culicidae) in Cabo Verde Archipelago: A Neglected Threat to Public Health

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17041291 ◽

2020 ◽

Vol 17 (4) ◽

pp. 1291

Author(s):

Silvânia Da Veiga Leal ◽

Isaias Baptista Fernandes Varela ◽

Aderitow Augusto Lopes Gonçalves ◽

Davidson Daniel Sousa Monteiro ◽

Celivianne Marisia Ramos de Sousa ◽

...

Keyword(s):

Public Health ◽

Aedes Aegypti ◽

Vector Control ◽

Disease Outbreaks ◽

Control Measures ◽

Domestic Water ◽

Breeding Sites ◽

Cabo Verde ◽

Larval Survey ◽

Vector Borne

Background: Mosquito-borne viruses, such as Zika, dengue, yellow fever, and chikungunya, are important causes of human diseases nearly worldwide. The greatest health risk for arboviral disease outbreaks is the presence of the most competent and highly invasive domestic mosquito, Aedes aegypti. In Cabo Verde, two recent arbovirus outbreaks were reported, a dengue outbreak in 2009, followed by a Zika outbreak in 2015. This study is the first entomological survey for Ae. aegypti that includes all islands of Cabo Verde archipelago, in which we aim to evaluate the actual risk of vector-borne arboviruses as a continuous update of the geographical distribution of this species. Methods: In order to assess its current distribution and abundance, we undertook a mosquito larval survey in the nine inhabited islands of Cabo Verde from November 2018 to May 2019. Entomological larval survey indices were calculated, and the abundance analyzed. We collected and identified 4045 Ae. aegypti mosquitoes from 264 positive breeding sites in 22 municipalities and confirmed the presence of Ae. aegypti in every inhabited island. Results: Water drums were found to be the most prevalent containers (n = 3843; 62.9%), but puddles (n = 27; 0.4%) were the most productive habitats found. The overall average of the House, Container, and Breteau larval indices were 8.4%, 4.4%, and 10.9, respectively. However, 15 out of the 22 municipalities showed that the Breteau Index was above the epidemic risk threshold. Conclusion: These results suggest that if no vector control measures are considered to be in place, the risk of new arboviral outbreaks in Cabo Verde is high. The vector control strategy adopted must include measures of public health directed to domestic water storage and management.

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Effect of polyaspartic acid on pharmacokinetics of gentamicin after single intravenous dose in the dog.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.5.1237 ◽

1996 ◽

Vol 40 (5) ◽

pp. 1237-1241 ◽

Cited By ~ 8

Author(s):

T Whittem ◽

K Parton ◽

K Turner

Keyword(s):

Aspartic Acid ◽

Elimination Rate ◽

Volume Of Distribution ◽

Intravenous Dose ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Peripheral Compartment ◽

Single Intravenous Dose ◽

Polyaspartic Acid ◽

Peripheral Tissues

The effects of poly-L-aspartic acid on the pharmacokinetics of gentamicin were examined by using a randomized crossover trial design with the dog. When analyzed according to a three-compartment open model, poly-L-aspartic acid reduced some first-order rate equation constants (A3, lambda 1, and lambda 3), the deep peripheral compartment exit microconstant (k31), the elimination rate constant (k(el)), and the area under the concentration-time curve from 0 to 480 h (AUC0-480) (0.21-, 0.60-, 0.26-, 0.27-, 0.72-, and 0.76-fold, respectively; P < 0.05) but increased the volume of distribution at steady state (Vss), the volume of distribution calculated by the area method (V(area)), the apparent volume of the peripheral compartment (Vp), and all mean time parameters. These results suggested that poly-L-aspartic acid increased the distribution of gentamicin to or binding within the deep peripheral compartment and that poly-L-aspartic acid may have delayed gentamicin transit through the peripheral tissues. In contrast, poly-L-aspartic acid did not alter pharmacokinetic parameters relevant to the central or shallow peripheral compartments to a clinically significant extent. Although gentamicin's pharmacokinetic parameters of relevance to therapeutic drug monitoring were not directly altered, this study has provided pharmacokinetic evidence that poly-L-aspartic acid alters the peripheral distribution of gentamicin. This pharmacokinetic interaction occurred after a single intravenous dose of each drug. Therefore, this interaction should be investigated further, before polyaspartic acid can be considered for use as a clinical nephroprotectant.

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High insecticide resistance mediated by different mechanisms in Culex quinquefasciatus populations from the city of Yaoundé, Cameroon

Scientific Reports ◽

10.1038/s41598-021-86850-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Abdou Talipouo ◽

Konstantinos Mavridis ◽

Elysée Nchoutpouen ◽

Borel Djiappi-Tchamen ◽

Emmanouil Alexandros Fotakis ◽

...

Keyword(s):

Insecticide Resistance ◽

Vector Control ◽

High Resistance ◽

Culex Quinquefasciatus ◽

Control Strategies ◽

Cuticular Hydrocarbon ◽

Control Measures ◽

High Frequencies ◽

The City ◽

Integrated Vector Control

AbstractCulex mosquitoes particularly Culex quinquefasciatus are important arboviral and filariasis vectors, however despite this important epidemiological role, there is still a paucity of data on their bionomics. The present study was undertaken to assess the insecticide resistance status of Cx. quinquefasciatus populations from four districts of Yaoundé (Cameroon). All Culex quinquefasciatus populations except one displayed high resistance to bendiocarb and malathion with mortalities ranging from 0 to 89% while high resistance intensity against both permethrin and deltamethrin was recorded. Molecular analyses revealed high frequencies of the ACE-1 G119S mutation (ranging from 0 to 33%) and kdr L1014F allele (ranging from 55 to 74%) in all Cx. quinquefasciatus populations. Significant overexpression was detected for cytochrome P450s genes CYP6AA7 and CYP6Z10, as well as for Esterase A and Esterase B genes. The total cuticular hydrocarbon content, a proxy of cuticular resistance, was significantly increased (compared to the S-lab strain) in one population. The study confirms strong insecticide resistance mediated by different mechanisms in Cx. quinquefasciatus populations from the city of Yaoundé. The expansion of insecticide resistance in Culex populations could affect the effectiveness of current vector control measures and stress the need for the implementation of integrated vector control strategies in urban settings.

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Predicting Aedes aegypti infestation using landscape and thermal features

Scientific Reports ◽

10.1038/s41598-020-78755-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Camila Lorenz ◽

Marcia C. Castro ◽

Patricia M. P. Trindade ◽

Maurício L. Nogueira ◽

Mariana de Oliveira Lage ◽

...

Keyword(s):

Remote Sensing ◽

Aedes Aegypti ◽

Vector Control ◽

Land Surface ◽

Urban Areas ◽

Negative Binomial ◽

Control Strategies ◽

Winter Season ◽

Landsat 8 ◽

Thermal Features

AbstractIdentifying Aedes aegypti breeding hotspots in urban areas is crucial for the design of effective vector control strategies. Remote sensing techniques offer valuable tools for mapping habitat suitability. In this study, we evaluated the association between urban landscape, thermal features, and mosquito infestations. Entomological surveys were conducted between 2016 and 2019 in Vila Toninho, a neighborhood of São José do Rio Preto, São Paulo, Brazil, in which the numbers of adult female Ae. aegypti were recorded monthly and grouped by season for three years. We used data from 2016 to 2018 to build the model and data from summer of 2019 to validate it. WorldView-3 satellite images were used to extract land cover classes, and land surface temperature data were obtained using the Landsat-8 Thermal Infrared Sensor (TIRS). A multilevel negative binomial model was fitted to the data, which showed that the winter season has the greatest influence on decreases in mosquito abundance. Green areas and pavements were negatively associated, and a higher cover of asbestos roofs and exposed soil was positively associated with the presence of adult females. These features are related to socio-economic factors but also provide favorable breeding conditions for mosquitos. The application of remote sensing technologies has significant potential for optimizing vector control strategies, future mosquito suppression, and outbreak prediction.

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Withdrawal of cefoperazone with milk after intramammary administration in dairy cows – prospective and retrospective analysis

Polish Journal of Veterinary Sciences ◽

10.1515/pjvs-2017-0031 ◽

2017 ◽

Vol 20 (2) ◽

pp. 261-268

Author(s):

A. Burmańczuk ◽

T. Grabowski ◽

T. Błądek ◽

C. Kowalski ◽

P. Dębiak

Keyword(s):

Dairy Cows ◽

Half Life ◽

Drug Distribution ◽

Compartment Model ◽

Clinical Mastitis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Lactation Period ◽

Milk Samples ◽

Drug Concentrations

Abstract The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

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