Oral hypomethylating agents: beyond convenience in MDS

Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.

Susceptibility of Boll Weevil (Coleoptera: Curculionidae) to Ethiprole, Differential Toxicity Against Selected Natural Enemies, and Diagnostic Concentrations for Resistance Monitoring

Synthetic insecticide application is one tactic for reducing boll weevil, Anthonomus grandis grandis Boheman (Coleoptera: Curculionidae), infestations during the cotton, Gossypium hirsutum L., reproductive stage. We assessed the susceptibility of the boll weevil and its natural enemies to ethiprole (mode of action 2B), a phenylpyrazole insecticide, and diagnostic concentrations of ethiprole indicative of boll weevil susceptibility. Differences in the lethal concentrations of ethiprole were calculated with susceptibility ratios based on LC50 ranging from 2.89- to 10.34-fold relative to a natural susceptible population. The lowest and the highest recommended field rates of ethiprole, 100 and 200 g a.i./ha, produced residues that caused 83.3% and 93.7% mortality of weevils caged with cotton leaves from field-treated plants for 8 d. We found that ethiprole was less toxic than fipronil to the boll weevil parasitoid Bracon vulgaris Ashmead (Hymenoptera: Braconidae) and to the red imported fire ant, Solenopsis invicta Buren (Hymenoptera: Formicidae), while fipronil was highly toxic to both. Adult earwigs, Euborellia annulipes Lucas (Dermaptera: Anisolabididae), were relatively tolerant to ethiprole and fipronil at the highest field rates. Pooled LC50-and LC95-concentrations of ethiprole calculated from studied populations were used as diagnostic for boll weevil mortality, and the outcome fitted to the expected mortality for boll weevil populations from different locations serving for further control failure assessment. Ethiprole appears to be suitable for boll weevil control with low impact on natural enemy communities.

DIFFERENTIAL TOXICITY OF PYRETHROID AND ORGANOPHOSPHATE INSECTICIDES TO THE HONEY BEE, APIS MELLIFERA AND THE YELLOW FEVER MOSQUITO, AEDES AEGYPTI

Six insecticide active ingredients (AIs) and five commercial insecticide formulations were applied by topical application and onto filter paper strips to determine differential toxicity to Aedes aegypti (L.) and Apis mellifera (L.), and to evaluate their potential use in future insecticide resistance monitoring surveys. For topical application, 0.1 or 1 µl of the technical insecticide solution was applied to the Ae. aegypti and A. mellifera thorax, respectively. For insecticide-impregnated strips the insecticide amount varied, according with the commercial formulation. By topical application deltamethrin was the most toxic AI (LD 50 = 0.057 µg/g) to Ae. aegypti and prallethrin was least toxic (LD 50 = 19.42 µg/g). For A. mellifera, the most toxic AIs were deltamethrin (LD 50 = 0.013 µg/g) and bifenthrin (LD50 = 0.156 µg/g); and the least toxic was chlorpyrifos (LD 50 = 3.246 µg/g). When the insecticide-impregnated papers method was used, Mosquitomist Two (chlorpyrifos 24.6%) was the most toxic insecticide for Ae. aegypti (LC50 = 0.024 µg/cm2 ), and Aqualuer (permethrin 20.6%, PBO 20.6%) was least toxic (LC50 = 0.408 µg/cm2 ). For A. mellifera the most toxic commercial insecticide formulations were Talstar (bifenthrin 7.9%; LC50 = 0.288 µg/cm2 ) and Mosquitomist Two (LC50 = 0.299 µg/cm2 ), with no significant differences, and the least toxic commercial formulation was Deltagard (deltamethrin 2.0%; LC50 = 15.084 µg/cm2 ). By topical application, more than 28 times of chlorpyrifos was needed to obtain the same mortality in A. mellifera as in Ae. aegypti. When using the insecticide-impregnated paper method, more than 206 times of Deltagard was needed to obtain the same mortality in A. mellifera as in Ae. aegypti. Even though Mosquitomist Two was the most toxic insecticide for both insect species, the honey bees were >12 times more tolerant to this insecticide, compared with the mosquitoes.

Permeability of the Cyanotoxin Microcystin-RR across a Caco-2 Cells Monolayer

Microcystins (MCs) are toxins produced by several cyanobacterial species found worldwide. While MCs have a common structure, the variation of two amino acids in their structure affects their toxicity. As toxicodynamics are very similar between the MC variants, their differential toxicity could rather be explained by toxicokinetic parameters. Microcystin-RR (MC-RR) is the second most abundant congener and induces toxicity through oral exposure. As intestinal permeability is a key parameter of oral toxicokinetics, the apparent permeability of MC-RR across a differentiated intestinal Caco-2 cell monolayer was investigated. We observed a rapid and large decrease of MC-RR levels in the donor compartment. However, irrespective of the loaded concentration and exposure time, the permeabilities were very low from apical to basolateral compartments (from 4 to 15 × 10−8 cm·s−1) and from basolateral to apical compartments (from 2 to 37 × 10−8 cm·s−1). Our results suggested that MC-RR would be poorly absorbed orally. As similar low permeability was reported for the most abundant congener microcystin-LR, and this variant presented a greater acute oral toxicity than MC-RR, we concluded that the intestinal permeability was probably not involved in the differential toxicity between them, in contrast to the hepatic uptake and metabolism.

LABORATORY TOXICITY OF MOSQUITO ADULTICIDES TO THE ASIAN TIGER MOSQUITOES, AEDES ALBOPICTUS AND THE HONEY BEES, APIS MELLIFERA

Aedes albopictus and Apis mellifera were exposed to six insecticide active ingredients and five commercial insecticide formulations by topical application and insecticide-impregnated paper strips respectively to determine the differential toxicity and the potential use of the two methods in insecticide resistance monitoring surveys. By topical application deltamethrin was the most toxic active ingredient (LD 50 = 0.018 µg/g) for Ae. albopictus whereas chlorpyrifos was the least toxic (LD 50 = 0.499 µg/g). For Apis mellifera, the most toxic active ingredients were bifenthrin (LD 50 = 0.047 µg/g) and deltamethrin (LD 50 = 0.055 µg/g) while chlorpyrifos (LD 50 = 0.215 µg/g) and permethrin (LD 50 = 0.287 µg/g) had comparatively low toxicity. When the insecticide-impregnated method was used, Mosquito Mist (a.i. chlorpyrifos) was the most toxic commercial formulation for both Ae. albopictus (LC50 = 0.028 µg/cm2 ) and A. mellifera (LC50 = 0.059 µg/ cm2 ). Duet and DeltaGard showed the least toxicity (LC50 = 2.429 µg/cm 2 and LC50 = 0.491 µg/cm 2 respectively) for Ae. albopictus and DeltaGard was the least toxic to A. mellifera (LC50 = 18.09 µg/cm2 ). When using the topical application method with insecticide active ingredients, more than 3 times permethrin and deltamethrin were required to obtain the same mortality rate in A. mellifera as in Ae. albopictus. However, chlorpyrifos was more toxic for A. mellifera than for Ae. albopictus. In the insecticide-impregnated paper-strip method with commercial insecticide formulations, more than 36 times of DeltaGard was required to obtain the same mortality rate in A. mellifera as in Ae. albopictus. Even though the Mosquito Mist is the most toxic commercial formulation for both insect species, A. mellifera were more than 2 times tolerant to this insecticide compared to Ae. albopictus. The study concludes the active ingredient deltamethrin or its commercial formulation DeltaGard is the best among tested insecticides to control Ae. albopictus with minimal effects to A. mellifera.