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Background Tofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis. Objectives This phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis. Methods Two tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm2 treatment area containing a target plaque with or without one or more nontarget plaques and normal skin. Results The primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) –54·4%] vs. vehicle 1 (LSM –41·5%), but not ointment 2 (LSM –24·2%) vs. vehicle 2 (LSM –17·2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2. Conclusions Tofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.

This was a cooperative study with Agrigenetics on their research station at Breckinridge, MN. Coated seed was made available from Grow Tec, Ltd in Nisku, Alberta, Canada. Plots were established in clay type soils and individual plots were 6 rows, 0.9 m on center, 6.10 m in length. Treatments were replicated 4 times, in a randomized complete block. Granular applications were mixed with the seed and planted on Apr 30. The at-plant broadcast liquids were applied immediately post plant and raked in lightly. First foliar applications at germination were made on 21 May. Uneven germination made it difficult to properly time these applications. Final foliar applications were made on 16 Jul.

From preliminary screening of 14 systemic compounds with cacao seedlings in Costa Rica, Thimet, Chipman R-6200 ( 0,0 -diethyl S-(2-diethylamino)ethyl phosphorothiolate), demeton, Isolan and dimefox were selected for further study. These five systemics were compared on the basis of their translocation and persistence in the foliar parts of mature cacao trees after trunk implantation, their effect on the flavor of chocolate produced from beans from the treated trees, and the level and nature of residues in the beans using radiotracer and anticholinesterase methods of analysis. Thimet and Chipman R-6200 were readily translocated into the foliar portions of cacao trees and persisted for as long as 20 months after a single implantation treatment. Little or no residues were found in the cacao beans at any time after treatment regardless of the pod position on the trees in relation to the site of implantation. Studies with radioactive R-6200 demonstrated a high concentration of phosphorus-containing residues in the cotyledons of the cacao beans but these materials did not partition into chloroform and did not inhibit cholinesterase and therefore cannot be considered as hazardous residues. No off flavors were detected in chocolate from beans harvested from any of the systemic treatments but definite off-flavors were obtained when BHC was used as a foliar spray. The insecticidal efficiency of the systemics was not studied because the insect populations in the treated areas were not adequate for this purpose.

Small plot experiments were conducted with Thimet and Bayer 19639 seed treatments used alone and in combination with an in-the-furrow fungicidal treatment with nabam. The systemic insecticide seed treatments were also compared with a standard toxaphene spray program. The seed treatments resulted in effective thrips control until midJune and some aphid control until midAugust. Bayer 19639 appeared to give slightly better aphid control than Thimet. In the April plantings, when the soil was cool and damp, there were serious reductions in stand in the systemic seed treatments. The addition of nabam to the systemic insecticide seed treatments resulted in much better stands, and also lessened the severity of the phytotoxic effects of both Thimet and Bayer 19639. Results indicated there should be no reduction in stand, provided the same number of seed are planted, from the use of the systemics under conditions conducive to good germination. Yields were not increased by the use of the systemic insecticides or toxaphene spray treatments. The maturity of the plants was delayed considerably in the plots having the seed treated with systemic insecticides.

A thorough knowledge of the chemical behavior and reactions of systemic insecticides in biological systems is essential in order to define clearly the nature of the toxic substance or substances derived by the system. Systemic insecticides are defined as those which are absorbed and translocated to other parts of the plant, thus exerting their toxic influence on insects throughout the entire plant. A systemically active substance may exert its action by being absorbed and distributed unchanged, as appears to be the case with some derivatives of 2-fluoroethyl alcohol (Schrader 1952), or it may be acted upon by certain systems in the plant and converted to toxic metabolic products. In general, the organo-phosphorus compounds appear to fall in the latter category, and it is with these substances that a great deal of effort has been expended upon the elucidation of their chemical behavior in biological systems. The identification and knowledge of the physico-chemical properties of these metabolic poisons is important not only from the standpoint of residual hazards to mammals but also for a clearer understanding of the systems involved, thus laying the foundation for th.3 development of future systemics.

Several systemic compounds were added to the nutrient solution of hydroponically grown roses and broadcast over beds of field-grown roses. UC 21149 [2-methyl-2-(methylthio) propionaldehyde O -(methylcarbamoyl)oxime] was the only compound that provided control without phytotoxicity. In addition, plants treated with UC 21149 responded with a considerable increase in growth and flower production.

Preplant soil applications of disulfoton, phorate, thiofanox, aldicarb, and carbofuran to tomatoes for control of Leptinotarsa decemlineata (Say) showed disulfoton to be the least effective material. Presently, disulfoton is the only soil systemic labeled for use on tomatoes for control of this insect. The other insecticides gave season-long control of Colorado potato beetle. Band treatments were more effective than furrow treatments.

A study to determine the effects of control of thrips, Frankiniella spp., on the growth and yield of peanuts was conducted over a 3-year period in Georgia. The insecticides used included both systemics and nonsystemics. Species of thrips infesting peanuts in 1965 were tobacco thrips, F. fusca (Hinds); flower thrips, F. tritici (Fitch); and F. bispinosa (Morgan). Rate of growth and flower production were not affected by use of insecticides. Infestation of thrips were reduced, but yields of peanuts were not increased when control measures were used.

Four experiments, beginning in 1963, were conducted at Gainesville, Florida, to evaluate insecticides for control of Diaphania nilidalis (Stoll) on summer squash. Carbaryl consistently gave as good or better control than other materials tested. Lindane, endosulfan, and trichlorfon also gave good control although trichlorfon was not so consistent. Monsanto CP-47114 (O,O -dimethyl O -4-nitro- m -tolyl phosphorothioate) at 1 1b active per acre gave excellent control and should be tested further, furadan® (2, 3-dihydro-2, 2-dimethyl-7-bellzofuranyl methylcarbamate) and Ortho 9006 ( O, S -dimethyl phosphoramidothioate), both systemics, also gave good control, but they are not likely to be recommended for usc on squash, unless it can be shown that they are rapidly degraded and will not leave hazardous residues.

Eleven organophosphorous compounds in carbon formulation were tested as seed systemics for phytotoxicity to barley and oats, and control of aphids on oats. Ph orate, Bayer 25198 ( O, O -dimethyl- O-p -(methylsulfinyl)phenyl phosphorothioate), Di-Syston®( O, O -diethyl S -2 (ethylthio)ethyl phosphorodithio-ate), dimethoate, and phosphamidon were promising. Phorate and Di-Syston did not. prevent transmission of barley yellow-dwarf virus to small plots of oats by migrating alate aphids.

Two vinyl phosphates which contain carboxyamide groupings (Shell 3562 (2-dimethylcarbamoyl-1-methylvinyl dimethyl phosphate) and phosphamidon) were found to be effectively localized in the cortical twig tissues of elm trees following trunk implantation. Shell 3562 prevented niches from exceeding 3.0 mm. for 15 and 29 days after treatment, respectively, with tree dosages of 6 and 18 gm. The method of assay involved feeding-niche length and beetle mortality of Scolytus multistriatus (Marsh.) when exposed to twigs from treated trees. The properties responsible for the above action of the systemics are apparently one or both of the following: (1) a high water solubility and (2) a phosphate or phosphorothiolate rather than a phosphorothionate or phosphorodithioate compound.

Certified B-size potatoes were planted 21 May at the University of Minnesota Agricultural Experiment Station, Rosemount. The field, a Waukegan silt loam, had been in soybeans the previous year. Treatments were 2 rows, 40 ft long with 40-inch row spacing. Treatments were randomized in complete blocks with 4 replications. Granular insecticides were applied at planting in furrow with a planter-mounted granular applicator and at emergence over the rows on 2 Jul and sidedressed on 23 Jul. An additional treatment consisted of 3 foliar sprays of Pydrin at 0.1 lb/acre on 16 Jul, 15 Aug, and 30 Aug. Plots were evaluated by counting CPB larvae by instar on 10 randomly selected plants in each plot on 7 Jul, 28 Jul, 11 Aug, 18 Aug, 23 Aug, 31 Aug, and 9 Sep. Plots were also evaluated for PLH by sampling 35 mid-plant leaves in each plot. Temik and Thimet plots were not sprayed with any foliar insecticide. On 15 Oct potatoes were harvested and sorted by grade. Two-way ANOVA was used to test for treatment differences in PLH and CPB densities.

The study reported here has 2 purposes: (1) to retest systemic insecticides previously tried by Johnson and Rediske (1964) and Hedlin (1962, 1964), and (2) to test other promising systemics for control of insects infesting the cones of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco).

Insecticidal tests to control a pinyon stunt needle midge, Janetiella sp. near coloradensis Felt, were conducted in a landscape planting in Fort Collins, Colorado. Acceptable control was obtained with the systemics carbofuran G and oxydemetonmethyl (foliar spray). Oxydemetonmethyl gave the better control. Dimethoate, as a foliar spray did not give acceptable control. Oxydemetonmethyl and carbofuran also killed an important larval parasite, Platygaster pini Fouts which acts as a natural control agent.

Systemic insecticides applied in the row with lettuce seeds gave promise of significantly reducing the incidence of aster yellows virus, Chlorogenus callistephi Holmes, vectored by the six-spotted leafhopper, Macrosteles fascifrons (Stal),(Thompson and Rawlins 1961). The virus causes a debilitating disease in lettuce and in a myriad of other plant species, resulting in losses of considerable magnitude. The systemics applied with the seeds are absorbed by the roots of the growing plants and translocated to the foliage. M. fascifrons adults succumb after feeding on treated plants and few or no nymphs are produced.

Ronnel (formerly designated Dow ET-57, O, O -dimethyl O -(2,4,5-trichlorophenyl) phosphorothioate, Trolene,® or Korlan®) was administered orally to steers at three locations at two dosage levels in the feed; 15 mg./kg./day for 7 days, and 25 mg./kg./day for 6 days. Bayer 21/199 also called Co-Ral® ( O -(3-chloro-4-methylumbelliferone) O, O -diethyl phosphorothioate) was applied to steers at two locations as either a 0.5% suspension or emulsion at 250 pounds pressure. There was no difference grub ( Hypoderma sp.) control, weight gain, feed efficiency or carcass grades between treatments at each location. Grub control at the three locations ranged from 76.3 to 98.6%.

Results of research with systemic insecticides for control of early season cotton pests have been reported by many workers. In general these workers showed that control of thrips, Frankliniella spp., was obtained witli systemic insecticides but that these materials were often phytotoxic when applied directly to the seed. However, applied as in-furrow granule treatments at planting, systemics appeared to be considerably less phytoioxic.

An irrigated trial was located in a commercial field at Kay Farms near Brooten, Minn. The field was planted 22 Apr with a 6-row commercial planter. Insecticide applicators were disconnected while the experimental area was being planted and then reconnected to complete field rows. The main field was treated with 3 lb (AI)/ acre of Thimet. Fertilizer, weed control, etc., were constant throughout the experimental and production field. Plots were 4 38-inch rows 30 ft long, replicated 3 times, and arranged in a randomized complete block design. The plot area was located 6 rows from the pivot road and extended 150 ft from the field edge into the main field. The soil was a sandy loam. At-plant treatments were applied on 23 Apr and lightly covered. Emergence treatments were applied 20 May. Foliars were applied on 22 Jun, 10 and 22 Jul, and 10 and 20 Aug. Foliars following emergence granular applications were applied on 3 and 22 Jul. Foliars were applied using a hand-held CO2 sprayer using 40 psi pressure and 12 gal total material/acre. Yields were taken by digging the 2 center plot rows, grading into #ls and B-size, and recording.

‘C-elete’ lima beans were planted 1 to 1.5 inches deep, in single row plots, 17 ft in length and 6 ft in width, on Jul 16. The treatments were arranged in a randomized split block design with 3 replications. The insecticide treatments were applied at planting time with a single spout electric drive Gandy (Model 901-2). Sidedress treatments were applied 2 inches to the side of the row and 2 inches below the seed. Dribble treatments were allowed to flow freely from the tube directly over the row behind the furrow press - wheel and followed by a drag chain. Band treatments were applied in a 6 inch wide band over the row behind the furrow press - wheel and followed by a drag chain.

The trial was located at the Northwest Experiment Station, Crookston, Minn. The major objective of the 1987 insecticide trials was to compare at-plant-and-time-of-emergence soil systemic treatments in dryland sites (Crookston, Minn., and Grand Forks, N. Dak.) and irrigated locations (Park Rapids and Brooten, Minn.). Soil systemic treatments were present at each site with various combinations of foliars. CPB are at least 100-fold resistant to Pydrin and 40-fold resistant to Ambush + Pounce at this location. Plots were 4 40-inch rows 25 ft long. Treatments were replicated 4 times and were arranged in a randomized complete block design. B-size Norchip seed was planted on 5 May and planting treatments of Temik and Thimet applied over the row. The soil was a clay type, permitting granules to fall into soil openings along the planting ridge. Soil moisture was very good. Emergence treatments were applied on 29 May when potato plants were 2 inches high. Soil was cultivated over the emergence treatment. Wintering CPB adults were present in higher than normal numbers on this date. Foliars were applied on 20 and 28 Jun, 10 and 22 Jul, and 8 Aug according to an experimental plan of 1, 3, and 5 foliars. Foliars applied over the emergence soil systemic were applied 20 Jun and 8 Aug. Adult emergence from an adjacent potato plot threatened to overwhelm these studies in July (note adult defoliation column in table). Thus, we waited for modest second-generation oviposition and then treated the entire study with 0.5 lb (AI)/acre of Penncap-M on 24 Jul. Three applications of fungicide were applied independently of insecticides. Yields were taken from the center 2 plot rows, graded #1 and B-size, weighed, and recorded.