Alendronate binds to tooth root surfaces and inhibits progression of feline tooth resorption: a pilot proof-of-concept study.

Tissue distribution, bioavailability, and efficacy of alendronate in preventing progression of resorption of teeth were evaluated in cats. [Butyl-4-14C-]-alendronate accumulates on subgingival tooth and alveolar bone surfaces adjacent to vascularized tissue resulting in concentration of the drug around tooth roots. Three cats were treated with a 0.03 mg/kg i.v. bolus of [butyl-4-14C-]-alendronate followed by blood, urine, and feces collection and euthanasia 24-hours later. Drug tissue distribution was accessed by autoradiography and sample combustion. To assess bioavailability, 12 cats were administered alendronate orally (3.0 or 9.0 mg/kg in water or 9.0 mg/kg in tuna water) and urine was collected for 24-hours. In these formulations, alendronate oral bioavailability in cats was approximately 3%. In addition, 10 cats with radiographic evidence of pre-existing tooth resorption (14 affected teeth) were treated with vehicle or 3.0 mg/kg alendronate per os once weekly for 22-weeks and, then, 9.0 mg/kg per os twice weekly for 27-weeks in a random, masked study. Radiographic area of resorption was measured and progression scored every 3 to 4-months. In placebo-treated cats, resorption progressed in five of six teeth (+ 97% average increase in area of resorption), whereas progression of resorption was seen in only three of eight affected teeth in alendronate-treated cats with a -22% average change (decrease) in area (P < 0.01 difference in number of teeth showing progression; P < 0.001 difference in area of resorption). Alendronate accumulated preferentially on subgingival tooth surfaces and adjacent alveolar bone and, at a dose of 9 mg/kg twice weekly, effectively slowed or arrested the progression of resorption.

Flavones from Struthiola argentea with anthelmintic activity in vitro.

Parasitic diseases caused by helminthes lead to significant health hazards to animals resulting in enormous economic impact. While a number of anthelmintics are currently available, all are encountering resistance and ones with a mode of action are needed. We report herein bioassay-guided isolation of three anthelmintic flavones 1-3, including the flavone, 5,6,2',5',6'-pentamethoxy-3',4'-methylenedioxyflavone (3) from the methanol extract of Struthiola argentea (Thymelaeaceae). The structure of 3 was elucidated by analysis of its 1D and 2D NMR and MS data. The two major flavones produced by this plant were also isolated and identified as yuankanin (4) and amentoflavone (5). A number of flavones related to the compounds isolated from S. argentea were acquired and tested to ascertain structure activity relationships. The isolation, structure, anthelmintic activity and structure activity relationships of the flavones are described. Compound 3 exhibited the most potent in vitro activity with 90% inhibition of larval motility at 3.1 microg/mL and compound 15 showed modest in vivo activity.

Anthelmintic constituents of Clonostachys candelabrum.

Five diastereomeric polyketide glycosides, roselipins 3A-3E (1-5), have been isolated from the acetone extract of Clonostachys candelabrum on the basis of their positive anthelmintic activity. The structures of these compounds were elucidated by comparison of their NMR and MS data to those of previously reported roselipins and related structures, and were confirmed by 2D-NMR spectral analysis. Known compounds linoleic acid (6) and aurantiogliocladin (7) were also isolated as active anthelmintic components, although much less potent than the roselipins.

Anthelmintic macrolactams from Nonomuraea turkmeniaca MA7364.

Two new macrolactams, 6-desmethyl-N-methylfluvirucin A1 (1) and N-methylfluvirucin A1 (2), have been isolated from the acetone extract of Nonomuraea turkmeniaca MA7364. These compounds were isolated by bioassay-guided fractionation as part of our search for new anthelmintics. The structures of these compounds were elucidated by comparison of their NMR and MS data to those of previously reported fluvirucins and confirmed by 2D NMR. Compound 1 exhibited in vitro activity (EC(90) 15 +/- 5 microg/mL) against Haemonchus contortus larvae, whereas compound 2, while a bit less active in vitro (EC(90) 29 +/- 8 microg/mL), showed modest in vivo activity against a surrogate organism, Heligmosomoides polygyrus in mice, at 50 mg/kg.

Anthelmintic activity of aporphine alkaloids from Cissampelos capensis.

Two known aporphine alkaloids, (S)-dicentrine (1) and (S)-neolitsine (2), have been isolated from the MeOH extract of the aerial parts of Cissampelos capensis (Menispermaceae). The structures of these compounds were elucidated by NMR and MS analysis and comparison to literature data. These compounds were isolated by bioassay-guided fractionation using the Haemonchus contortus larval development assay. Compounds 1 and 2 exhibited EC90 values (concentration at which 90% loss of larval motility is observed) of 6.3 and 6.4 microg/mL, respectively. In an IN VIVO assay, administration of 1 resulted in 67% reduction of worm counts in mice at 25 mg/kg when dosed orally.

Scutiaquinones A and B, perylenequinones from the roots of Scutia myrtina with anthelmintic activity.

Haemonchus contortus is a worm that causes serious infections in livestock. Two new perylenequinones, scutiaquinone A (1) and scutiaquinone B (2), have been isolated from a methanol extract of the roots of Scutia myrtina by bioassay-guided fractionation, using an assay that kills this parasite in vitro. The structures of compounds 1 and 2 were elucidated by analysis of their 1D- and 2D-NMR and MS spectra. The isolation, structure, and anthelmintic activities of compounds 1 and 2 are reported.