Vocalizations in juvenile anurans: common spadefoot toads (Pelobates fuscus) regularly emit calls before sexual maturity.

Acoustic communication is prominent in adult anuran amphibians, in reproductive, territorial and defensive contexts. In contrast, reports on vocalizations of juvenile anurans are rare and anecdotal, and their function unstudied. We here provide conclusive evidence for vocalizations in juvenile spadefoot toads (Pelobates fuscus) in very early terrestrial stages. While the aquatic tadpoles did not emit sounds, first vocalizations of metamorphs were heard as early as in stages 42-43, and calls were regularly emitted from stage 44 on, often from specimens still bearing extensive tail stubs. Three main types of calls could be distinguished, of which one consists of a series of short notes, one of a typically single longer and pulsed note, and one of a single tonal note. In experimental setups, the number of calls per froglet increased with density of individuals and after feeding, while on the contrary calls were not elicited by playback. The function of these juvenile calls remains unclarified, but they might reflect a general arousal in the context of feeding. Further evidence is necessary to test whether such feeding calls could confer a signal to conspecifics and thus might represent intraspecific acoustic communication in these immature terrestrial amphibians.

Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa).

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED(50) of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.