Frog secretions and hunting magic in the upper Amazon: identification of a peptide that interacts with an adenosine receptor.

A frog used for "hunting magic" by several groups of Panoan-speaking Indians in the borderline between Brazil and Peru is identified as Phyllomedusa bicolor. This frog's skin secretion, which the Indians introduce into the body through fresh burns, is rich in peptides. These include vasoactive peptides, opioid peptides, and a peptide that we have named adenoregulin, with the sequence GLWSKIKEVGKEAAKAAAKAAGKAALGAVSEAV as determined from mass spectrometry and Edman degradation. The natural peptide may contain a D amino acid residue, since it is not identical in chromatographic properties to the synthetic peptide. Adenoregulin enhances binding of agonists to A1 adenosine receptors; it is accompanied in the skin secretion by peptides that inhibit binding. The vasoactive peptide sauvagine, the opioid peptides, and adenoregulin and related peptides affect behavior in mice and presumably contribute to the behavioral sequelae observed in humans.

Cephalosporin therapeutics in cystic fibrosis.

Cephalosporins modified at the C-3 and C-7 positions of the cephem-nucleus have high antimicrobial activity and are safe. With evolution through first, second, and third generations, they have gained increasing gram-negative activity, but often at the expense of potency against gram-positive organisms. All third-generation cephalosporins have some intrinsic anti-Pseudomonas activity, indicating their potential benefit in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Rational therapy in this clinical setting requires recognition of the pharmacodynamic and pharmacokinetic idiosyncrasies intrinsic to this patient population. When these priorities are recognized, only two of the available agents, cefsulodin and ceftazidime, appear to be of any therapeutic value. Both agents have been evaluated extensively in the treatment of acute pulmonary exacerbation in cystic fibrosis, and both have been found to be safe and effective.

Pharmacokinetic determination of ranitidine pharmacodynamics in pediatric ulcer disease.

The pharmacokinetics and pharmacodynamics of ranitidine were evaluated during three methods of administration in 12 children ranging in age from 3.5 to 16 years with documented gastric or duodenal ulcer disease. First, a continuous intravenous infusion of ranitidine was administered to determine the serum concentration necessary to suppress gastric acid secretion by at least 90%. From these data a therapeutic dose of ranitidine was calculated and administered on separate days via the intravenous bolus and oral routes. Half-life, volume of distribution, and clearance values for ranitidine were the same after intravenous bolus and oral doses (1.8 vs 2.0 hours, 2.3 vs 2.5 L/kg, and 794.7 vs 788.0 ml/min/1.73 m2, respectively). The bioavailability of ranitidine given orally averaged 48%. Serum ranitidine concentrations necessary to inhibit gastric acid secretion by at least 90% ranged between 40 and 60 ng/ml for all children studied. No adverse clinical or biochemical effects were observed in any child during the 6 weeks of orally administered treatment. Endoscopic reevaluation after 6 weeks indicated complete healing of initial ulcers.

Dosing implications of rapid elimination of trimethoprim-sulfamethoxazole in patients with cystic fibrosis.

The first-dose and steady-state pharmacokinetics of trimethoprim and sulfamethoxazole were determined in 14 patients with cystic fibrosis. When pharmacokinetic data from the first dose were compared with those at steady state, both TMP and SMZ showed expected accumulations in serum concentrations and decreases in total body clearance. The area under the SMZ serum concentration-time curve was significantly greater at steady state, suggesting drug accumulation during long-term therapy. When pharmacokinetic characteristics for TMP and SMZ obtained in patients with cystic fibrosis were compared with those reported for normal adults, the patients were found to have shorter elimination half-lives and greater plasma clearances. In addition, the apparent volume of distribution for TMP was smaller for patients with cystic fibrosis than for normal adults, consistent with their reduced mass of adipose tissue. Our data support the need for increased dosing or decreased dosing intervals when administering TMP-SMZ to patients with cystic fibrosis.

Occurrence of skin alkaloids in non-dendrobatid frogs from Brazil (Bufonidae), Australia (Myobatrachidae) and Madagascar (Mantellinae).

Several taxa of small frogs from the southern hemisphere contain alkaloids similar or identical to compounds previously known only from neotropical poison frogs of the family Dendrobatidae. Skin of the Brazilian toad Melanophryniscus moreirae (family Bufonidae) contains a new alkaloid 8-hydroxy-8-methyl-6-(5'-hydroxy-2'-methyl-hexylidene)-1-azabicycl o-[4.3.0] nonane (C16H29NO2), which is designated pumiliotoxin 267C. Such a structure is typical of the pumiliotoxin-A class of dendrobatid alkaloids. Melanophyryniscus moreirae contains smaller quantities of an alkaloid (C19H33NO3) identical in chromatographic and mass spectral properties to the dendrobatid alkaloid allopumiliotoxin 323B. Allopumiliotoxin 323B and an isomer of 267C occur with unidentified alkaloids in skin of the Australian frog Pseudophryne semimarmorata (family Myobatrachidae) and also in the skin of the Madagascan frog Mantella aurantiaca (family Ranidae, subfamily Mantellinae). In addition to new compounds, Mantella aurantiaca and M. madagascariensis also contain other alkaloids (e.g. histrionicotoxin and pumiliotoxin B) that were known previously only in dendrobatid frogs. Such alkaloids have not been detected in a phylogenetically wide array of other anuran amphibians, and the dendrobatid alkaloids thus become an evolutionary enigma. Certain of these compounds may have arisen convergently from new biosynthetic pathways in several families of frogs, or these alkaloids may represent parallel expression of shared-primitive pathways that are unexpressed or lost in related frogs.

Histrionicotoxins: roentgen-ray analysis of the novel allenic and acetylenie spiroalkaloids isolated from a Colombian frog, Dendrobates histrionicus.

The structures and absolute configuration of two unique alkaloids isolated from the Colombian frog, Dendrobates histrionicus, have been elucidated by Roentgen-ray (x-ray) crystallography. Histrionicotoxin is (2pR, 6S, 7pS, 8aS)-7-(cis-1-buten-3-ynyl)-8-hydroxy-2-(cis-2-penten-4- ynyl)-1-azaspiro[5.5] undecane, while in dihydro-isohistrionicotoxin the acetylenic 2-pentenynyl side chain is replaced by an allenic 2-(3,4 pentadienyl) substituent. Dendrobates histrionicus exhibits remarkable interpopulational variations in amounts and composition of skin toxins, in behavior, and in phenotypic characters, aspects of which are illustrated in a color plate. The histrionico-toxins are the third class of alkaloids isolated from the defensive skin secretions of Neotropical (Dendrobatidae) frogs.

Toxicity of Panamanian poison frogs (Dendrobates): some biological and chemical aspects.

A small Neotropical frog, Dendrobates pumilio, undergoes interpopulational variation in color, degree of toxicity, size, and habits. Differences in body coloration encompass the visible spectrum from red to blue, as well as achromatic black and white. There are wide variations in the degree of toxicity, but these variations are not correlated with supposed warning colors. Extracts of skin yield two toxic compounds characterized as steroidal alkaloids with molecular formulae C(19)H(33)NO(2) and C(l9)H(33)NO(3). The rapid rate of divergent evolution among populations of this frog may result from isolation and chance restriction of original heterozygosity, with subsequent selection acting on different and greatly limited mixtures of alleles.