Morphological characterisation of Andrya Railliet, 1893, Neandrya n. g. and Paranoplocephala Lühe, 1910 (Cestoda: Anoplocephalidae) in rodents and lagomorphs.

The taxonomic significance of the main morphological features of the 25 species allocated to Andrya Railliet, 1893 and Paranoplocephala Lühe, 1910 is re-evaluated in the light of the recent molecular phylogenetic hypotheses for anoplocephaline cestodes. The present analysis and the existing phylogenetic data suggest that the structure and complexity of the early uterus are not, as previously assumed, the main phylogenetic or systematic determinants for anoplocephaline cestodes. Instead, the position of the early uterus with respect to other organs, combined with the morphology of the female genitalia, appear to allow a fairly straightforward discrimination of the three genera recognised here, without contradicting current phylogenetic hypotheses. A new genus, Neandrya n. g., is proposed for N. cuniculi (Blanchard, 1891) n. comb. (previously in Andrya), amended diagnoses are provided for Andrya and Paranoplocephala and a diagnostic key to these three genera is presented.

Phylogeography of the circumpolar Paranoplocephala arctica species complex (Cestoda: Anoplocephalidae) parasitizing collared lemmings (Dicrostonyx spp.).

The Paranoplocephla arctica complex (Cyclophyllidea, Anoplocephalidae), host-specific cestodes of collared lemmings Dicrostonyx, include two morphospecies P. arctica and P. alternata, whose taxonomical status now must be considered ambiguous. The genetic population structure and phylogeography of the P. arctica complex was studied from 83 individuals sampled throughout the Holarctic distribution range using 600 bp of the mitochondrial cytochrome c oxidase subunit I gene (COI). The mitochondrial DNA (mtDNA) phylogeny divides the species complex into one main Nearctic and one main Palaearctic phylogroup, corresponding to the main phylogenetic division of the hosts. In the Palearctic phylogroup, the parasite clades correspond to the host clades although the parasites from Wrangel Island form an exception as the host on this island, D. groenlandicus, belongs to the Nearctic phylogroup. In the Nearctic, northern refugia beyond the ice limit of the Pleistocene glaciations are proposed for the hosts. All reconstructions of parasite phylogeny show a genetically differentiated population structure that in the Canadian Arctic lacks strict congruence between phylogeny and geography. The parasite phylogeny does not show complete congruence with host relationships, suggesting a history of colonization and secondary patterns of dispersal from Beringia into the Canadian Arctic, an event not proposed by the host phylogenies alone.

Synthesis and structure elucidation of potential 6-oxygenated metabolites of (22R)-6alpha,9alpha-difluoro-11beta,21-dihydroxy-1 6alpha,17alpha-propyl methylenedioxypregn-4-ene-3,20-dione, and related glucocorticosteroids.

(22R)-6alpha,9alpha-Difluoro-11beta,21-dihydroxy-16 alpha,17alpha-propylmethylenedioxypregn-4-ene-3,20-dione (rofleponide) is a synthetic glucocorticosteroid with high affinity for the rat thymus glucocorticoid receptor and a very high biotransformation rate demonstrated through incubation with a human liver S9 subcellular fraction. Because oxidation in the 6-position is an important metabolic pathway of glucocorticosteroids, the potential 6beta-hydroxy and 6-oxo metabolites of rofleponide were synthesized to be used as reference compounds. Three alternative routes were used to reach the 6-hydroxy compound: (a) a one-step procedure involving allylic oxidation of rofleponide by selenium dioxide, (b) selenium dioxide oxidation of the corresponding 1,4-diene followed by selective 1,2-hydrogenation using Wilkinson's catalyst, and (c) autoxidation of a 3-methoxypregna-3,5-diene derivative. All three routes proceeded stereospecifically. Routes (a) and (c) gave approximately the same overall yield of the 6beta-hydroxy epimer, whereas the overall yield from route (b) was much lower, primarily because of incomplete 1,2-hydrogenation. The 6-oxo compound was prepared through Pfitzner/Moffat oxidation of the 6-hydroxy compound. The stereochemistry of the 6-hydroxy substituent is discussed on the basis of 1H-NMR spectroscopy and supplementary 2D NOESY experiments.

Analgesic use disorders among orthopedic and chronic pain patients at a rehabilitation clinic.

Interviews were conducted with 265 orthopedic and chronic pain patients, using a structured diagnostic instrument (ADDIS/SUDDS) concerning their use of analgesics. Twenty-two percent of the patients met criteria for analgesic use disorders in accordance with DSM-III-R; 18.5% fulfilled DSM-IV criteria. Dextropropoxyphene was the most common analgesic prescribed and was used by 47% of the patients who met criteria for analgesic use disorders. It is concluded that patients with chronic pain using narcotic analgesics are at considerable risk of developing analgesic use disorders. Assessment of the use of analgesics should be offered to pain patients taking narcotic drugs.

6 alpha-Fluoro- and 6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione: synthesis and evaluation of activity and kinetics of their C-22 epimers.

It is generally accepted that the anti-inflammatory effect of glucocorticosteroids cannot be separated from their adverse effects at the receptor level. However, modification of the pharmacokinetics through structural alterations could provide steroids with a better therapeutic index than those currently used. Thus, new 16 alpha,17 alpha-acetals between butyraldehyde and 6 alpha-fluoro- or 6 alpha,9 alpha-difluoro-16 alpha-hydroxycortisol were synthesized and studied. Acetalization of the corresponding 16 alpha,17 alpha-diols or transacetalization of their 16 alpha,17 alpha-acetonides in dioxane produced mixtures of C-22 epimers, which were resolved by preparative chromatography. Alternatively, an efficient method was used to produce the 22R-epimer stereoselectively through performing the acetalization and transacetalization in a hydrocarbon with an inert material present. The C-22 configuration of (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione was unambiguously established by single crystal X-ray diffraction. The present compounds, especially the 22R-epimer just mentioned, bind to the rat thymus glucocorticoid receptor with high potency. The C-22 epimers of the 6 alpha,9 alpha-difluoro derivatives showed a 10-fold higher biotransformation rate than the budesonide 22R-epimer when incubated with human liver S9 subcellular fraction. The high receptor affinity in combination with the high biotransformation rate indicates that (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione may be an improved 16 alpha,17 alpha-acetal glucocorticosteroid for therapy of inflammatory diseases, in which the mucous membranes are involved, such as those in the intestinal tract as well in the respiratory tract.

Prevalence of abuse and dependency in chronic pain patients.

A series of 414 chronic pain patients referred to Are Hospital, Are, Sweden, for evaluation and rehabilitation were administered a structured diagnostic interview to detect alcohol and drug misuse and dependence according to DSM-III-R criteria. A total of 97 (23.4%) met criteria for active alcohol, analgesic, or sedative misuse or dependency; an additional 39 (9.4%) met criteria for a remission diagnosis. Current dependency was most common for analgesics (12.6%) followed by alcohol (9.7%) and sedatives (7.0%).