Efficacy and safety of a novel synergistic drug candidate, CRx-102, in hand osteoarthritis.

OBJECTIVE: The novel synergistic drug candidate CRx-102 comprises dipyridamole and low dose prednisolone and is in clinical development for the treatment of immunoinflammatory diseases. The purpose of this clinical study was to examine the efficacy and safety of CRx-102 in patients with hand osteoarthritis (HOA). METHODS: The study was conducted as a blinded, randomised, placebo-controlled trial at four centres in Norway. Eligibility criteria included being of age 30-70 years, at least one swollen and tender joint, a Kellgren-Lawrence (K-L) score of 2 or higher on radiographs, and a score of at least 30 mm pain on the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) visual analogue pain scale (VAS). The primary endpoint was a reduction in pain from baseline to day 42 on the AUSCAN pain subscale. Two-sided p values for the differences in least squares (LS) means adjusted for baseline are presented. RESULTS: The mean age of the 83 patients with HOA was 60 years and 93% were females. CRx-102 was statistically superior to placebo at 42 days for changes in AUSCAN pain (LS mean -14.2 vs -4.0) and for clinically relevant secondary endpoints (joint pain VAS (-18.6 vs -6.3), patient global VAS (-15.9 vs -4.2)) in the intention to treat population. The most frequently reported adverse event during the study was headache (52% in CRx-102 vs 15% in the placebo group). CONCLUSIONS: The novel synergistic drug candidate CRx-102 demonstrated efficacy by statistically reducing pain compared to placebo in HOA and was generally well tolerated.

Trace element contamination of Norwegian Lake sediments.

Concentrations of Sb, Hg, Bi, Cd, Mo, As, Co, Ni, Cr, Cu, V, Pb and Zn in surface and preindustrial sediments from 210 lakes in Norway were used for studying modern atmospheric depositions of these elements. Surface sediments had considerably higher concentrations of Sb, Hg, Bi, Cd, As, Pb than preindustrial sediments. The differences decreased with latitude and altitude. A multivariate analysis including the trace elements and the major constituents (organic matter, Si, Al, Fe and Mn) of surface sediments suggested the following relationships: Sb, Hg, Bi, As, and Pb formed a group with strong associations to organic matter. Ni, Cr and Cu formed a second group, weakly associated to the inorganic sediment fraction (Si and Al). Zn and Cd formed a third group with weak associations to organic matter. Co was associated to Mn, whereas Mo and V showed no important covariations with any other trace elements or major components.

Heavy metal surveys in Nordic lakes; concentrations, geographic patterns and relation to critical limits.

In the autumn of 1995, coordinated national lake surveys were conducted in the Nordic countries, including Russian Kola. The 11 metals (Pb, Cd, As, Zn, Cu, Ni, Co, Fe, Mn, Cr, V) investigated in nearly 3000 lakes have generally low concentrations and distinct geographical patterns. Direct and indirect influence of long-range transported air pollution is the major important factor for distribution of Pb, Cd, Zn and to a certain degree Co. Total organic carbon (TOC) concentrations in lakes are important for Fe and Mn but also to a certain degree for As, Cr and V. Bedrock geology is the major controlling factor for Cu and Ni, with the exception of areas around the smelters in the Kola peninsula, where the Cu and Ni concentrations in lakes are very high due to local airborne pollution. Bedrock and surficial geology is also an important factor for controlling the concentrations of As, Co, Cr and V. The results indicate that heavy metal pollution in lakes is a minor ecological problem on a regional scale in the Nordic countries.

Some effects of the fungicide propiconazole on cytochrome P450 and glutathione S-transferase in brown trout (Salmo trutta).

The fungicide propiconazole (1-(2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-ylmethyl) -1H-1,2,4-triazole) induced the hepatic cytochrome P4501A (CYP1A) activity towards ethoxyresorufin-O-deethylase (EROD), the content of CYP1A protein as quantified by enzyme-linked immunosorbent assay (ELISA) and the glutathione S-transferase (GST) activity towards the three commonly used substrates CDNB(1-chloro-2,4-dinitrobenzene), cumene hydroperoxide (CU) and ethachrynic acid (EA) in brown trout (Salmo trutta) depending on dose and body weight. An exponential dose response relationship existed between propiconazole exposure and CYP1A activity. A 2. order polynomial regression of the propiconazole concentration (square root transformed) on the data for CDNB, EU and CU revealed a bell-shaped pattern of the GST induction. Reverse-phase HPLC of the GSH-affinity chromatography purified GST isozymes in trout exposed to respectively 8.3, 23, 93, 313 and 606 microg l(-1) propiconazole in the water indicated that the propiconazole treatment may lead to changes in the composition of the subunits compared to the controls. Thus, propiconazole exposure through the water changed the properties of the brown trout hepatic CYP1A and GST, and these changes may be used as a bioindicator on the molecular level of exposure and effect of propiconazole in controlled experiments. The use in monitoring of propiconazole exposure under natural field conditions is possible, however needs further investigation.

Genetic evidence for different migration routes of freshwater fish into Norway revealed by analysis of current perch (Perca fluviatilis) populations in Scandinavia.

To elucidate the colonization of freshwater fish into Norway following the last deglaciation of Europe 10,000 years ago, we have performed a survey using mitochondrial DNA variation (20 populations) and multilocus DNA fingerprinting (14 populations) of the widely distributed perch (Perca fluviatilis) from the Scandinavian peninsula and the Baltic Sea. Sequence analysis of a 378 bp segment of the perch mitochondrial control region (D-loop) revealed 12 different haplotypes. A nested clade analysis was performed with the aim of separating population structure and population history. This analysis revealed strong geographical structuring of the Scandinavian perch populations. In addition, the level of genetic diversity was shown to differ considerably among the various populations as measured by the bandsharing values (S-values) obtained from multilocus DNA fingerprinting, with intrapopulation S-values ranging from 0.19 in Sweden to 0.84 in the central part of Norway. Analysis of the intrapopulation S-values, with S-value as a function of lake surface area and region, showed that these differences were significant. The mitochondrial and DNA fingerprinting data both suggest that the perch colonized Norway via two routes: one from the south following the retreating glacier, and the other through Swedish river systems from the Baltic Sea area. Perch utilizing the southern route colonized the area surrounding Oslofjord and the lakes which shortly after deglaciation were close to the sea. Fish migrating from the Baltic Sea seem to have reached no further than the east side of Oslofjord, where they presumably mixed with perch which had entered via the southern route. It seems likely that the migration events leading to the current distribution of perch also apply to other species of freshwater fish showing a similar distribution pattern.

Permanent impairment in the feeding behavior of grayling (Thymallus thymallus) exposed to methylmercury during embryogenesis.

Embryos of grayling (Thymallus thymallus) were exposed to different concentrations of methylmercury (0.16, 0.8, 4.0 and 20 micrograms Hg l-1) during the first 10 days of development. The exposure resulted in body concentrations in the newly hatched fry of 0.09, 0.27, 0.63 and 3.80 micrograms Hg g-1 wet wt., respectively. A control group had a body concentration of 0.01 microgram Hg g-1. Morphological disturbances were only found in the highest exposure group. Three years later, at a size of 13.8 +/- 0.8 cm, the different groups were tested for sublethal toxicant effects on foraging behavior. In the first series of experiments we tested the foraging efficiency of the fish when kept alone for 5 min in small flow-through aquariums. In the second series of experiments we tested the competitive ability of eight individuals from an exposed group vs. eight individuals from a control group when kept together for 30 min in a 300-1 aquarium. In both experiments live Dapnia magna were used as prey. We found impaired feeding efficiencies and reduced competitive abilities in grayling from the exposed groups which as yolk-fry had Hg concentrations of 0.27 microgram g-1 or more. In the foraging efficiency experiments these groups were 15-24% less efficient as compared to the control group. In the competitive ability experiments the control group caught two to six times as many preys as these exposed groups. Such harmful body concentrations of Hg (> 0.27 microgram g-1) may be found in eggs from piscivorous fishes in lakes receiving diffuse atmospheric depositions of mercury. We suggest such concentrations may have ecological consequences by reducing the fitness of the affected populations.

Morning stiffness and nightime pain in ankylosing spondylitis. A comparison between enteric-coated and plain naproxen tablets.

Thirty-nine patients with ankylosing spondylitis participated in a randomized, double-blind, double-dummy, multi-cross-over study with enteric-coated (ECT) and plain (PT) naproxen tablets. The duration of the study was 24 days with 6 treatment periods of 4 days. The majority of the patients were taking 750 mg naproxen daily. The mean plasma concentration of naproxen in the morning was 36% higher with ECT (p < 0.001). No significant differences regarding duration of morning stiffness and night time pain were found in this patient category. The mean duration of morning stiffness was 116 minutes (ECT) and 125 minutes (PT). We were not able to show correlation between plasma concentration of naproxen and duration of morning stiffness.