To investigate whether the location and extent of the CT hyperdense artery sign (HAS) at presentation affects response to IV alteplase in the randomized controlled Third International Stroke Trial ...(IST-3).
All prerandomization and follow-up (24-48 hours) CT brain scans in IST-3 were assessed for HAS presence, location, and extent by masked raters. We assessed whether HAS grew, persisted, shrank, or disappeared at follow-up, the association with 6-month functional outcome, and effect of alteplase. IST-3 is registered (ISRCTN25765518).
HAS presence (vs absence) independently predicted poor 6-month outcome (increased Oxford Handicap Scale OHS) on adjusted ordinal regression analysis (odds ratio OR 0.66, p < 0.001). Outcome was worse in patients with more (vs less) extensive HAS (OR 0.61, p = 0.027) but not in proximal (vs distal) HAS (p = 0.420). Increasing age was associated with more HAS growth at follow-up (OR 1.01, p = 0.013). Treatment with alteplase increased HAS shrinkage/disappearance at follow-up (OR 0.77, p = 0.006). There was no significant difference in HAS shrinkage with alteplase in proximal (vs distal) or more (vs less) extensive HAS (p = 0.516 and p = 0.580, respectively). There was no interaction between presence vs absence of HAS and benefit of alteplase on 6-month OHS (p = 0.167).
IV alteplase promotes measurable reduction in HAS regardless of HAS location or extent. Alteplase increased independence at 6 months in patients with and without HAS.
This study provides Class I evidence that for patients within 6 hours of ischemic stroke with a CT hyperdense artery sign, IV alteplase reduced intra-arterial hyperdense thrombus.
The characterization of herbal materials is a significant challenge to analytical chemists. Goldenseal (Hydrastis canadensis L.), which has been chosen for toxicity evaluation by NIEHS, is among the ...top 15 herbal supplements currently on the market and contains a complex mixture of indigenous components ranging from carbohydrates and amino acids to isoquinoline alkaloids. One key component of herbal supplement production is botanical authentication, which is also recommended prior to initiation of efficacy or toxicological studies. To evaluate material available to consumers, goldenseal root powder was obtained from three commercial suppliers and a strategy was developed for characterization and comparison that included Soxhlet extraction, HPLC, GC-MS, and LC-MS analyses. HPLC was used to determine the weight percentages of the goldenseal alkaloids berberine, hydrastine, and canadine in the various extract residues. Palmatine, an isoquinoline alkaloid native to Coptis spp. and other common goldenseal adulterants, was also quantitated using HPLC. GC-MS was used to identify non-alkaloid constituents in goldenseal root powder, whereas LC-MS was used to identify alkaloid components. After review of the characterization data, it was determined that alkaloid content was the best biomarker for goldenseal. A 20-min ambient extraction method for the determination of alkaloid content was also developed and used to analyze the commercial material. All three lots of purchased material contained goldenseal alkaloids hydrastinine, berberastine, tetrahydroberberastine, canadaline, berberine, hydrastine, and canadine. Material from a single supplier also contained palmatine, coptisine, and jatrorrhizine, thus indicating that the material was not pure goldenseal. Comparative data for three commercial sources of goldenseal root powder are presented. Keywords: Goldenseal; Hydrastis canadensis L.; alkaloids; palmatine; berberine; hydrastine; canadine; HPLC; GC-MS; LC-MS
A fast, practical ambient extraction methodology followed by isocratic liquid chromatography (LC) analysis with UV detection was validated for the determination of berberine, hydrastine, and canadine ...in goldenseal (Hydrastis canadensis L.) root powder. The method was also validated for palmatine, a major alkaloid present in the possible bioadulterants Coptis, Oregon grape root, and barberry bark. Alkaloid standard solutions were linear over the evaluated concentration ranges. The analytical method was linear for alkaloid extraction using 0.3-2 g goldenseal root powder/100 mL extraction solvent. Precision of the method was demonstrated using 10 replicate extractions of 0.5 g goldenseal root powder, with percent relative standard deviation for all 4 alkaloids < or = 1.6. Alkaloid recovery was determined by spiking each alkaloid into triplicate aliquots of neat goldenseal root powder. Recoveries ranged from 92.3% for palmatine to 101.9% for hydrastine. Ruggedness of the method was evaluated by performing multiple analyses of goldenseal root powder from 3 suppliers over a 2-year period. The method was also used to analyze Coptis root, Oregon grape root, barberry bark, and celandine herb, which are possible goldenseal bioadulterants. The resulting chromatographic profiles of the bioadulterants were significantly different from that of goldenseal. The method was directly transferred to LC with mass spectrometry, which was used to confirm the presence of goldenseal alkaloids tetrahydroberberastine, berberastine, canadaline, berberine, hydrastine, and canadine, as well as alkaloids from the bioadulterants, including palmatine, jatrorrhizine, and coptisine.
In two kidney-one clip renovascular hypertension (2K1C), blood flow is reduced in the clipped kidney leading to ischaemia. The non-clipped kidney is characterized by increased shear stress. ...Circulating Ang II is elevated. All these factors are stimuli of the paracrine renal endothelin system. Indeed, we demonstrated an activation of the renal endothelin system in the 2K1C rat model.
We analysed the effects of chronic treatment with the ETA receptor antagonist BQ-123 on blood pressure, heart rate, plasma renin activity, and on the progression of glomerulosclerosis, interstitial fibrosis and vascular remodeling in the clipped and non-clipped kidney.
Long-term treatment with BQ-123 led to a fibrotic atrophy of the clipped kidney characterized by a significantly reduced weight of the clipped kidney compared to the clipped kidney of the placebo-treated group. Computer-aided image analysis revealed a markedly enhanced interstitial fibrosis of these clipped kidneys after long-term ETA blockade. The effects of ETA receptor antagonists on the non-clipped kidney were less pronounced. Neither blood pressure nor plasma renin activity were significantly altered by BQ-123 treatment.
The present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.
Allograft transplantation with concomitant chemotherapy has proven successful in the treatment of malignant bone tumors. However, these chemotherapeutic agents may delay tissue healing, resulting in ...clinical complications. To clarify the effects of cisplatin on the healing of bone grafts, we studied the incorporation of stably fixed massive diaphyseal femoral syngeneic and allogeneic grafts in rats treated with cisplatin. These data were compared with those of historical controls from animals that did not receive cisplatin. Rats that were to receive a fresh syngeneic graft or frozen allogeneic graft were given cisplatin every 4 weeks starting 9 weeks preoperatively and continuing until the time of death. The total bone area of the graft in animals that received cisplatin was smaller than that of the graft in untreated control rats that did not receive cisplatin. The area of the frozen allograft did not increase between 2 and 4 months. Revascularization was incomplete in cisplatin-treated groups at 2 months, but by 4 months, vessel ingrowth in fresh syngeneic grafts approached control values. Frozen allografts remained poorly revascularized at 4 months. Host-graft union was poor at 2 months in cisplatin-treated rats compared with controls. In cisplatin-treated rats, the host-graft union of the frozen allograft remained inferior at 4 months while that of the syngeneic graft improved. Allogeneic cortical bone grafts are incorporated more slowly and incompletely than syngeneic grafts, and this handicap is exacerbated by the administration of cisplatin.
An isocratic high-performance liquid chromatography (HPLC) method was developed for the analysis of hydrastinine, palmatine, berberine, hydrastine, and canadine, all alkaloid components known to be ...present in goldenseal root powder. Optimized separation was achieved on a Zorbax Eclipse-XDB column at 30°C using a mobile phase of 10 mM ammonium acetate/acetonitrile (70:30, v/v) at a flow rate of 1.0 mL/min with ultraviolet detection at 235 nm. The method showed linearity for palmatine, berberine, hydrastine, and canadine at approximately 4-400 μg/mL, while hydrastinine was linear at approximately 4-80 μg/mL. Method precision and robustness were investigated. An example of an HPLC analysis of goldenseal root powder extract is presented here also. These studies indicate that the method described here is usable for analysis of goldenseal extracts.
This study analyzed if the paracrine liver endothelin system participates in the pathogenesis of CCl4-induced hepatotoxicity. Wistar Kyoto rats were divided into four groups: a bosentan (mixed ...endothelin ETA and ETB receptor antagonist) treated group with CCl4 intoxication, a vehicle treated group with CCl4 intoxication, a nontreated control group and a bosentan treated control group. Hepatotoxicity was assessed by determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) followed by histopathological examinations. Tissue endothelin-1 concentrations and expression of endothelin receptor subtypes were analyzed. The tissue levels of endothelin-1 in the liver of rats with CCl4 intoxication were significantly higher than those in normal rats. Scatchard analysis revealed no differences in the density and binding constant of endothelin ETA and ETB receptor between rats with CCl4 intoxication and controls. Bosentan treatment of rats undergoing CCl4 inhalation resulted in a significant protection against elevation of ALT, AST, LDH and bilirubin. Histopathological examination of live sections for necrotic, swollen and lipid-laden cells revealed findings that were in agreement with the serum enzyme data. In conclusion, this study showed that the paracrine endothelin system is involved in the pathogenesis of CCl4-induced hepatotoxicity and that the blockade of the stimulated liver endothelin systems reduces CCl4-induced liver injury.
We determined whether the paracrine liver endothelin (ET) system participates in the pathogenesis of CCl4-induced hepatotoxicity. Wistar-Kyoto rats were divided into four groups: a bosentan-treated ...group with CCl4 intoxication, a vehicle-treated group with CCl4 intoxication, a nontreated control group, and a bosentan-treated control group. Hepatotoxicity was assessed by determination of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Tissue ET-1 concentrations and expression of endothelin receptor subtypes were analyzed. The liver tissue levels of ET-1 in rats with CCl4 intoxication were significantly higher than in normal rats. Scatchard analysis revealed no differences in the density and binding constants of ETA and ETB receptors between rats with CCl4 intoxication and controls. Bosentan treatment of rats undergoing CCl4 inhalation resulted in significant protection against elevation of ALT, AST, LDH, and bilirubin. In conclusion, this study showed that the paracrine ET system in involved in the pathogenesis of CCl4-induced hepatotoxicity and that blockade of the stimulated liver endothelin system reduces CCl4-induced liver injury.
PDF
