Apolipoprotein-AI-containing particles and atherosclerosis.
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Animals↗
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[Effect of ebrantil, a new antihypertensive agent, on lipid metabolism and electrolyte balance].
The influence of Ebrantil on serum electrolytes, lipids, and lipoproteins was studied in 8 normotensives and 10 hypertensives. For this purpose, Ebrantil sustained-release capsules were administered after a 7-10 day diet phase concomitantly with the diet for a period of 2 weeks. Before and after the diet phase, as well as subsequent to the treatment period, laboratory parameters were determined in fasting blood. The serum levels of sodium, potassium, calcium, and magnesium were identical at all measuring times. The concentrations of triglycerides, phospholipids, total cholesterol, VLDL-, LDL-, HDL-cholesterol, and of the apolipoproteins AI, AII and B measured in all patients at the end of the treatment period deviated only slightly from those determined in the diet phase. The mean value for the arteriosclerosis index LDL/HDL decreases significantly during treatment. The results reveal that Ebrantil has no negative influence on electrolyte balance and lipometabolism.
Adult↗
Cytotoxic isoprenylated xanthones from Cudrania tricuspidata.
Eight new isoprenylated xanthones, cudratricusxanthones A-H (1-8), were isolated from the roots of Cudrania tricuspidata, together with ten known compounds, cudraxanthones H (9) and M (10), xanthone V(1a) (11), toxyloxanthone C (12), macluraxanthone B (13), 1-hydroxy-3, 6, 7-trimethoxyxanthone (14), cycloartocarpesin (15), artocarpesin (16), cudraflavone B (17), and kaempferol (18). Their structures were characterized by spectroscopic methods. Xanthones 5, 7, 10, and 12 showed inhibitory effects on four kinds of human digestive apparatus tumor cell lines (HCT-116, SMMC-7721, SGC-7901, and BGC-823) with IC(50) values of 1.6-11.8 microg/mL. Xanthones 2, 4, and 11 displayed significant cytotoxicity against HCT-116, SMMC-7721, and SGC-7901 (IC(50)=1.3-9.8 microg/mL). Flavonoids 15-17 were almost inactive.
Antineoplastic Agents↗
Dissecting the anti-obesity components of ginseng: How ginseng polysaccharides and ginsenosides target gut microbiota to suppress high-fat diet-induced obesity.
INTRODUCTION: Ginseng demonstrates therapeutic potential in treating obesity, with both experimental and clinical studies suggesting its anti-obesity effects are mediated by gut microbiota. Nonetheless, the specific chemical components responsible for this effect remain largely unidentified. OBJECTIVES: This study aims to investigate the anti-obesity effects and mechanisms of ginseng polysaccharides (GP) and ginsenosides (GS), the primary chemical components of ginseng, with a focus on their impact on gut microbiota. METHODS: The impact of GP and GS on high-fat diet (HFD)-induced obesity was assessed using a mouse model. Molecular mechanisms were explored through a combination of chemical analysis, metagenomics, RT-qPCR, ELISA, and biochemical assays. RESULTS: GP or GS administration effectively prevented adiposity in HFD-fed mice, and both effects were mediated by gut microbiota. Chemical analysis revealed diverse glycosyl groups in GP and GS. Metagenomics data suggested that GP-enriched species, e.g., Bacteroides stercorirosoris and Clostridiales bacterium encoded carbohydrate-active enzymes GH35, GH43 and PL9_1, while GS-enriched Sulfurospirillum halorespirans encoded GH16_5. These enzymes facilitated the utilization of glycosyl groups in GP and GS, selectively stimulating bacterial growth and reshaping the gut microbiota. Furthermore, bacterial species enriched by GP or GS encoded specific functional genes involved in short-chain fatty acid (SCFA) synthesis (K00625 and K00925 for GP; K18118, K00100, and K18122 for GS) and intestinal gluconeogenesis (IGN) (K01678, K00024, and K01596 for GP; K18118 and K00278 for GS). Consequently, the SCFA-GLP-1/PYY signaling and IGN were activated by both GP and GS to ameliorate obesity phenotypes. CONCLUSION: GP and GS, containing diverse glycosyl groups, selectively stimulate specific gut bacteria, triggering mechanisms involved in SCFA-GLP-1/PYY signaling and IGN activation to reduce adiposity in HFD-fed mice. The study enhances understanding of the chemical components crucial for the gut microbiota-mediated anti-obesity effect of ginseng. The mechanistic understanding provides valuable insights for developing ginseng-based drugs or health products to combat obesity.
Gastrointestinal Microbiome↗
Cytotoxic ent-kauranoids from Isodon leucophyllus.
Two new compounds, baiyecrystals D and E (1, 2), together with eight known analogues, xerophilusin B (4), macrocalin B (5), oridonin (6), rosthorin A (7), lasiocarpanin (8), rabdoternin A (9) and phyllostachysin A (10) and B (11), were isolated from the aerial parts of Isodon leucophyllus. The structures of 1 and 2 and 4-11 were elucidated on the basis of spectroscopic methods, especially the 2D NMR spectral analysis. Compounds 2, 6-8 and 10 were evaluated for their antineoplastic activities in vitro. Among them, lasiocarpanin (8) showed significant inhibitory activities against K562 and Bcap37 cells, with the IC50 values of 0.13 and 1.26 microg mL(-1), respectively, which were lower than those of the positive control.
Antineoplastic Agents, Phytogenic↗
Ketoconazole renders poor CYP3A phenotype status with midazolam as probe drug.
Drugs metabolized by cytochrome CYP3A isoenzymes have wide interindividual variability and normally distributed plasma clearance distributions. This makes precise dosing difficult to achieve clinically, which may compromise safe therapy. We hypothesized that with potent inhibition of CYP3A, we could clinically render patients "poor metabolizer" phenotype status, and thus reduce interindividual pharmacokinetic variability of midazolam, a well-known CYP3A substrate. Intravenous bolus midazolam at doses of 2.5 mg and 1 mg were administered to 28 and 29 patients with cancer with and without co-administration of 200 mg of oral ketoconazole twice per day respectively for 3 days, starting 1 day before midazolam. Pharmacokinetic analyses of midazolam on both groups were derived using noncompartmental methods and compared. The mean clearance (CL) of midazolam was reduced 6 times by ketoconazole. Midazolam CL were normally distributed in both groups, and ranged from 1.7 to 51.9 and 1.4 to 8.2 L/hour in the control and ketoconazole groups, respectively, corresponding to a 7-fold reduction in dispersion between the 2 groups. Area-under-the-curve variability was reduced by >100%. A limited sampling model consisting of time points at 15 and 300 minutes was validated as a phenotype for CYP3A activity to facilitate the use of midazolam as a probe drug for CYP3A activity. Potent inhibition of CYP3A by ketoconazole reduced midazolam CL and area-under-the-curve variability, allowing for more precise achievement of therapeutic target drug exposure. Prospective evaluation of this approach, together with dose adjustment based on limited sampling, seems warranted.
Administration, Oral↗
Cell viability of chitosan-containing semi-interpenetrated hydrogels based on PCL-PEG-PCL diacrylate macromer.
Chitosan-modified biodegradable hydrogels were prepared by UV irradiation of solutions in mild aqueous acidic media of poly(caprolactone)-co-poly(ethylene glycol)-co-poly(caprolactone) diacrylate (PCL-PEG-PCL-DA) and chitosan. Hydrogels obtained were characterized using FT-IR, DSC, TGA and XPS. FT-IR, TGA and DSC revealed the semi-interpenetrating polymer network structure formed in the hydrogel. Though the water swelling degree of these chitosan-modified hydrogels was substantial in the range of 322-539%, it was found that fibroblasts could still attach, spread and grow on them; this is in contrast to the commonly investigated PEG-diacrylate hydrogel. The MTT assay demonstrated that cells could grow better on 3 or 6% chitosan-modified hydrogel than unmodified PCL-PEG-PCL-DA hydrogels or low-content (1%) chitosan-modified PCL-PEG-PCL-DA hydrogel. Increased chitosan content resulted in increased cell interaction and also decreased water swelling, both of which results in increased cell attachment and spread.
Acrylates↗
High density lipoproteins stimulate placental lactogen release and adenosine 3',5'-monophosphate (cAMP) production in human trophoblast cells: evidence for cAMP as a second messenger in human placental lactogen release.
Recent studies from our laboratory indicate that high density lipoproteins (HDL) and apolipoproteins-AI, -AII, and -CI stimulate the release of human placental lactogen (hPL) from human placental explants and trophoblast cells. However, the intracellular mechanisms by which HDL stimulate hPL release are unknown. Since earlier investigations from our laboratory indicated that pharmacological agents that increase intracellular cAMP levels [such as (Bu)2cAMP, isobutylmethylxanthine, and cholera toxin] also stimulate hPL release, we have performed studies to determine whether the stimulation of hPL release by HDL may be mediated by cAMP. Exposure of an enriched fraction of enzymatically dispersed hPL-producing cells to HDL (10-1500 micrograms/ml) for 0.5 h resulted in a significant dose-dependent stimulation of both cAMP production and hPL release. The half-maximal effective HDL dose for cAMP production and hPL release was 60-100 micrograms/ml. When perifused trophoblast cells were exposed to HDL (150 micrograms/ml) for 25 min, the increase in cAMP production preceded the increase in hPL release. The increase in cAMP production occurred during the first 5 min of exposure to HDL and reached a maximum (12.1 +/- 1.6-fold greater than base-line levels) 10 min after exposure. The increase in hPL release occurred about 10 min after the initial increase in cAMP production, reaching a maximum (9.7 +/- 1.4-fold greater than base-line levels) 15 min after exposure to HDL. HDL (300 micrograms/ml) also stimulated a 2.7-fold (P less than 0.001) increase in adenylate cyclase activity in placental plasma membranes, a magnitude of stimulation comparable to that caused by epinephrine (1 mM). Apolipoprotein-AII stimulated cAMP formation and hPL release in trophoblast cells with a pattern identical to that of HDL. These results, the first to demonstrate an effect of HDL on adenylate cyclase activity and cAMP production, strongly suggest a role for cAMP as a second messenger in HDL-stimulated hPL release.
Apolipoproteins↗
Effects of matrine, artemisinin, tetrandrine on cytosolic [Ca2+]i in guinea pig ventricular myocytes.
AIM: To compare the effects of matrine, artemisinin, and tetrandrine on intracellular Ca2+ concentration ([Ca2+]i) in guinea pig ventricular myocytes. METHODS: A single ventricular myocyte was loaded with Fluo 3-acetoxymethyl (Fluo 3-AM). [Ca2+]i was recorded by laser scanning confocal microscope and represented by fluorescence intensity (FI). RESULTS: 1) KCl 60 mmol . L-1 elevated the FI from 299 +/ -19 to 1389 +/- 325 (P < 0.01) in the presence of extracellular Ca2+ 1.8 mmol . L-1. 2) Both matrine and artemisinin at the concentration of 100 micromol . L-1 could enhance the increase of FI by KCl 60 mmol . L-1. The FI values reached 1495 +/- 320 and 1646 +/- 308 from 301 +/- 14 and 299 +/- 16 (P < 0.01), respectively. 3) Both tetrandrine 1, 10, and 100 micromol . L-1 and verapamil 10 micromol . L-1 inhibited the influx of extracellular Ca2+ induced by KCl 60 mmol . L-1. 4) Matrine 1, 10, and 100 micromol . L-1 could elevate the FI in the presence of extracellular Ca2+. The FI values reached 441 +/- 96, 504 +/- 112, and 643 +/- 126 from 303 +/- 27, 300 +/- 32, and 296 +/- 19 (P < 0.05), respectively. 5) Tetrandrine 1 and 10 micromol . L-1 could apparently inhibited Ca2+ release from intracellular calcium stores induced by caffeine 20 mmol . L-1 (P < 0.05). CONCLUSION: Effects of matrine, artemisinin, and tetrandrine on [Ca2+ )]i in ventricular
Alkaloids↗
[Influence of the watery extract of jiangzhining decoction on the genetic expression of hepatocyte LDLR of hyperlipidemic rats].
OBJECTIVE: To study the influence of Jiangzhining decoction on the genetic expression of Liver LDLR of the rats suffered from hyperlipemia. METHOD: Laboratory animals were male wister rats with hyperlipemia resulting from high fat feeding. Prescription was the douche of stomach with Jiangzhining decoction (200%) with a dosage of 1.4 g.kg-1, for 15 successive days. Total RNA was extracted from the liver tissue of treated rats and LDLRmRNA was detected by Dot blot hybridization. Expression levels of LDLRmRNA was estimated by a ratio of LDLRmRNA and beta-actin mRNA. RESULT: The difference between expression levels of LDLRmRNA for normal group and those for hyperlipemia group (100% +/- 19% vs 39% +/- 14%) was significant (P < 0.05); and the difference between decoction group (108 +/- 8%) and hyperlipimia group was also highly significant (P < 0.01). CONCLUSION: High fat feeding reduces the expression of liver LDLRmRNA while the decoction can greatly increase it. The study and development of Jiangzhining are significant in preventing and curing cadiocerebral diseases.
Actins↗
[Effects of oxymatrine on serum levels of Th1/Th2 type cytokines in HBsAg transgenic mice].
OBJECTIVE: To explore the effects of oxymatrine on serum levels of Th1/Th2 cytokines in HBsAg transgenic mice. METHODS: HBsAg transgenic mice were divided into oxymatrine group and control group. Each mouse was injected with either oxymatrine 200 mg/kg 0.2 ml or 0.9% NaCl 0.2 ml intraperitoneally once a day for 30 days. Serum IFN-gamma, IL-2 and IL-4, IL-10 were quantitated before and after different treatment. RESULTS: There was no significant difference on the levels of IFN-gamma and IL-4 before and after treatment in control group. While in oxymatrine group, the levels of IFN-gamma before and after treatment were (3.108+/-3.172) pg/ml and (11.059+/-6.971) pg/ml; those of IL-4 were (29.045+/-13.235) pg/ml and (13.024+/-9.002) pg/ml (both P less than 0.001). After treatment, the levels of IL-2 in control and oxymatrine group were (1.070+/-0.447) pg/ml and (5.537+/-2.887) pg/ml (P less than 0.000 1); and those of IL-10 were (97.226+/-73.306) pg/ml and (33.607+/-23.154) pg/ml (P less than 0.01). CONCLUSION: After injection of oxymatrine to HBsAg transgenic mice, the serum concentration of Th1 cytokines increased while the Th2 cytokines decreased. This can help us understand more better on the mechanisms of anti-HBV effect of oxymatrine.
Alkaloids↗
[An experimental study on antiviral effects of IFN alpha].
OBJECTIVE: To investigate the effects of different subtypes IFN alpha (IFN alpha2b, IFN alpha2a, and IFN alpha1b) transduction molecular STAT1, STAT2, IFNAR, PKR, and RNase L, and to study the differences of their antiviral effects and to evaluate the key signaling transduction molecules. METHODS: (1) After HepG2 cells were treated with IFN alpha2b, IFN alpha2a, or IFN alpha1b, the mRNA levels of STAT1, STAT2, IFNAR, PKR, and RNase L were detected by RT-PCR. (2) After HepG2 cells were treated with 1000 U/ml IFN alpha2b, IFN alpha2a, or IFN alpha1b, the protein expression levels of STAT1 and IFNAR were examined by Western blot. RESULTS: RT-PCR results: (1) IFNAR, STAT1, and STAT2 mRNA expression levels were slightly higher in the IFN alpha1b group than those in the IFN alpha2b group (P > 0.05). The mRNA expression levels in IFN alpha1b or IFN alpha2b groups were significantly higher than in the IFN alpha2a group (P < 0.05). (2) The PKR mRNA expression showed no significant differences among IFN alpha1b, IFN alpha2b, and IFN alpha2a groups. (3) The RNase L mRNA expression was very weak. We could not compare the differences of the RNase L mRNA levels in different groups by RT-PCR. Western blot results: (1) The IFNAR, and STAT1 protein expressions were greatly up-regulated after IFN alpha induction compared with the untreated group (P < 0.05). (2) The IFNAR, and STAT1 protein expression levels in IFN alpha1b group were slightly higher than the IFN alpha2b group. IFNAR, and STAT1 protein levels of IFN alpha1b or IFN alpha2b group were significantly higher than IFN alpha2a group (P < 0.05). CONCLUSION: STAT1, STAT2, IFNAR mRNA and protein expressions could all be markedly up-regulated after IFN alpha treatment. Effects of IFN alpha1b or IFN alpha2b were greatly stronger than IFN alpha2a. The PKR mRNA expression also was greatly up-regulated after IFN alpha treatment. Expression levels of PKR in IFN alpha1b, IFN alpha2b, and IFN alpha2a groups were all similar. The mRNA level results were consistent with the protein level results. Our results showed that the antiviral activity of IFN alpha1b or IFN alpha2b were stronger than that of IFN alpha2a. The signal transduction molecules STAT1, STAT2, and IFNAR could be regarded as a key index to evaluate antiviral activity of IFN alpha. Further confirmation is still needed to see whether PKR could be regarded as a key index.
Antiviral Agents↗
[Phase I clinical trail of intravenous pegylated recombinant human granulocyte colony-stimulating factor].
BACKGROUND & OBJECTIVE: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is effective in the prophylaxis and management of chemotherapy-induced neutropenia, but requires daily administration because of its short half-life. Pegylated rhG-CSF (PEG-rhG-CSF) is a long-acting reagent that permits less frequent injection. This study was to evaluate the safety and tolerance of PEG-rhG-CSF in Chinese patients, and to explore its efficacy of enhancing absolute neutrophil count (ANC) and CD34+ cell count in peripheral blood. METHODS: Naïve non-small lung cancer or breast cancer patients with normal bone marrow function were eligible for this open-labeled, dose-escalation trial. All patients received 2 cycles of chemotherapy of identical regimen. In cycle 1, rhG-CSF (150 microg/day) was administrated in case of febrile neutropenia or grade 4 neutropenia; in cycle 2, patients received a single injection of PEG-rhG-CSF (30 microg/kg, 60 microg/kg, 100 microg/kg, or 200 microg/kg) 48 h after administration of paclitaxel and carboplatin. RESULTS: All the 16 patients enrolled (4 in each dose group) were evaluable for safety and efficacy of PEG-rhG-CSF. Main adverse events related to PEG-rhG-CSF were musculoskeletal pain or arthralgia (13/16), fatigue (10/16), dizziness (2/16), and injection-site pain (1/16). All adverse events were mild to moderate, and most of them were reversible without treatment. PEG-rhG-CSF enhanced ANC in a dose-dependent manner to some extent, and PEG-rhG-CSF at 60 microg/kg or higher doses prevented chemotherapy-induced neutropenia with sustained effect; CD34+ cells in peripheral blood were also increased. CONCLUSIONS: PEG-rhG-CSF is well tolerated, with no serious adverse event in this trial. The recommended dose of PEG-rhG-CSF for phase II trial is 100 microg/kg because of its adequate efficacy and less adverse events than those of 200 microg/kg.
Adult↗
[Effects of tyrosine kinase receptor B and brain-derived neurotrophic factor on chemoresistance in neuroblastoma].
OBJECTIVE: Neuroblastoma (NB) is a pediatric solid tumor derived from neural crest precursor cells. It is resistant to current therapeutic protocols, including high dose chemotherapy. The mechanisms of chemoresistance are very complex. The recent studies have shown that the levels of tyrosine kinase receptor B (TrkB) and brain-derived neurotrophic factor (BDNF) are high in NB tumors with poor prognosis. The aim of this research was to explore the effects of TrkB and BDNF levels on the chemotherapeutic sensitivity in neuroblastoma by using the NB cell line SH-SY5Y in vitro. METHODS: The expression of TrkB protein was detected with Western-blot after the treatment with different concentrations of all trans-retinoic acid (ATRA). Cell survival rate was analyzed using MTT. Apoptosis was detected using flow cytometry (FCM) and a transmission electron microscope (TEM). RESULTS: (1) The expression of TrkB protein was undetectable in SY5Y. It was positive, however, after the treatment with ATRA (1, 10, 100 nmol/L) for five days. The level of TrkB protein was increased with adding of ATRA at different concentrations. (2) The difference of the survival and apoptotic rate between the BDNF (10 ng/ml) + ATRA (10 nmol/L) + cisplatin (CP, 5 microg/ml) group (survival rate 46.51% +/- 13.44%, apoptosis rate 11.79% +/- 1.53%) and the CP alone group (survival rate 38.51% +/- 9.66%, apoptosis rate 14.95% +/- 2.06%) was not statistically significant (P > 0.05). The survival rate of the BDNF (50 ng/ml and 100 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group (66.85% +/- 18.39%, 94.30% +/- 10.71%) was greatly higher than CP alone group (P < 0.05, P < 0.01), whereas the apoptotic rate (9.36% +/- 1.03%, 5.20% +/- 1.99%) was significantly lower than that of the CP alone group (P < 0.01, P < 0.01). The survival rates of BDNF (100 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group were higher than those of BDNF (50 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group (P < 0.01), whereas the apoptotic rates were lower than those of BDNF (50 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group (P < 0.05). There were no significant difference between the ATRA (1 nmol/L) + BDNF (50 ng/ml) + CP group (survival rate 45.33% +/- 11.83%, apoptosis rate 12.48% +/- 2.48%) and the CP alone group in the survival and apoptotic rates (P > 0.05). The survival rates of the ATRA (10 nmol/L, 100 nmol/L) + BDNF (50 ng/ml) + CP (61.62% +/- 18.53%, 105.02% +/- 5.55%) group were greatly higher than those of the CP alone group (P < 0.05, P < 0.01), whereas the apoptotic rate (9.36% +/- 1.03%, 5.05% +/- 1.88%) was significantly lower than that of the CDDP alone group (P < 0.05, P < 0.01). The survival rates of the ATRA (100 nmol/L) + BDNF (50 ng/ml) + CP group were higher than those of the ATRA (10 nmol/L) + BDNF (50 ng/ml) + CP group (P < 0.01), whereas the apoptotic rates were lower than the ATRA (10 nmol/L) + BDNF (50 ng/ml) + CP group (P < 0.01). (3) Some of the cells showed apoptotic changes in the CP alone group, whereas the intranuclear chromoplasma was well-distributed, the nuclear membrane was clear, and mitochondria, ribosome and solvent were present in the ATRA (10 nmol/L) + BDNF (50 ng/ml) + CP group. CONCLUSIONS: The sensitivity of SY5Y to CP was affected by TrkB and BDNF. The higher the level of TrkB and BDNF was, the lower the sensitivity of SY5Y to CP.
Antineoplastic Agents↗
Aromatase inhibitors for therapy of advanced breast cancer.
In postmenopausal women with advanced breast cancer, numerous phase III trials have been performed comparing the third-generation non-steroidal aromatase inhibitors (NS-AIs) anastrozole and letrozole and the steroidal AI (S-AI) exemestane in the "first-line" setting against tamoxifen and in the "second-line" setting against megestrol acetate. In both settings, the AIs were at least as efficacious or superior in some endpoints with a preferable toxicity profile including a lower incidence of thrombotic events. Relatively small differences in potency between the three AIs have been identified and it has not been demonstrated that these differences have clinical implications. The recent establishment of the value of AIs in the adjuvant setting for postmenopausal women will impact on their utilization in advanced disease. In premenopausal women the third-generation AIs have not been studied as monotherapy and there is a paucity of data in combination with ovarian function suppression in the advanced disease setting. The main area of future investigations for the AIs in premenopausal women will be in the adjuvant therapy setting in combination with suppression of ovarian function.
Anastrozole↗
Comparison of oestrous synchronization regimens for lactating dairy cows.
The objective of this experiment was to evaluate various programmes for synchronization of oestrus. The focus of the study was to evaluate rates of detection of oestrus, synchrony of oestrus, pregnancy rate, and effect of ovarian status at initiation of the programmes on rates of detection of oestrus and pregnancy rate. Spring-calving, lactating dairy cows (n = 2009) were allocated at random to one of six treatments: (1) A (n = 335), progestogen (controlled intravaginal drug release; CIDR) inserted per vaginum 10 d before breeding season for 8 d, 10 microg of buserelin at CIDR insertion, PGF2alpha treatment on the day prior to CIDR removal, and AI of cows detected in oestrus within 6 d after CIDR withdrawal; (2) B (n = 330), as in A, plus 1 mg of oestradiol benzoate i.m. 10 h post CIDR withdrawal; (3) C (n = 347), as in A, except buserelin was replaced by 10 mg of oestradiol benzoate; (4) D (n = 335), as in A, plus PGF2alpha and oestradiol benzoate at CIDR insertion; (5) E (n = 332), CIDR containing a 10 mg oestradiol benzoate capsule inserted per vaginum for 12 d; or (6) F (n = 330), as in E, plus PGF2alpha on the day prior to CIDR withdrawal. The oestrous detection rate (number of cows detected in oestrus within 6 days of CIDR withdrawal as a proportion of the number of cows submitted for synchronization of oestrus) and oestrous synchrony (oestrous detection rate within 2 d of CIDR withdrawal), respectively, were greater (P<0.05) following B (95.7% of 330, 98.7% of 316) compared with any of the other programmes for synchronization of oestrus (A: 87.5 of 335, 79.4% of 293; C: 86.7% of 347, 80.0% of 301; D: 90.1% of 335, 89.8% of 302; E: 74.4% of 332, 70.4% of 247; F: 76.4% of 330, 78.5% of 252). The oestrous detection rate was reduced (P<0.05) among cows in metoestrus administered E (64.0% of 50) relative to similar cows administered F (82.8% of 64). Pregnancy rate was greater (P<0.05) following B (57.9% of 330) than A (48.9% of 335, P = 0.06), C (43.2% of 347), E (40.0% of 332), and F (35.1% of 330) but not D (59.3% of 302), when based on those cows presented for oestrous synchronization programmes. In conclusion, 1 mg of oestradiol benzoate administered 10 h post CIDR withdrawal (B) resulted in the best overall oestrous detection, oestrous synchrony, and pregnancy rates, which would be beneficial to a fixed-time AI program.
Administration, Intravaginal↗
Modeling for cost-effective-adjuvant aromatase inhibitor strategies for postmenopausal women with breast cancer.
BACKGROUND: To determine cost-effective (CE) strategies comparing adjuvant upfront aromatase inhibitor (AI) with sequential tamoxifen (TAM) AI in postmenopausal (PM) women with breast cancer (BC). DESIGN: A Markov model was constructed to calculate cumulative costs and quality-adjusted life year (QALY) gains for upfront AI and TAM-AI in a hypothetical cohort of 60-year-old PM women with BC. Costs, utilities and probabilities were derived from the literature. The hazard ratios (HRs) of AI strategies were applied to a baseline cancer recurrence risk (RR) to determine CE strategies at the $50,000/QALY gain threshold. A direct payer perspective is utilized, and costs and benefits were discounted at 3%. RESULTS: Two-way sensitivity analyses are presented to determine CE strategies across a wide range of HRs and in different clinical scenarios including varying RRs (low, average, high and very high). TAM-AI is the preferred CE strategy at low and average RR, while upfront AI is CE at very high RR. The CE strategy in patients with high RR was dependent on the scenario examined. CONCLUSIONS: This model may help health care providers select CE-adjuvant AI strategies in PM women with BC, until further direct evidence is available from randomized clinical trials.
Anastrozole↗
Metabolism of tetradecapeptide, angiotensinogen and angiotensin I and II by isolated perfused rat hindlimbs.
1. We investigated the mechanism of tetradecapeptide-induced vasoconstriction by studying the metabolism of tetradecapeptide (TDP), angiotensinogen, and angiotensin I (AI) and angiotensin II (AII) by isolated perfused rat hindlimbs. 2. Using HPLC and specific RIAs we have quantified six angiotensin peptides: pentapeptide(4-8), hexapeptide(3-8), heptapeptide(2-8), octapeptide(1-8), nonapeptide(2-10) and decapeptide(1-10) in hindlimb effluent. 3. TDP-induced vasoconstriction was associated with generation of predominantly AI and AII, with smaller amounts of the other peptides measured. 4. Captopril prevented vasoconstriction and inhibited AII production by 80%, indicating a dominant role for AI generation in the vascular response to TDP. 5. Evidence that renin is not the enzyme responsible for AI generation from TDP includes: first, the failure of angiotensinogen to cause vasoconstriction or angiotensin peptide generation despite very high amounts of AI and AII generation from TDP; second, the resistance of the TDP-induced vasoconstriction and angiotensin peptide generation to inhibition by pepstatin; and third, the failure of bilateral nephrectomy 24 h before the experiment to influence the vascular and angiotensin peptide response to TDP. 6. AII was cleared with 41% efficiency, with generation of penta-, hexa-, and heptapeptides. 7. AI was cleared with 59% efficiency; this was reduced to 24% by captopril, indicating a conversion of at least 35% of AI to AII by ACE. 8. These studies have identified vascular metabolism of AI and AII to be an efficient process, with both ACE and aminopeptidases playing an important role, and indicate that those peptidases which cleave TDP to generate AI are unlikely to play any role in AI generation in vivo.
Angiotensin I↗