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BACKGROUND: Growing evidence supports the idea that de novo steroidogenesis has an important role in prostate cancer's progression to the castration-resistant state following androgen deprivation therapy. Therefore, reducing the availability of cholesterol for use as a precursor in androgen synthesis may reduce proliferation and disease progression. METHODS: LNCaP xenograft-bearing mice were castrated and administered simvastatin via diet, and tumor volume and PSA concentration were monitored for 8 weeks post castration. Levels of serum and intratumoral androgens along with serum simvastatin and common toxicity markers were measured at end point. RESULTS: Reduced post-castration tumor growth rate in simvastatin-treated mice correlated with delayed time to castration-resistant progression, determined by two serum PSA doublings from post-castration nadir, when compared with xenografts in mice on control diet. At 8 weeks post castration, serum simvastatin levels were comparable to clinically relevant human doses with no evidence of overt muscle or liver toxicity. This suppressed post-castration tumor growth in the simvastatin diet group was correlated with reduced intratumoral testosterone and dihydrotestosterone levels. CONCLUSIONS: Reduced tumor growth and intratumoral androgen levels observed in simvastatin-treated, castrated mice harboring LNCaP xenograft suggests that suppressing de novo steroidogenesis can delay castration-resistant progression of this tumor model.

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A modified gas chromatographic assay, using mass-selective detection, has been developed for the quantitation of fentanyl in swine serum. Fentanyl and sufentanil, the internal standard, were extracted using a single-step liquid-liquid extraction with dichloromethane. Sensitivity and selectivity were improved by using electron-impact ionization (EI) in the selected-ion monitoring (SIM) mode, where fentanyl and sufentanil were monitored using the fragment ions at m/z 245 and 289, respectively. The limit of quantitation (LOQ) is 0.05 ng/ml, using 1 ml of sample, with a C.V. of 10.8% and a signal-to-noise ratio of 29. Standard curves were linear (r2 = 0.999) over the working range of 0.05-1/5 ng/ml, using 1/y2 as a weighting factor. Recoveries averaged 69.8 +/- 4.7%, 91.0 +/- 13.0% and 90.9 +/- 10.3% at serum concentrations of 1.5, 0.5 and 0.1 ng/ml, respectively. Intra- and inter-day variances, were < 12% at 0.1 ng/ml, and < 10% at concentrations of 0.5, 1 and 1.5 ng/ml. Bias was 6.2% at the LOQ and < or = 12.8% at every other standard curve concentration. Applicability of the assay is demonstrated for the pharmacokinetic study of transdermally administered fentanyl in a postoperative swine.

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A modified gas chromatographic-mass spectrometric (GC-MS) assay has been developed to quantitate metoclopramide (MCP) and two of its metabolites [monodeethylated-MCP (mdMCP), dideethylated-MCP (ddMCP)] in the plasma, bile and urine of sheep. The heptafluorobutyryl derivatives of the compounds were formed and quantitated using electron-impact ionization in the selected-ion monitoring mode (MCP, m/z 86, 380; mdMCP, m/z 380 and ddMCP, m/z 380). No interference was observed from endogenous compounds following the extraction of various biological fluids obtained from non-pregnant sheep. Sample preparation has been simplified and the method is more selective and sensitive (2 fold) than our previous assay using electron-capture detection. The limit of quantitation for MCP, mdMCP and ddMCP was 1 ng/ml in plasma, urine and bile, requiring 0.5 ml of sample. This represents 2.5 pg of the analytes at the detector. The standard curves were linear over a working range of 1-40 ng/ml. Absolute recoveries in plasma ranged from 76.5-94.7%, 79.2-96.8%, 80.3-102.2% for MCP, mdMCP and ddMCP, respectively. In urine, recoveries ranged from 56.5-87.8%, 61.5-87.5%, 62.6-90.2% for MCP, mdMCP and ddMCP, respectively. Recoveries in bile ranged from 83.5-100.9%, 78.5-90.5%, 66.9-79.2% for MCP, mdMCP and ddMCP, respectively. Overall intra-day precision ranged from 2.9% for MCP in plasma to 12.6% for mdMCP in bile. Overall inter-day precision ranged from 5.9% for MCP in urine to 14.9% for ddMCP in bile. Bias was the greatest at the 1 ng/ml concentration in all biological fluids ranging from a low of 2.4% for mdMCP in plasma to a high of 11.9% for ddMCP in urine. Applicability of the assay for pharmacokinetic studies of MCP, mdMCP and ddMCP in the plasma and urine of a non-pregnant ewe is demonstrated.

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Effects of phenobarbital, phenytoin, carbamazepine, cimetidine, erythromycin, combination of sulfamethoxazole + trimethoprim (5:1), and rifampicin (rifampin) on the elimination of aminophylline were examined in female rats. Aminophylline was administered i.p. in a dose of 13.33 mg/kg. Blood samples were collected 0.5, 2, 4 and 7 h after the administration of the injection; one measurement was performed from one blood sample. Plasma aminophylline levels were measured by a modified HPLC method. The elimination half-life of the untreated control group (n = 27) was 4.62 h. The pretreatments with drugs examined were carried out by a gastric tube. The half-life of aminophylline after phenobarbital (10 mg/kg, 7 days, n = 29) was 2.09 h; after phenytoin (10 mg/kg, 7 days, n = 29), 2.47 h; after carbamazepine (400 mg/d, 7 days, n = 25), 2.19 h; after cimetidine (in cimetidine-treated group the blood samples were collected 0.5, 4 and 7 h after the aminophylline injection) (40 mg/kg, 7 days, n = 13), 1.77 h; after erythromycin (800 mg/d, 7 days, n = 28), 2.51 h; after the combination of sulfamethoxazole + trimethoprim in ratio of 5:1 (50 mg/kg, 7 days, n = 23), 2.85 h; and after rifampicin (300 mg/kg, 21 days, n = 23), 2.74 h. Sulfamethoxazole presumably interfered with the HPLC examination of aminophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

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The effect of the enzyme inducer flumecinolum, m-trifluoromethyl-alpha-ethylbenzhydrol (Zixoryn), on aminophylline metabolism was examined in rats. Aminophylline plasma levels were determined by HPLC. Aminophylline T1/2 was 2.85 hours (r = 0.9353) in the pretreated group and 3.75 hours (r = 0.9471) in the untreated control group. Flumecinolum was found to accelerate the elimination of aminophylline and the effect became significant 3.92 hours after the administration of aminophylline.

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The development of drug tolerance in two groups of asthmatics treated with beta-adrenergic bronchodilators was studied by respiratory function methods. During one-year treatment with conventional therapeutic doses of selective beta-2-receptor stimulant aerosols, none of the patients showed subsensitivity to the bronchodilatory effect of terbutaline. Dose-response curves were plotted upon the inhalation of salbutamol in two-week intervals in patients treated with betamimetics. There was no decrease in the airways beta-adrenergic receptor function as compared to the untreated control group. The results show that prolonged treatment with therapeutic doses of inhaled beta-adrenergic bronchodilators does not result in drug tachyphylaxis, which is in accord with the clinical experience that there is no loss of effect of the preparations during their continuous administration.

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