Resveratrol and its glycon piceid are stable polyphenols.

Plant extracts containing phytopolyphenols, including resveratrol, are extensively used as nutraceutical supplements. Recent reports allege their lack of stability at ambient conditions. We have studied the stability of resveratrol and its glycon piceid in a mixture with a whole grape extract for 2 years (long-term stability) under Good Manufacturing Practice pharmaceutical protocols (at 60% humidity and 25 degrees C). The neat compounds were followed for 4 years under conditions of "accelerated stability," at 75% humidity and 40 degrees C, all in the presence of ambient air. Chromatographic analysis did not detect any instability, thus disproving the claims to the opposite. No storage precautions are necessary for these nutritional supplements.

Iosimenol, a low-viscosity nonionic dimer: preclinical physicochemistry, pharmacology, and pharmacokinetics.

RATIONALE AND OBJECTIVES: Newer radiologic techniques require fast bolus injections and thus low-viscosity, high-concentration, well-tolerated contrast media (CM), especially in vulnerable patients. To this end, we designed and developed iosimenol, a novel isotonic nonionic dimer, and have conducted tests to enable its clinical evaluation. METHODS: Standard physicochemical methods were used. Effects on erythrocyte morphology and coagulation were investigated in human and rat blood. Neural tolerance was assessed by behavioral tests in rats after intracisternal injection. Immunosensitizing potential was evaluated by the skin sensitization test in guinea pigs and by the popliteal lymph node assay in rats. Pharmacokinetics and biotransformation were investigated in rats and dogs. RESULTS: Iosimenol is extremely hydrophilic, it is less viscous than any other isotonic CM, has little effect on erythrocytes and blood coagulation, and has good neural tolerance. No immunosensitizing effect was found in validated animal models. Pharmacokinetics are identical with other angio- and urographic CM. CONCLUSIONS: Iosimenol is the only CM which, although isotonic, affords, unlike current nonionic dimers, at the same iodine concentration the low viscosity of monomeric, nonionic agents, which are all hypertonic. Iosimenol's pharmacologic characteristics closely resemble those of iotrolan and iodixanol.

No difference among modern contrast media's effect on neointimal proliferation and restenosis after coronary stenting in pigs.

RATIONALE AND OBJECTIVES: Recent clinical trials indicate that the choice of radiographic contrast media (CM) may influence the late outcome of coronary interventions. This might be explained by the different effects of various CM on neointimal proliferation. METHODS: The effect of a 1-hour incubation of bovine aortic smooth muscle cells in ioxaglate or iopromide solution on in vitro cell division was tested. Furthermore, in 12 pigs randomized into 3 groups (iopromide, ioxaglate, and iosimenol; a novel nonionic dimer), coronary angiography was performed followed by implantation of stents. After 28 days, restenosis was assessed by quantitative angiography and histomorphometry. RESULTS: Compared with saline, CM did no change cell counts up to 15 days after incubation. Baseline parameters in the pigs indicated no difference between the test groups. After 28 days, the test groups showed no significant differences in the parameters characterizing in-stent restenosis. CONCLUSIONS: Under the experimental conditions iopromide, ioxaglate, and iosimenol had no or very similar direct or otherwise mediated effect on cell proliferation and restenosis.

Contrast media as carriers for local drug delivery. Successful inhibition of neointimal proliferation in the porcine coronary stent model.

BACKGROUND: Lipophilic taxanes can be dissolved in contrast media at significantly higher concentration than in saline. As contrast media have occasionally been observed to delineate the contour of coronary arteries for some seconds they may serve as a matrix for an antiproliferative drug aimed at preventing restenosis. The aim of this study was to test a novel taxane-contrast agent formulation for this new approach in the setting of coronary stenting. METHODS AND RESULTS: In cell culture experiments (bovine vascular smooth muscle cells), 60-min incubation with contrast agent-taxane formulations (iopromide-paclitaxel, iopromide-protaxel) induced a significant, concentration-dependent inhibition of vascular smooth muscle cell (VSMC) proliferation over 12 days. Shorter incubation times of 10 and 3 min showed the same efficacy. For in vivo investigation, 16 stents were implanted into the coronary arteries of eight pigs using a 1.3 to 1 overstretch ratio. A control group received iopromide 370 alone while the treatment group was injected with a iopromide-protaxel formulation at a dose of 74 micromol/l, which is far below protaxel levels inducing systemic toxicity. Quantitative angiography and histomorphometry of the stented arteries asserted statistic equality of the baseline parameters between the control and treatment groups. After 28 days, the treatment group showed a marked reduction of the parameters characterizing in-stent restenosis, especially a 34% reduction of the neointimal area. CONCLUSIONS: First evidence is provided that using a contrast agent as solvent for a taxane constitutes a new drug delivery mechanism able to inhibit in-stent restenosis in the porcine restenosis model.

Herbal composition PC-SPES for management of prostate cancer: identification of active principles.

BACKGROUND: The herbal mixture PC-SPES, used to manage advanced prostate cancer, has proven thrombogenic and highly estrogenic in clinical trials. However, attempts to identify the active compounds in PC-SPES have yielded incongruous results. Moreover, warfarin was identified in the serum of a patient taking PC-SPES who experienced a bleeding disorder. To determine the active components in PC-SPES potentially responsible for these effects, we analyzed PC-SPES lots manufactured from l996 through mid-2001. METHODS: Antineoplastic activity of PC-SPES and its individual component extracts was determined by colony-forming assays with several prostate cancer cell lines, and estrogenicity was determined by analyzing expression of an estrogen-responsive reporter gene in breast cancer cells. High-pressure liquid chromatography was used to isolate, identify, and quantify components of PC-SPES. Components were also identified by proton nuclear magnetic resonance, gas chromatography/mass spectrometry, and mass spectra analysis. RESULTS: PC-SPES lots manufactured from 1996 through mid-1999 contained the synthetic compounds indomethacin (range = 1.07-13.19 mg/g) and diethylstilbestrol (range = 107.28-159.27 micro g/g) and were two to six times more antineoplastic and up to 50 times more estrogenic than lots manufactured after the spring of 1999. In lots manufactured after mid-1999, gradual declines in the concentrations of indomethacin (from 1.56 to 0.70 mg/g), diethylstilbestrol (from 46.36 to 0.00 micro g/g), and total phytosterols (from 0.586 to 0.085 mg/g) were observed. Warfarin was identified for the first time in lots manufactured after July 1998 (range = 341-560 micro g/g). In the August 2001 lot, increases were found in concentrations of the natural products licochalcone A (from 27.6 to 289.2 micro g/g) and baicalin (from 12.5 to 38.8 mg/g). CONCLUSIONS: The phytochemical composition of PC-SPES varied by lot, and chemical analyses detected various amounts of the synthetic drugs diethylstilbestrol, indomethacin, and warfarin and several natural products. To qualify for clinical pharmacologic exploration, nutritional supplements including herbal mixtures should meet standards of quality control under the Good Manufacturing Practice system, and the manufacturers of such supplements should provide reliable analytical quality assurance.

Fluridil, a rationally designed topical agent for androgenetic alopecia: first clinical experience.

BACKGROUND: Fluridil, a novel topical antiandrogen, suppresses the human androgen receptor. While highly hydrophobic and hydrolytically degradable, it is systemically nonresorbable. In animals, fluridil demonstrated high local and general tolerance. OBJECTIVE: To evaluate the safety and efficacy of a topical anti- androgen, fluridil, in male androgenetic alopecia. METHODS: In 20 men, for 21 days, occlusive forearm patches with 2, 4, and 6% fluridil, isopropanol, and/or vaseline were applied. In 43 men with androgenetic alopecia (AGA), Norwood grade II-Va, 2% fluridil was evaluated in a double-blind, placebo-controlled study after 3 months clinically by phototrichograms, hematology, and blood chemistry including analysis for fluridil, and at 9 months by phototrichograms. RESULTS: Neither fluridil nor isopropanol showed sensitization/irritation potential, unlike vaseline. In all AGA subjects, baseline anagen/telogen counts were equal. After 3 months, the average anagen percentage did not change in placebo subjects, but increased in fluridil subjects from 76% to 85%, and at 9 months to 87%. In former placebo subjects, fluridil increased the anagen percentage after 6 months from 76% to 85%. Sexual functions, libido, hematology, and blood chemistry values were normal throughout, except that at 3 months, in the spring, serum testosterone increased within the normal range equally in placebo and fluridil groups. No fluridil or its decomposition product, BP-34, was detectable in the serum at 0, 3, or 90 days. CONCLUSION: Topical fluridil is nonirritating, nonsensitizing, nonresorbable, devoid of systemic activity, and anagen promoting after daily use in most AGA males.

Acute cardiac tolerance of current contrast media and the new taxane protaxel using iopromide as carrier during porcine coronary angiography and stenting.

RATIONALE AND OBJECTIVES: The systemic tolerance thresholds of modern low-osmolar x-ray contrast media (CM) are similarly high, but their effects on the cardiovascular system and on the coagulation differ. The aim of this study was to comparatively evaluate the cardiovascular tolerability of iopromide, ioxaglate, and iosmin, and of a novel taxane protaxel, dissolved in iopromide, as a carrier, by coronary angiography and stenting. METHODS: Sixteen pigs were randomized into four groups: iosmin (350 mg iodine/mL, n = 4, nonionic dimer), iopromide (370 mg iodine/mL, n = 4, nonionic monomer), ioxaglate (320 mg iodine/mL, n = 4, ionic dimer), and 70-micromol protaxel dissolved in iopromide 370 mg iodine/mL, intended to prevent restenosis. Coronary angiography was performed via the left carotid artery followed by implantation of stents into the left anterior descending and the circumflex arteries. About 80 mL per animal was used in each group. RESULTS: There were no thrombotic complications and no significant adverse events of electrocardiography, blood pressure, or contractility during or after CM injections. There were no differences among the CM tested except that ioxaglate was the only agent showing a significant reduction in dp/dt after 50 seconds compared to iosmin. The values of preinjection parameters were most rapidly regained after iosmin, compared with other CM tested. CONCLUSIONS: The novel iso-osmolar nonionic CM iosmin is well tolerated in porcine coronary angiography and subsequent stenting. The cardiac tolerance of iopromide has not been adversely affected by addition of the cytostatic protaxel.

Grape Extract, Resveratrol, and Its Analogs: A Review.

The recent and essential reports on the biological activity of the principal phytophenols of Vitis vinifera and wine, with special attention to resveratrol, are reviewed. The phytophenols are arbitrarily divisible into single-ring phenolic acids, bisphenols including stilbenes, tricyclic phenols (flavonoids) and their subclasses, and oligomeric and polymeric species, the proanthocyanidins and anthocyanidins. Their precursors and the stilbenes, including resveratrol with its analogs and conjugates, appear to be of preventative and possibly therapeutic value in atherosclerosis and certain neoplastic and inflammatory afflictions. The probable mechanisms are free radical scavenging and selective interference with a multitude of factors affecting the division cycle of rapidly and abnormally proliferating mammalian cells. Reviewed are studies of natural occurrence, extraction methods, bioavailability, analytical detection, and metabolism of resveratrol, as well as its effects on cancer and inflammation, atherosclerosis, and neurons. Because grape extracts are a convenient alimentary source of salutary phytochemicals to supplement currently prevalent occidental food and resveratrol appears to be especially useful, it could conveniently be added in biosignificant amounts to the grape extracts provided that their extraction, contents, and quality controls are instituted.