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Journal of Pharmaceutical and... Nov 2006To evaluate the relative bioavailability of anethole trithione (ATT) from self-microemulsifying drug delivery system (SMEDDS) and tablet, a sensitive, accurate and... (Comparative Study)
Comparative Study
To evaluate the relative bioavailability of anethole trithione (ATT) from self-microemulsifying drug delivery system (SMEDDS) and tablet, a sensitive, accurate and reliable liquid chromatography method was developed and validated to determine ATT in rabbit plasma. Chromatographic separation was performed on a Diamonsil C18 column by using a mixture of methanol-water (90:10, v/v) delivered at a flow rate of 1.0 ml/min. The wavelength was set at 348 nm and mifepristone was used as the internal standard. A linear relationship for ATT was found in the range of 0.5-32 ng/ml. The mean extraction recoveries of ATT determined over three concentrations were 84.7+/-5.8, 92.3+/-3.4 and 89.9+/-5.1%. After administration of SMEDDS and tablets to rabbits, significant differences were found in main pharmacokinetic parameters of Tmax, Cmax and AUC(0-infinity) between these two formulations, and a 2.5-fold enhancement of relative bioavailability of ATT was observed from the SMEDDS compared with tablets.
Topics: Anethole Trithione; Animals; Biological Availability; Chromatography, High Pressure Liquid; Drug Delivery Systems; Emulsions; Male; Rabbits; Reproducibility of Results; Sensitivity and Specificity; Tablets
PubMed: 16824723
DOI: 10.1016/j.jpba.2006.05.013 -
Journal of Neural Transmission (Vienna,... May 2006Anethole dithiolethione (ADT) is a clinically available, pluripotent antioxidant proposed as a neuroprotectant for Parkinson's disease (PD). Here, using extracts from... (Comparative Study)
Comparative Study
Anethole dithiolethione (ADT) is a clinically available, pluripotent antioxidant proposed as a neuroprotectant for Parkinson's disease (PD). Here, using extracts from cultured astrocytes, containing both monoamine oxidase (MAO) A and B activity, we demonstrate that ADT concentration-dependently inhibits MAO-B activity in a clinically relevant concentration range (0.03-30 microM, IC-50 = 0.5 microM) without affecting MAO A activity. Considering the alleged contribution of MAO activity in general, and MAO-B in particular, to oxidative stress and neurodegeneration in PD, our data further support the neuroprotective potential of ADT.
Topics: Analysis of Variance; Anethole Trithione; Animals; Animals, Newborn; Antioxidants; Astrocytes; Basal Ganglia; Cells, Cultured; Clorgyline; Dose-Response Relationship, Drug; Enzyme Activation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Rats
PubMed: 16252076
DOI: 10.1007/s00702-005-0350-0 -
Nihon Shokakibyo Gakkai Zasshi = the... Jul 2005
Topics: Aged; Anethole Trithione; Female; Humans; Pneumatosis Cystoides Intestinalis; Sjogren's Syndrome
PubMed: 16038437
DOI: No ID Found -
Epilepsia 2004Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male... (Comparative Study)
Comparative Study
PURPOSE
Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male children experience a higher incidence of epilepsy or unprovoked seizures than do female children. Sex-specific differences in the development of seizure-suppressing neuronal networks may account, at least in part, for this increased age- and sex-related susceptibility to seizures. The control of seizures can be influenced by the substantia nigra pars reticulata (SNR) in an age- and sex-specific manner. In the adult male rat SNR, two topographically discrete regions (SNRanterior and SNRposterior) mediate distinct effects on seizures, by using divergent output networks in response to localized infusions of gamma-aminobutyric acid (GABA)A agents, such as muscimol. The GABAA-sensitive "anticonvulsant" region is located in the SNRanterior, whereas the GABAA-sensitive "proconvulsant region is in the SNRposterior. In immature postnatal day (PN)15-21 male rats, the SNR is not topographically segregated, and GABAAergic drug infusions produce similar effects when applied in the SNRanterior or SNRposterior. Only a GABAA-sensitive proconvulsant network is evident. By contrast, female SNR does not contain any region that mediates muscimol-related proconvulsant effects. As with the adult, immature female rats do not develop a proconvulsant SNR region at any age.
METHODS
We measured the effects of SNR muscimol infusions on seizures in male rats castrated at birth to better understand the effects of testosterone on the formation of age- and sex-specific features of the SNR.
RESULTS
Neonatal castration permanently alters the maturation of the muscimol-sensitive SNR effect on seizures. The SNR of neonatally castrated rats develops functionally like the "female" SNR. The "proconvulsant" SNR region does not develop in the absence of testosterone in the immediate postnatal period. The "male" type of SNR effects can be induced in neonatally castrated rats by restoration of testosterone levels or in female rats by artificially increasing testosterone levels. Dihydrotestosterone and estrogen, produced by the reduction and aromatization of testosterone, respectively, are the direct mediators of testosterone actions. At PN0, only beta estrogen receptors are equally expressed in the SNRs of males and females and may be responsible for testosterone-mediated effects in both sexes.
CONCLUSIONS
The phenotype of SNR GABAergic neurons, as characterized by GABAA-receptor subunit composition, by muscimol-induced electrophysiologic responses, and by connectivity of output networks each may be altered by the presence of testosterone. Higher KCC2 messenger RNA (mRNA) expression in female PN15 SNR neurons compared with males may be responsible for sex-related differences in muscimol-induced electrophysiologic responses. In summary, a growing body of compelling evidence identifying sex-related differences in the SNR implicates postnatal testosterone as a critical factor in the development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.
Topics: Age Factors; Anethole Trithione; Animals; Animals, Newborn; Anticonvulsants; Brain; Convulsants; Female; Gonadal Steroid Hormones; Humans; Male; Rats; Receptors, GABA-A; Seizures; Sex Factors; Substantia Nigra; Testosterone
PubMed: 15610187
DOI: 10.1111/j.0013-9580.2004.458002.x -
Pathologie-biologie Jul 2004Tendinopathy and tendon rupture are the adverse effects observed with fluoroquinolone antibiotics in old patients. The aim of this study was to investigate the effect of...
Tendinopathy and tendon rupture are the adverse effects observed with fluoroquinolone antibiotics in old patients. The aim of this study was to investigate the effect of anethole dithiolethione (5-[p-methoxyphenyl]3H-1,2-dithiole-3-thione) on the oxidative stress induced by three fluoroquinolones (pefloxacin, ofloxacin, ciprofloxacin) incubated with rabbit tenocyte cell line. Anethole dithiolethione is a well known antioxidant and glutathione inducer. Anethole dithiolethione is widely used in human therapy for its choleretic, sialogogic properties and recently proposed as cytoprotective agent in lung precancerous lesions prevention in smokers. In this purpose, protection against oxidative stress induced by fluoroquinolones has been assessed using cytofluorimetric probes to quantify cytotoxicity and reactive oxygen species production. Fluorescence signal was quantified in 96-well microplates, using cold light cytofluorometer. Significant reactive oxygen species production was detected after 45 minutes for all fluoroquinolones tested. Anethole dithiolethione has been evaluated on this parameter. Anethole dithiolethione significantly (*: P<0.05) reduces and normalizes reactive oxygen species induced by fluoroquinolones. So, anethole dithiolethione (Sulfarlem), well known for its antioxidant and glutathione inducing properties, good tissue diffusion and good tolerance in humans, could be beneficially associated to fluoroquinolones, and be proposed as a therapeutic adjuvant to prevent oxidative stress and tendinous adverse effects induced by xenobiotics and more precisely by fluoroquinolones.
Topics: Anethole Trithione; Animals; Anticarcinogenic Agents; Cell Line; Cell Survival; Cells, Cultured; Humans; Lung Neoplasms; Oxidative Stress; Precancerous Conditions; Rabbits; Reactive Oxygen Species; Tendons
PubMed: 15261372
DOI: 10.1016/j.patbio.2003.11.001 -
Cancer Radiotherapie : Journal de La... Nov 2003During more than a half of century, numerous compounds have been tested in different models against radiation-induced cataract. In this report, we will review the... (Comparative Study)
Comparative Study Review
During more than a half of century, numerous compounds have been tested in different models against radiation-induced cataract. In this report, we will review the radioprotectors that have been already tested for non-human crystalline lens protection. We will focus on the most important published studies in this topic and the mechanisms of cytoprotection reported in vitro and in vivo from animals. The most frequent mechanisms incriminated in the cytoprotective effect are: free radical scavenging, limitation of lipid peroxidation, modulation of cycle progression increase of intracellular reduced glutathion pool, reduction of DNA strand breaks and limitation of apoptotic cell death. Amifostine (or Ethyol) and anethole dithiolethione (or Sulfarlem), already used clinically as chemo- and radioprotectants, could be further tested for ocular radioprotection particularly for radiation-induced cataract.
Topics: Amifostine; Anethole Trithione; Animals; Apoptosis; Cataract; Cattle; Cell Cycle; Cells, Cultured; Clinical Trials as Topic; Cytoprotection; DNA Damage; Eye; Female; Fluorometry; Free Radical Scavengers; Humans; Lens, Crystalline; Lipid Peroxidation; Male; Microscopy, Fluorescence; Radiation Dosage; Radiation Injuries; Radiation Injuries, Experimental; Radiation-Protective Agents; Radiotherapy; Radiotherapy Dosage; Rats; Time Factors
PubMed: 15124544
DOI: No ID Found -
Free Radical Research Jun 2002alpha-Lipoic acid (LA), an antioxidant with broad neuroprotective capacity, is thought to act by scavenging reactive oxygen species and stimulation of glutathione...
alpha-Lipoic acid (LA), an antioxidant with broad neuroprotective capacity, is thought to act by scavenging reactive oxygen species and stimulation of glutathione synthesis. LA shows structural resemblance to dithiolethiones, like anethole dithiolethione (ADT). ADT protects against oxidative damage, primarily by induction of phase II detoxication enzymes, in particular NAD(P)H:quinone oxidoreductase (NQO1) and glutathione-S-transferase (GST). Therefore, we investigated whether LA, like ADT, is capable also of inducing these protective enzymes. Our data show that LA, like ADT, induces a highly significant, time- and concentration dependent, increase in the activity of NQO1 and GST in C6 astroglial cells. The LA or ADT mediated induction of NQO1 was further confirmed by quantitative PCR and western blot analysis. This work for the first time unequivocally demonstrates LA mediated upregulation of phase II detoxication enzymes, which may highly contribute to the compounds' neuroprotective potential. Moreover, the data support the notion of a common mechanism of action of LA and ADT.
Topics: Anethole Trithione; Animals; Antioxidants; Astrocytes; Astrocytoma; Central Nervous System Neoplasms; Glutathione Transferase; Inactivation, Metabolic; NAD(P)H Dehydrogenase (Quinone); Neuroprotective Agents; Oxidoreductases; Rats; Thioctic Acid; Transferases; Tumor Cells, Cultured
PubMed: 12180195
DOI: 10.1080/10715760290029155 -
Journal of the National Cancer Institute Jul 2002Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of ADT in smokers with bronchial dysplasia.
METHODS
One hundred twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. We used changes in histopathologic grade and nuclear morphometry index (MI) as the primary and secondary end point biomarkers, respectively. Chi-square tests with continuity correction were used to compare response rates on a lesion- and person-specific basis between the two study groups. All statistical tests were two-sided.
RESULTS
One hundred one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, progression rate of pre-existing dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (P<.001; difference = 9%, 95% confidence interval [CI] = 4% to 15%). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (P =.013; difference = 27%, 95% CI = 6% to 48%). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment (29 in the ADT group and 25 in the placebo group), the progression rate in the ADT group (41%) was substantially lower than that in the placebo group (60%), although the difference was not statistically significant (P =.28; difference = 19%, 95% CI = -11% to 49%). Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication.
CONCLUSION
Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.
Topics: Adult; Aged; Anethole Trithione; Antineoplastic Agents; Bronchi; Case-Control Studies; Cell Nucleus; Double-Blind Method; Female; Humans; Lung Neoplasms; Male; Metaplasia; Middle Aged; Odds Ratio; Precancerous Conditions; Smoking
PubMed: 12096085
DOI: 10.1093/jnci/94.13.1001 -
Rheumatology (Oxford, England) Jun 2002To examine salivary function in patients with primary Sjögren's syndrome (SS) by assessing unstimulated and stimulated flows using 5 mg of pilocarpine in a 5% solution,... (Clinical Trial)
Clinical Trial Comparative Study
OBJECTIVES
To examine salivary function in patients with primary Sjögren's syndrome (SS) by assessing unstimulated and stimulated flows using 5 mg of pilocarpine in a 5% solution, in order to define their clinical usefulness in the evaluation of xerostomia in patients with primary SS as well as to identify those factors related to the increase in salivary flow after pilocarpine stimulation.
METHODS
We investigated the clinical and immunological characteristics of 60 consecutive patients with primary SS. All patients fulfilled four or more of the preliminary diagnostic European criteria for SS. We measured unstimulated (basal) salivary flow (BSF) in all patients. In patients with BSF =1.5 ml, stimulated salivary flows (SSF) were also measured after stimulation with an ophthalmic 5% pilocarpine solution (0.1 ml=5 mg, administered sublingually). SSF was also measured after oral administration of 50 mg anetholetrithione (ANTT) in the same patients. These stimulated salivary flows were measured 1, 2 and 3 h after the stimulus.
RESULTS
Of the 60 patients, 55 were women and five men, with a mean age at the SS onset of 61 yr (range 18-82 yr). The mean BSF for SS patients was 1.40+/-0.17 ml. Fifty (83%) patients showed a BSF less than 1.5 ml. The stimulated salivary flow after 1 h was 3.23 ml in the pilocarpine group and 0.57 in the ANTT group (P<0.001); after 2 h it was 1.32 ml in the pilocarpine group and 0.52 in the ANTT group (P=0.02) and after 3 h it was 0.80 ml in the pilocarpine group and 0.41 in the ANTT group (P=0.046). No clinical or immunological differences were found between SS patients with BSF more or less than 1.5 ml, although patients with a BSF less than 1.5 ml showed a parotid scintigraphy class III or IV more frequently (42 vs 0%, P=0.01). SS patients with a pilocarpine SSF less than 1.5 ml had a longer duration of SS (73.3 vs 31.3 months, P=0.03) and a higher prevalence of positive anti-Ro/SS-A (70 vs 36%, P=0.038), anti-La/SS-B (65 vs 32%, P=0.038), parotid scintigraphy class III-IV (79 vs 9%, P<0.001) and positive salivary gland biopsy (90 vs 43%, P<0.001).
CONCLUSION
The study of xerostomia using basal and pilocarpine SSF is simple to perform, acceptable to patients and needs no special equipment. We describe a significant increase in SSF using a solution of 5% pilocarpine in comparison with salivary flow obtained after stimulation with ANTT. Twenty-two of the 46 patients with low BSF had stimulated flows over 1.5 ml. These 'responder' patients showed a shorter duration of sicca symptoms, a lower frequency of positive immunological markers and milder grades of scintigraphic patterns and lymphocytic infiltrates in salivary gland biopsies. This subset of patients probably maintain a residual capacity of their salivary glands, as opposed to the 'non-responder' patients, who had a longer duration of sicca syndrome evolution with more severe involvement of the salivary glands.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anethole Trithione; Cholinergic Agents; Female; Humans; Male; Middle Aged; Parotid Gland; Pilocarpine; Predictive Value of Tests; Radionuclide Imaging; Reproducibility of Results; Saliva; Sjogren's Syndrome; Sodium Pertechnetate Tc 99m; Xerostomia
PubMed: 12048294
DOI: 10.1093/rheumatology/41.6.670 -
International Journal of Cancer 2001Lens epithelium disorganization, glutathione (GSH) depletion, and epithelial cell death have been incriminated in the cytopathogenic mechanisms that lead to cataract...
Lens epithelium disorganization, glutathione (GSH) depletion, and epithelial cell death have been incriminated in the cytopathogenic mechanisms that lead to cataract formation following UVB and x-ray exposures. The objective of this study was to determine the in vitro capacity of the aminothiol WR-1065, the active metabolite of amifostine, and anetholedithiolethione (ADT or Sulfarlem) to protect bovine lens epithelial cells against x-ray irradiation. WR-1065 and ADT were used at a concentration of 20 microM. A single dose of 10 Gy was delivered at a rate of 2 Gy/min. Fluorimetric assays were then performed using a neutral red probe to evaluate cell viability, a Hoechst 33342 probe (HO) to evaluate nuclear condensation and apoptosis, and a monobromobimane probe to estimate the intracellular GSH pool. Twenty-four hours after x-ray exposure, cells pretreated with WR-1065 showed increased GSH levels, improved cell viability, and decreased HO fluorescence in addition to a lesser proportion of cells with apoptotic nuclear modifications. Between 72 and 120 hr postirradiation, ADT-pretreated cells also showed increased intracellular GSH levels and cell viability and decreased HO fluorescence and apoptotic cell morphology. This in vitro study demonstrates that WR-1065 and ADT protects lens epithelial cells from x-ray injury; thus, ADT and amifostine are appropriate candidates for clinical trials in humans. They are currently used in preventing radiation-induced xerostomia and should be further tested in the prevention of late radiation-induced ocular complications such as sicca syndrome and cataract.
Topics: Amifostine; Anethole Trithione; Animals; Apoptosis; Benzimidazoles; Cattle; Cell Death; Cell Membrane; Cell Nucleus; Cell Survival; Cells, Cultured; Dose-Response Relationship, Radiation; Epithelial Cells; Flow Cytometry; Glutathione; Lens, Crystalline; Mercaptoethylamines; Microscopy, Fluorescence; Radiation-Protective Agents; Spectrometry, Fluorescence; Time Factors; Ultraviolet Rays; X-Rays
PubMed: 11992383
DOI: 10.1002/ijc.10346