Anethole Trithione Research Articles

Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy

Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSCmed cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.

Biomimetic material degradation for synergistic enhanced therapy by regulating endogenous energy metabolism imaging under hypothermia

Inefficient tumour treatment approaches often cause fatal tumour metastases. Here, we report a biomimetic multifunctional nanoplatform explicitly engineered with a Co-based metal organic framework polydopamine heterostructure (MOF-PDA), anethole trithione (ADT), and a macrophage membrane. Co-MOF degradation in the tumour microenvironment releases Co2+, which results in the downregulation of HSP90 expression and the inhibition of cellular heat resistance, thereby improving the photothermal therapy effect of PDA. H2S secretion after the enzymatic hydrolysis of ADT leads to high-concentration gas therapy. Moreover, ADT changes the balance between nicotinamide adenine dinucleotide/flavin adenine dinucleotide (NADH/FAD) during tumour glycolysis. ATP synthesis is limited by NADH consumption, which triggers a certain degree of tumour growth inhibition and results in starvation therapy. Potentiated 2D/3D autofluorescence imaging of NADH/FAD is also achieved in liquid nitrogen and employed to efficiently monitor tumour therapy. The developed biomimetic nanoplatform provides an approach to treat orthotopic tumours and inhibit metastasis.

A data-driven pipeline to extract potential adverse drug reactions through prescription, procedures and medical diagnoses analysis: application to a cohort study of 2,010 patients taking hydroxychloroquine with an 11-year follow-up.

ContextReal-life data consist of exhaustive data which are not subject to selection bias. These data enable to study drug-safety profiles but are underused because of their temporality, necessitating complex models (i.e., safety depends on the dose, timing, and duration of treatment). We aimed to create a data-driven pipeline strategy that manages the complex temporality of real-life data to highlight the safety profile of a given drug.MethodsWe proposed to apply the weighted cumulative exposure (WCE) statistical model to all health events occurring after a drug introduction (in this paper HCQ) and performed bootstrap to select relevant diagnoses, drugs and interventions which could reflect an adverse drug reactions (ADRs). We applied this data-driven pipeline on a French national medico-administrative database to extract the safety profile of hydroxychloroquine (HCQ) from a cohort of 2,010 patients.ResultsThe proposed method selected eight drugs (metopimazine, anethole trithione, tropicamide, alendronic acid & colecalciferol, hydrocortisone, chlormadinone, valsartan and tixocortol), twelve procedures (six ophthalmic procedures, two dental procedures, two skin lesions procedures and osteodensitometry procedure) and two medical diagnoses (systemic lupus erythematous, unspecified and discoid lupus erythematous) to be significantly associated with HCQ exposure.ConclusionWe provide a method extracting the broad spectrum of diagnoses, drugs and interventions associated to any given drug, potentially highlighting ADRs. Applied to hydroxychloroquine, this method extracted among others already known ADRs.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12874-022-01628-3.

Respirometry Outcomes in a 7 Days Post-Fertilization Danio Rerio Fed Different Dietary Conditions.


 
 
 More than a third of the adults in the Appalachia are affected by obesity, which is associated with diets that are high in fats and cholesterol as well as the development of many diseases such as diabetes, hypertension and cardiovascular diseases. These diets lead tochronic inflammation and cellular damage from production of free radicals such as Reactive Oxygen Species (ROS). We compared the respirometry outcomes in a 7 days post- fertilization zebrafish (Danio rerio) larvae after different diet conditions. Larvae were either fed nothing at all, a low fat diet (LFD), a high fat diet (HFD), or a HFD plus a drug that mitigates oxidative stress (Anethole Trithione and mito-TEMPO). We expected that the HFD would cause the mitochondria to be put under more stress due to oxidative phosphorylation of lipids and would decrease in the larvae treated with the drugs. Respirometry was obtained using the XFe24 Extracellular Flux Analyzer (Agilent Technologies) and a modified Cell Mito Stress Test. We found basal respiration is higher in the HFD and lower in the other two treatment diets, indicating that high fat diets do produce more oxidative stress in mitochondria, and the drugs tested are able to successfully mitigate it. The analysis of drug interaction readings is in progress. In the future, we will test other drugs that can affect mitochondrial metabolism (i.e. Curcumin, Pitastatin, Mdivi-1 and PPPA).
 Supported by NIH Grant P20GM103434 to the West Virginia IDeA Network for Biomedical Research Excellence.
 
 

Beneficial effects of a preventive treatment with anethole trithione on pulmonary hypertension

Pulmonary hypertension (PH) is a multifactorial disease characterized by pulmonary arteries (PA) and right ventricular (RV) alterations. Mitochondria dysfunction and associated reactive oxygen species production were shown to contribute to these phenomena. OP2 Drugs start-up demonstrated that anethole trithione (ATT), the active ingredient of its principal lead OP2113, specifically inhibits mitochondrial ROS production from complex I. In this context, this study aims to assess the effects of ATT on PH set-up. By using osmotic mini-pump, influence of a preventive treatment with ATT or its vehicle was tested on PH development in male rats exposed to three weeks of chronic hypoxia (CH - 10 % O2). PA and cardiac PH hallmarks (remodelling, fibrosis and hemodynamic parameters) were assessed. Contraction and intracellular calcium signal of isolated cardiomyocytes from RV were simultaneously measured by IonOptix system. We quantified cardiac mitochondrial mass by measuring VDAC1 expression by western blotting. The effect of preventive or acute treatment with ATT on PA reactivity was measured by isometric tension. In rats with PH, preventive treatment with ATT reduced PA remodelling and RV systolic pressure, whereas RV hypertrophy and fibrosis seemed not to be affected. However, this preventive treatment abolished the decrease of both speed of cardiomyocytes contraction and VDAC1 expression induced by CH. Preventive and acute treatment with ATT reversed PA hyperreactivity to 5-HT in rats with PH. Acute ATT treatment triggered a sustained relaxation of preconstricted PA in both control and PH conditions. L-NAME (eNOS inhibitor) and CHAPS (non-denaturing detergent used to remove endothelium) did not affect the acute effect of ATT on PA contraction and relaxation whereas glibenclamide (KATP channel inhibitor) attenuated ATT induced relaxation. Y27632 (a ROCK inhibitor) and ATT induced additive reduction of 5-HT contraction. Altogether, these results highlighted the benefit of an ATT preventive treatment on PA reactivity and remodelling as well as RV cardiac function suggesting a potential therapeutic interest of ATT in PH set-up. Whereas ATT effect on reactivity seemed to be endothelium and ROCK-independent, KATP channel was partly involved in ATT-induced relaxation.

Activation of UCP2 by anethole trithione suppresses neuroinflammation after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family, which uncouples oxidative phosphorylation from ATP synthesis by facilitating proton leak across the mitochondrial inner membrane. UCP2 has been reported to modulate inflammation. In this study we investigated whether and how UCP2 modulated neuroinflammation through microglia/macrophages following ICH in vitro and in vivo. We used an in vitro neuroinflammation model in murine BV2 microglia to mimic microglial activation following ICH. ICH in vivo model was established in mice through collagenase infusion into the left striatum. ICH mice were treated with anetholetrithione (ADT, 50 mg· kg-1 ·d-1, ip) or the classical protonophoric uncoupler FCCP (injected into hemorrhagic striatum). We showed that the expression and mitochondrial location of microglial UCP2 were not changed in both in vitro and in vivo ICH models. Knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ICH models, suggesting that endogenous UCP2 inhibited neuroinflammation and therefore played a protective role following ICH. ADT enhanced mitochondrial ROS production thus inducing mitochondrial uncoupling and activating UCP2 in microglia. ADT robustly suppressed neuroinflammation, attenuated brain edema and improved neurological deficits following ICH, and these effects were countered by striatal knockdown of UCP2. ADT enhanced AMP-activated protein kinase (AMPK) activation in the hemorrhagic brain, which was abrogated by striatal knockdown of UCP2. Moreover, striatal knockdown of AMPK abolished the suppression of neuroinflammation by ADT following ICH. On the other hand, FCCP-induced mitochondrial uncoupling was independent of UCP2 in microglia; and striatal knockdown of UCP2 did not abrogate the suppression of neuroinflammation by FCCP in ICH mice. In conclusion, the uncoupling activity is essential for suppression of neuroinflammation by UCP2. We prove for the first time the concept that activators of endogenous UCP2 such as anetholetrithione are a new class of uncouplers with translational significance.

ATT has positive effects on pulmonary hypertension hallmarks

Pulmonary hypertension (PH) is a multifactorial disease characterized by pulmonary arteries (PA) hyperreactivity and remodelling involving an imbalance of contractile and proliferative agents such as 5-hydroxytryptamine (5-HT). Mitochondria and associated reactive oxygen species (ROS) production were shown to contribute to these phenomena. OP2 Drugs recently demonstrated that Anethole Trithione (ATT), the active ingredient of its principal lead OP2113, specifically inhibits mitochondrial ROS (mtROS) production from complex I in its reverse mode. In this context, this study aims to assess the effects of ATT on PH hallmarks. Male rats were either exposed to normoxia or chronic hypoxia (10% O2) during 3 weeks to induce PH (CH-PH). The effect of ATT on PA reactivity was determined ex vivo by isometric tension measurements of arterial rings. PA contraction was induced by 5-HT, prostaglandin F2α (PGF2α), phenylephrine (Phe) or endothelin-1 (ET-1) whereas relaxation was induced by carbachol (Cch) on preconstricted vessels with PGF2α. The effect of ATT on calcium responses induced by 5-HT was assessed in rat PA smooth muscle cells using confocal imaging. Proliferative responses induced by 5-HT were evaluated by ELISA BrdU on human PASMC in presence or absence of ATT. In rats with CH-PH, ATT reduced contractile hyperreactivity induced by 5-HT and PGF2α. In control rats, ATT treatment also decreased contraction to 5-HT and Phe, but not contraction to ET-1 and PGF2α as well as relaxation to Cch. Interestingly, acute ATT exposure did not modify basal cytosolic calcium signal in control rat PASMC. However, the number of 5-HT responding cells was reduced in presence of ATT whereas neither maximal peak of cytosolic calcium responses nor the global calcium variations were affected. Finally, 5-HT-induced proliferation was reduced by ATT in control human PASMC. In conclusion, ATT improves vascular hyperreactivity of PA from rats with CH-PH whereas in control condition ATT altered 5-HT-induced contraction in rat PA, calcium signalling to 5-HT in rat PASMC and 5-HT-induced human PASMC proliferation. Although mechanisms underlying ATT influence on PH hallmarks need to be further elucidated, these Results suggest that OP2113 may be used to develop new PH therapies.

MEANS AND METHODS OF STIMULATION OF SALIVATION (LITERATURE REVIEW)

Currently, a large number of tools and methods are proposed to reduce dryness in the mouth and restore the deficiency of biologically active substances entering the mouth with saliva. Stimulation of salivation can be carried out by both local and systemic means.
 The aim of our study was to analyze pharmacological and systemic stimulators of salivation.
 Results and discussion
 Only three drugs were subjected to a detailed study - bromhexidine, anethole trithione and pilocarpine hydrochloride.
 Currently, the development of long-acting (prolonged) drugs is underway, which is a promising solution for long-term treatment of patients with dry mouth.
 Local stimulation of salivation is based on irritation of the nerve endings of the oral cavity, which transmit a signal to the salivary glands. Various methods are offered, it is chewing of gums, menthol-containing substances, inert means like paraffin. Chewing gum, mint or citric acid tablets (lollipops) and rinses are recommended in everyday life. Frequent use of these tools is not always effective due to various negative factors. The most important of them is short-term effect, but not the possibility of frequent use. In some patients, drugs such as citric acid can irritate the mucous membranes, especially if its content is increased due to dry mouth. Frequent use of these tools can cause demineralization of teeth.
 Many authors recommend so-called "saliva substitutes" or "saliva compensators". Various options of replacement therapy in the form of gels, rinses, sprays, toothpastes, etc. are offered.
 To prevent caries during hyposalivation, the authors propose a composition of artificial saliva with a high content of fluoride ions, with the introduction of hydroxyapatite from animal bones.
 Researchers offer various methods of stimulation the functional activity of the salivary glands, but the main factor in choosing the appropriate treatment is a favorable assessment of the degree of violation of the patient's salivary glands and the mechanism of violation.
 Conclusion. Owing to the review of the literature, we can conclude that the timely diagnosis and treatment of xerostomia is an urgent problem of modern dentistry. Patients need xerostomia correction, because the deficiency of oral fluid significantly affects the condition of teeth, mucous membranes of the mouth and periodontal tissues and the quality of life in general.
 Due to the fact that the treatment of xerostomia in some cases is ineffective and impossible, such patients need symptomatic therapy to alleviate the manifestations and consequences of xerostomia. The dental market offers a large number of tools for symptomatic correction of xerostomia. Many literature sources contain conflicting data on their effectiveness.
 Therefore, we consider it appropriate to study the comparative evaluation of tools that facilitate the manifestations of xerostomia, as well as to assess the effectiveness of correction of xerostomia depending on the causes of its development.

Synthesis, Characterization, and In Vivo Evaluation of Desmethyl Anethole Trithione Phosphate Prodrug for Ameliorating Cerebral Ischemia-Reperfusion Injury in Rats.

Anethol trithione (ATT) has a wide range of physiological activities, but its use is limited due to its poor water solubility. To improve the solubility of ATT, we synthesized and characterized a novel phosphate prodrug (ATXP) relying on the availability of the hydroxy group in 5-(4-hydroxyphenyl)-3H-1,2-dithiole3-thione (ATX), which was transformed from ATT rapidly and extensively in vivo. Our results showed that ATXP significantly improved drug solubility. ATXP was rapidly converted to ATX and reached a maximum plasma concentration with a Tmax of approximately 5 min after intravenous (iv) administration. Furthermore, after the oral administration of ATXP, the Cmax was 3326.30 ± 566.50 ng/mL, which was approximately 5-fold greater than that of the parent drug form, indicating that ATXP has greater absorption than that of ATT. Additionally, the oral phosphate prodrug ATXP increased the ATX in the area under the plasma concentration vs time curves (AUC0–t = 3927.40 ± 321.50 and AUC0–∞ = 4579.0 ± 756.30), making its use in practical applications more meaningful. Finally, compared to the vehicle, ATXP was confirmed to maintain the bioactivity of the parent drug for a significant reduction in infarct volume 24 h after reperfusion. Based on these findings, the phosphate prodrug ATXP is a potentially useful water-soluble prodrug with improved pharmacokinetic properties.

P4607A specific complex I-induced ROS modulator, OP2113, is a new cardioproctective agent against acute myocardial infarction injuries during reperfusion

Abstract Introduction Hospital death rates due to myocardial infarction are still a concern and heart failure occurs in nearly a quarter of older patients who present with ST elevation myocardial infarction. Novel therapies are thus desperately needed to reduce infarct size to preserve left ventricular function and to prevent the onset of heart failure. Purpose OP2113, trithio-p-methoxyphenylpropene (anethole trithione, 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione, anethole dithionethiol), a potential suppressor of complex I superoxide/hydrogen peroxide (ROS) production was evaluated in a sheep model of regional ischemia in order to demonstrate cardioprotective properties against infarct size and left ventricular function remodeling. Methods A series of experiments was performed in vitro on isolated mitochondria and on C2C12 cells to clarify the mechanism of action and to test whether OP2113 impacts biological variables of mitochondria. In vivo, anesthetized sheep underwent 60 min ischemia and 120 min reperfusion and either received OP2113 (1–5 μg/kg, i.v at start of and for the duration of the reperfusion) or the vehicle. The animals underwent then a 3-day follow-up period until euthanasia. Ischemic biomarkers, troponin I, CPK, and ventricular function through echocardiography were quantified during reperfusion and infarct size through histological analysis. Results OP2113 reduced ROS production from site IQ in mitochondria isolated from rat skeletal muscle, with IC50 of 26±1.4 μM (n=3). It is specific; IC50 values for other sites are at least 15-fold higher (site IIIQo – 414 μM; site IIF – 582 μM; sites IF/DH, PF, GQ >5 mM). Furthermore, OP2113 did not affect oxidative phosphorylation, respiration or growth of C2C12 cells. In the sheep model, OP2113 (1–10 μg/kg) dose-dependently prevented reperfusion-induced ST segment increase during the first minutes. When OP2113 plasmatic concentration was superior to 1 ng/mL (generally associated with a threshold dose of 5 μg/kg), troponin Ic levels measured over the experiment was strongly decreased and the cardiac function significantly improved (+86%), when compared to the vehicle group (left panel). Finally, the infarct size was diminished by 57% comparing to the vehicle group (10.3% vs 23.8%, respectively, right panel). Conclusion In a large animal model of ischemia-reperfusion, OP2113 with very low infused dose, reduced ST segment elevation, reduced troponin release, improved left ejection fraction and reduced infarct size. Collectively, these results demonstrate that OP2113, through a new mechanism of action, is a potent cardioprotective compound.

Hydrogen sulfide donors in research and drug development

This review summarized most of the H2S donors such as inorganic compounds, natural products, anethole trithione derivatives and synthetic compounds used in research and drug development. These special bioactivities provided us some effective strategies for antiphlogosis, cancer therapy, cardiovascular protection and so on.

Enhancement of Phosphatidylinositol Turnover and Cyclic Nucleotide Accumulation by Chronic Anethole Trithione Treatment in Rat Submaxillary Glands

The effect of chronic treatment with anethole trithione (ANTT) on the phosphatidylinositol (PI) turnover and cyclic (c)AMP and cGMP accumulation in rat submaxillary glands (SMG) has been compared with the effect of chronic treatment with atropine and a cholinesterase inhibitor, diisopropylfluorophosphate (dyflos, DFP). Experiments were performed 24, 48 and 24 h after the last dose of ANTT, atropine and dyflos, respectively. ANTT and atropine enhanced carbachol-stimulated [32P] incorporation into phosphatidic acid in the SMG slices, while dyflos showed no effect. Pilocarpine-stimulated in-vivo incorporation of [3H]myoinositol into inositol phosphates was significantly enhanced by ANTT, but not by atropine or by dyflos. Phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by ANTT and atropine, but not by dyflos. Pilocarpine-stimulated in-vivo accumulation of cAMP and cGMP was enhanced by ANTT and atropine, but dyflos reduced cAMP accumulation without affecting cGMP accumulation. The enhancement of PI turnover and cyclic nucleotide accumulation seems to contribute to the development of supersensitivity of the salivary gland caused by chronic treatment with ANTT and atropine, while reduction of cAMP accumulation may be responsible for the subsensitivity caused by dyflos.

Anethole Trithione Raises Levels of Substance P in Human Saliva

The effect of the sialogogue, anethole trithione, on saliva levels of neuropeptide substance P was studied in five healthy volunteers. Peak saliva substance P level (approx. 23 fmol mL−1) was achieved 10 min after lunch and then declined to baseline (approx. 9 fmol mL−1) within 60 min. After a single oral administration of anethole trithione (25 mg), peak plasma anethole trithione level (approx. 1.1 ng mL−1) was achieved at 120 min after administration. Saliva substance P concentrations rose similarly with peak level (approx. 15 fmol mL−1) 60 to 240 min after anethole trithione administration, whereas plasma substance P levels did not change significantly. Substance P nerve in the salivary gland may be involved in the enhancement of the salivary secretion by anethole trithione treatment.

Anethole Trithione Raises Levels of α‐Calcitonin Gene‐related Peptide in Saliva of Healthy Subjects

The effect of sialogogue, anethole trithione, on saliva levels of neuropeptide α-calcitonin gene-related peptide (α-CGRP) was studied in six healthy volunteers. Peak saliva α-CGRP level (6.1 fmol mL−1) was achieved 10 min after lunch and then declined to baseline (2.8 fmol mL−1) within 60 min. After a single oral administration of anethole trithione (25 mg), peak plasma anethole trithione level (1.l ng mL−1) was achieved 120 min after the administration. Saliva α-CGRP concentrations and saliva volume rose similarly 30–240 min after the administration. Plasma α-CGRP levels did not change significantly. Saliva α-CGRP concentration correlated significantly with the amount of saliva (r = 0.92). The α-CGRP nerve in salivary glands may be involved in the enhancement of the salivary secretion by anethole trithione treatment.

An HPLC–MS/MS method for the quantitative determination of 4-hydroxy-anethole trithione in human plasma and its application to a pharmacokinetic study

A selective, rapid and sensitive method for the quantitation of 4-hydroxy-anethole trithione (ATX) in human plasma based on high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) was developed and validated. Paracetamol was used as the internal standard (I.S.). After liquid–liquid extraction of 500 μL plasma with ethyl acetate, ATX and the I.S. were chromatographed on an Inertsil ® ODS-3 column. The mobile phase was consisted of methanol–water (75:25, v/v) with a flow rate of 0.25 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. The calibration curve was linear over the range of 0.452–603 ng/mL ( r 2 ≥ 0.99) with a lower limit of quantitation (LLOQ) of 0.452 ng/mL. The intra- and inter-day precision (relative standard deviation, R.S.D.) values were below 13% and the accuracy (relative error, R.E.) was from −2.7% to −7.5% at three quality control levels. The assay herein described was successfully applied to a pharmacokinetic study of anethole trithione (ATT) tablet in healthy volunteers after oral administration.

Design, synthesis, and pharmacological evaluation of the aqueous prodrugs of desmethyl anethole trithione with hepatoprotective activity

A metabolite-based prodrug strategy to increase the solubility of anethole trithione was reported to facilitate the clinical application of this hepatoprotective agent. Water-soluble analogs of anethole trithione were synthesized via substituting the methyl group of anethole trithione with the simple hydrophilic alkylamino group, and subjected to physiochemical, pharmacological and metabolic studies. The prodrugs displayed increased solubility as well as other physiochemical properties favorable for parenteral use. Among the analogs synthesized, the compound 5a exhibited best hepatoprotective activity at the dose of 2.0 mg/kg in mice equal to that of anethole trithione. The in vivo metabolic investigation demonstrated that the straight-side chain prodrug 5a could convert to desmethyl anethole trithione in vivo, while the ring-side chain prodrug 5d could not. The hepatoprotective activity of the prodrugs might result from the active metabolite desmethyl anethole trithione.

Enhancement of salivary secretion and neuropeptide (substance P, alpha-calcitonin gene-related peptide) levels in saliva by chronic anethole trithione treatment.

Anethole trithione, a choleretic, has been reported to be effective in the treatment of dry mouth. We have examined the effects of chronic treatment with anethole trithione on salivary secretion, substance P immunoreactive substance (SP-IS) and alpha-calcitonin gene-related peptide immunoreactive substance (alpha-CGRP-IS) concentrations in human saliva. Anethole trithione caused significant increases of saliva SP-IS concentrations from the day 13 (25.3 +/- 1.6 pg mL(-1)) to day 14 (25.8 +/- 1.7 pg mL(-1)) compared with day 1 (19.9 +/- 1.9 pg mL(-1)). Anethole trithione caused significant increase in saliva alpha-CGRP-IS concentration on day 14 (39.9 +/- 4.7 pg mL(-1)) compared with day 1 (27.7 +/- 4.7 pg mL(-1)). Anethole trithione significantly increased the sialosis volumes from day 11 to day 14 (1.6 +/- 0.1-1.7 +/- 0.2 mL) compared with the day 1 (1.2 +/- 0.2 mL). Simple linear regression of the increase in sialosis volume with saliva SP-IS (r = 0.94) and alpha-CGRP-IS (r = 0.97) concentrations was found. These results demonstrated that chronic treatment with anethole trithione affected saliva SP-IS and alpha-CGRP-IS concentration in human saliva and sialosis volume.

The clinical therapic efficiency of anethol trithione on dry eye

To investigate anethol trithione therapic efficiency on dry eye. It was a prospective random double-blind controlled study. Eighty cases diagnosed dry eye in Ocular Surface Out-patient Clinic of Xiamen University Affiliated Xiamen Eye Center from 2006 to 2008 were divided into two groups: anethol trithione group and control group, 40 cases in each group. Every group was then divided into two subgroups: weak dry eye subgroup,middle and severe dry eye subgroup. All groups had been added with 0.05% refresh drops. All patients had been detected and evaluated by subjective symptoms of dry eye, visual acuity, corneal fluorescent staining (F1), break-up time (BUT) and Schirmer I test (SIT) at pretherapy and 3, 7, 28 d of post-therapy. All groups had been compared and analyzed by F test and sample mean difference (SMD) or median difference (MD) comparison between pre-therapy and post-therapy. Except of tear and red eye,the other subjective symptoms of dry eye, Fl, BUT and SIT of weak dry eye subgroup of both groups had been improved at 7 d after therapy. Only those of middle and severe dry eye subgroup of anethol trithione group had been improved at 7 d after therapy compared with those of pretherapy: SMD = 0.96 (visual tiredness), 1.26 (dry and unsmooth sensation), 0.82 (foreign body sensation), 1.28 (burning sensation), 1.05 ( photophobia), 1.48 (pain); MD = 0.30 (visual acuity), 4.00 (Fl), 5.00 (BUT), 5.00 (SIT) [F = 15.30 (visual tiredness), 15.68 (dry and unsmooth sensation), 13.56 (foreign body sensation), 20.91 (burning sensation), 18.90 (photophobia), 27.22 (pain), 10.54 (visual acuity),188.21 (F1), 261.76 (BUT), 269.05 (SIT); P < 0.05]. Those of middle and severe dry eye subgroup of control group hadn't significantly been improved at 28 d after therapy: SMD = 0.10 (visual tiredness), 0.16 (dry and unsmooth sensation), 0.09 (foreign body sensation), 0.38 (burning sensation), 0.24 (photophobia), 0.36 (pain), 0.23 (red eye); MD = 0.10 (visual acuity), 0.50 (Fl), 0.50 (BUT), 0.50 (SIT) [F = 1.76 (visual tiredness), 1.61 (dry and unsmooth sensation), 1.02 (foreign body sensation), 2.39 (burning sensation), 2.42 (photophobia), 2.73 (pain), 2.55 (red eye), 1.46 (visual acuity), 2.35 (Fl), 2.90 (BUT), 2.76 (SIT); P > 0.05]. SIT of anethol trithione group had been improved more significantly after therapy (F = 13.77, P < 0.05). Anethol trithione could significantly improve middle and severe dry eye patients' symptoms and signs whose lacrimal gland function survival and it has clinical application value.

Self-Nanoemulsifying Drug Delivery System (SNEDDS) of Anethole Trithione by Combined Use of Surfactants

The characteristics of self-nanoemulsifying drug delivery system (SNEDDS) of Anethole trithione (ATT) for oral administration by the combined use of surfactants were investigated. In combination with surfactants, the SNEDDS provided smaller particle size, more oil loading, and shorter emulsification time. ATT from the SNEDDS rapidly dissolved in dissolution media whereas the ATT tablets showed different dissolution patterns according to the dissolution media. Furthermore, loading of ATT in SNEDDS improved the stability of ATT, and particle size of ATT nanoemulsion generated upon dilution was kept constant both in simulated gastric fluid and simulated intestinal fluid without enzyme.

New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity

One dithiolthione and two new methanethiosulfonate derivatives of valproic acid (VPA) were synthesized and tested in vitro as histone deacetylase (HDAC) inhibitors. The new molecules, as well as their sulfurated moieties, exhibited a much stronger inhibition of HDAC enzymatic and antiproliferative activities and histone hyperacetylation than VPA. ACS 2 is the most interesting compound among the new VPA derivatives and its sulfurated moiety, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, also known to be a metabolite of anethole trithione, seems to contribute significantly to its activity. This is the first time that HDAC inhibitory activity is described for dithiolethiones and thiosulfonates.