Back Cover: Macromol. Biosci. 11/2015.

Back Cover: The micellar prodrugs of desmethyl anethole dithiolethione (ADT-OH) with different hydrolysis rates prepared from block copolymers having ADT-OH linked via an ester bond using glycine and isoleucine linkers are presented. Micelles having a glycine linker inhibit proliferation of cancer cells. Further details can be found in the article by U. Hasegawa, N. Tateishi, H. Uyama, A. J. van der Vlies on page 1512.

Hydrolysis-Sensitive Dithiolethione Prodrug Micelles.

Prodrug micelles carrying 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), a compound possessing chemopreventive properties, are prepared from amphiphilic block copolymers linking ADT-OH via an ester bond using glycine (PAM-PGlyADT) and isoleucine linkers (PAM-PIleADT). The release of ADT-OH from the PAM-PIleADT micelles is much slower than the PAM-PGlyADT micelles. The PAM-PGlyADT micelles show comparable toxicity with ADT-OH in different cancer cell lines, whereas the PAM-PIleADT micelles are not toxic up to 400 µM. This ADT-ester prodrug micelle approach enables to modulate the release rate of ADT-OH and thus might find application in cancer therapy and prevention.

[The clinical therapic efficiency of anethol trithione on dry eye].

OBJECTIVE: To investigate anethol trithione therapic efficiency on dry eye. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

[Anethole dithiolethione: an antioxidant agent against tenotoxicity induced by fluoroquinolones]. / L'anethole dithiolethione: un agent cytoprotecteur contre la ténotoxicité induite par les fluoroquinolones.

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.

A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia.

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.

Treatment of xerostomia with the bile secretion-stimulating drug anethole trithione: a clinical trial.

BACKGROUND: Saliva protects the oral mucosa, inhibiting microbial overgrowth. Hyposalivation, therefore, induces multiple oral disorders, although treatment of hyposalivation is very difficult. METHODS: A cholagogue, anethole trithione (AT) was administered to patients with symptomatic hyposalivation (xerostomia) caused by senile hypofunction (4 men and 17 women; senile group), medications (6 men and 17 women; drug group), and oral cancer therapy (two men and three women; cancer group). For control groups, an artificial saliva was administered to 45 patients consisting of senile hypofunction (10 men and 16 women), drug-induced xerostomia (3 men and 10 women) and oral cancer therapy-induced xerostomia (four men and two women). RESULTS: Two weeks after administration of AT (6 tablets per day), both nonstimulated salivary flow rate (SFR) and stimulated SFR increased in a statistically significantly manner from 0.76 +/- 0.41 and 5.18 +/- 3.02 to 1.54 +/- 1.33 (P<0.05) and 9.07 +/- 4.10 mL/10 min (P<0.05), respectively. Of the three groups, the drug group showed the largest increases in both SFRs, from 0.90 +/- 0.54 and 6.29 +/- 4.12 to 1.69 +/- 1.65 and 12.09 +/- 5.10 mL/10 min (P<0.05 and P<0.02, respectively). Patients in the control group had almost constant SFRs. After AT administration, the salivary viscosity was, however, mildly decreased and concentrations of secretory-immunoglobulin A, lactoferrin, potassium, and chloride in nonstimulated saliva were almost constant. Corresponding with the increase of salivation, oral discomfort and inflammation were improved or resolved in 41 patients of the AT group within about 4 weeks, whereas improvement was observed in only nine patients of the control group. CONCLUSIONS: These results indicate that AT sufficiently stimulates salivation and improves xerostomia.

A comparative study of the effects of yohimbine and anetholtrithione on salivary secretion in depressed patients treated with psychotropic drugs.

OBJECTIVE: The present study compares the effects of yohimbine, an alpha 2 adrenoceptor antagonist, and anetholtrithione, a reference drug in the treatment of dry mouth, in patients treated with psychotropic drugs (tricyclic antidepressants or neuroleptics) and suffering from xerostomia. METHODS: Ten patients were included in a randomized, double-blind, cross-over study, and receiving after yohimbine (3 x 6 mg per day) or anetholtrithione (3 x 25 mg per day) orally for 5 days. Salivary secretion was estimated under resting conditions, before any drug, and then on day 6, 1 h after the ingestion of yohimbine or anetholtrithione. RESULTS: Compared with basal secretion, the increase in salivary flow was significantly more marked after yohimbine than after anetholtrithione. CONCLUSION: This study demonstrates the sialogenic effect of yohimbine in drug-induced dry mouth.

Assessment of the role of glutathione conjugation in the protection afforded by anethol dithiolthione against hexachloro-1,3-butadiene-induced nephrotoxicity.

Administration of anethol dithiolthione (ADT) to rodents can afford protection against some chemically induced toxicities. The aim of the present study was to assess the effects of ADT on hexachloro-1,3-butadiene (HCBD)-induced nephrotoxicity in the rat and to determine the mechanism of its action. Renal integrity was evaluated by measuring urinary excretion of glucose, protein, and gamma-glutamyl transpeptidase and by histological evaluation. A 3-day pretreatment with ADT (300 mg/kg/day) protected against the toxicity of various doses of HCBD (ranging from 15.6 to 62.5 mg/kg). The pretreatment increased (1.4-fold) the nonprotein sulfhydryl content (NPSH) of the liver. However, it did not modify the biliary excretion of radiolabeled materials in [14C]HCBD- treated (20 mg/kg) rats, nor that of the bioactivated HCBD metabolite, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-glutathione (PCBG). Moreover, ADT pretreatment protected rats against the nephrotoxicity induced by PCBG (20 mg/kg) itself. The extent of covalent binding to kidney proteins of [14C]HCBD-derived metabolites was not modified by pretreatment with ADT. Incubation of rat kidney cortical slices in a medium containing 0.1 mM of the nephrotoxic glutathione (PCBG) or cysteine (PCBC, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine) conjugates of HCBD for 30 min resulted in a 75% reduction in the slice/medium ratio of p-aminohipurate (PAH) compared to that seen in controls. When the cortical slices were incubated with ADT (30 min, 0.2 mM) prior to incubation with the nephrotoxic conjugates, the reduction was only 33%. Neither the in vitro nor the in vivo treatments did modify the activity of renal cytosolic beta-lyase; however, the latter treatment caused an increase in NPSH content. A 15-min incubation of kidney cortical slices with glutathione (10 mM) resulted in a 5-fold increase of NPSH, but failed to prevent the reduction in PAH uptake caused by PCBG and PCBC. Altogether, the in vivo and renal slice data suggest that ADT protects rats against HCBD-induced nephrotoxicity by a mechanism that does not involve the modulation of HCBD conjugation with liver GSH, nor the modulation of the kidney NPSH level and beta-lyase activity. The mechanism of protection conferred to rats by an ADT pretreatment against HCBD-induced nephrotoxicity appears to take place in the kidney at a step beyond the generation of ultimate toxic metabolites derived from PCBC.

Pilocarpine and other cholinergic drugs in the management of salivary gland dysfunction.

Sialagogues constitute an important component in the management of salivary gland dysfunction. Of the pharmacologic agents available, pilocarpine has been used extensively over the last century. Many clinical trials have documented the efficacy of this alkaloid, with doses that range from 1 to 15 mg normally taken four times a day. There is considerable individual variation in response although it is usually possible, in the presence of sufficient responsive exocrine tissue, to establish a therapeutic regimen that promotes increased salivation without significant side effects.

An unusual presentation of chronic graft-versus-host disease in an unrelated bone marrow transplantation.

The case described is that of an unrelated bone marrow transplantation in a 43-year-old man. Although the major histocompatibility complex met the criteria for a perfect genotypic match, de novo graft-versus-host disease developed with unusual manifestations involving structures of the oral cavity and associated areas. The loss of taste and smell, as well as profound xerostomia, was treated by stimulating salivary flow. Synergistic sialagogues were used with the hope that an increase in salivary production would mediate an improvement in taste and smell.

Pharmacological studies on anethole trithione.

Pharmacological studies on trithio-p-methoxy-phenylpropene (anethole trithione, ANTT, Felviten) were performed. ANTT at a dose of 100 mg/kg, p.o. lowered the increased serum transaminases GOT and GPT, and protected the liver from injuries caused by CCl4 in mice. In other studies in vivo, ANTT at a dose of 1000 mg/kg showed no effect on the central nervous system or the autonomic nervous system. In vitro experiments with smooth muscle preparations showed no significant effects of ANTT.

Xerostomia due to Sjögren's syndrome. Diagnostic criteria, treatment and outlines for a continuous dental care programme and an open trial with Sulfarlem.

The initial evaluation of 25 patients suspected of suffering from Sjögren's syndrome (SS) disclosed that sialopenia and glandular atrophy without focal sialo-adenitis was the second most common cause, after SS itself, of patient complaints. This emphasizes the importance of conclusive diagnostic criteria to prevent overdiagnosis and to form a sound basis for management of xerostomia patients. We found that at the time of diagnostic evaluation, the dental status of our SS patients did not differ from that of the normal Finnish population. This suggests that SS patients can greatly benefit from adequate dental care, assuming that attention is paid to early diagnosis and management. Accordingly, the diagnostic and therapeutic approach needs to be multidisciplinary. We present our current programme for oral and dental care of xerostomia patients and the results of an open trial with Sulfarlem (trithioparamethoxyphenylpropene) which was found not to be the drug of choice in the treatment of dry mouth associated with SS.

Systemic therapy of salivary gland hypofunction.

Salivary gland hypofunction occurs most often as a consequence of numerous drug therapies, anti-neoplastic treatments, or systemic disease. There are no universally accepted means of treating gland dysfunction and the resultant subjective xerostomia. A few studies have suggested that treatment of underlying inflammatory connective tissue disease will improve salivary performance in Sjögren's syndrome. Most of these reports, however, have either been limited to a small number of patients or have failed to include objective measures of salivary gland output. A larger body of literature deals with attempts using many different sialogogues to stimulate salivary function in a variety of conditions. Again, many studies have failed to document salivary improvement objectively. Recently, interest has focused on three drugs: bromhexine, anethole-trithione, and pilocarpine hydrochloride. Studies with these agents are reviewed, and current clinical investigations with pilocarpine are presented in detail.

Treatment of xerostomia in patients with primary Sjögren's syndrome with sulfarlem.

Stimulated by a recent report on the favorable effect of Anetholtritione (Sulfarlem S 25) on symptoms and salivary flow rate in patients with Sjögren's Syndrome (SS), we examined the effect of Sulfarlem in an open study on 16 patients characterized by severe xerostomia. Fourteen had primary SS and two xerostomia only. The patients were examined by whole resting saliva secretion rate measurement (SR) once a week during the study period of 7 weeks. At the same time the patients assessed their symptoms of xerostomia on a 1-10 visual analogue scale. Following the third examination (2 weeks), Sulfarlem was given p.o. 25 mg X 3 daily for 3 weeks, after which the patients were examined for another 2 weeks. The average SR before treatment was 0.07 ml/15 min. Two patients had increased secretion rates, but only one of these described improvement in symptoms. Two had improvement in symptoms and 12 had no positive subjective or objective effect from treatment. Side effects were abdominal discomfort and flatulence, seen in 7 patients (44%). One of these patients in addition had diarrhea and nausea. The side effects were persistent during treatment only. The medication was terminated following one week of treatment in two patients. It is concluded that Sulfarlem in a daily dose of 75 mg have no marked effect on salivation in patients with primary SS and severe xerostomia. Gastrointestinal side effects may occur.

Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity.

Administration of tert-butyl-4-hydroxyanisole or of two dithiolthiones to female CD-1 mice protected against the acute toxic effects of two hepatotoxic agents, acetaminophen and carbon tetrachloride. Reduced mortality of mice was observed following pretreatment with tert-butyl-4-hydroxyanisole or dithiolthiones. Pretreatment reduced or prevented hepatic glutathione depletion produced by these two hepatotoxic agents. Liver damage, i.e., as determined by serum transaminase and sorbitol dehydrogenase activities, was less after pretreatment with tert-butyl-4-hydroxyanisole or dithiolthiones. Administration of dithiolthiones resulted in increased (from four- to over six-fold) activities of liver glutathione-S-transferases.