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Purpose: Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors., Patients and Methods: INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan-Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry., Results: Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 μg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed., Conclusions: INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond. See related commentary by Slingluff Jr, p. 529 ., (©2019 American Association for Cancer Research.)

Background: Neoadjuvant hormonotherapy has recently been used for downstaging large or locally advanced (LA) breast cancer in postmenopausal women., Patients and Methods: A phase II study was conducted in postmenopausal, hormone-receptor (HR) positive, T2-T4 patients, receiving 25 mg/day exemestane for 16 weeks., Results: Among 42 patients, 57.1% underwent conservative surgery. The clinical objective response rate (ORR) was 73.3%, without progression. A pathological partial response was achieved in 16.7% of the patients. Exemestane significantly reduced the expression of Ki-67 and progesterone receptors (PgR) (p<0.001). A significant decrease in PgR was correlated with clinical ORR (p=0.028). The responders presented higher baseline PgR levels (p=0.017). No relationship was found between ORR and mRNA expression of aromatase or oestrogen receptors beta (ER-beta)., Conclusion: Neoadjuvant exemestane provided satisfactory efficacy and safety profiles in LA breast cancer. The main biological effects consisted of a reduction in PgR expression for responders and a decrease in Ki-67 expression.

The epidermal growth factor receptor (EGFR) signaling pathway is often activated in NSCLC, and thus represents a promising therapeutic target. We studied the antitumor activity of gefitinib (Iressa), an orally active EGFR-tyrosine kinase inhibitor, alone and in combination with standard chemotherapy in 5 recently established human NSCLC xenografts with wild-type EGFR. Mice were treated with 2 protocols of chemotherapy based on cisplatin (CDDP) combined with either gemcitabine (GEM) or vinorelbine (VNR). Gefitinib alone significantly inhibited tumor growth (TGI) in 4 of the 5 tumor xenografts (mean TGI of 58%, range: 25-70%). CDDP+VNR alone failed to achieve any significant responses, while CDDP+GEM achieved significant responses in 2 xenografts (TGI of 93 and 47%). Addition of gefitinib to CDDP+GEM potentialized chemotherapy in the 3 CDDP+GEM-resistant xenografts, but did not potentialize the CDDP+VNR combination. The effect of gefitinib treatment on the activity of extra cellular-regulated kinase (Erk), Akt, JNK and p38 kinases was assessed in IC9LC11 and IC1LC131, two NSCLC xenografts selected for their sensitivity and resistance to gefitinib, respectively. In IC9LC11, gefitinib strongly inhibited Erk, Akt and Jnk phosphorylation, but P38 remained active. Inversely, in IC1LC131, Erk and Akt pathways remained active, while Jnk and P38 pathways were inhibited by gefitinib. The data indicate that the antitumor activity of gefitinib in NSCLC, alone or in combination with chemotherapy, is tumor-dependent and is influenced by downstream signaling events independent of EGFR status., ((c) 2006 Wiley-Liss, Inc.)

Cultures of human carcinoma A-431, A-549 and HeLa cells were challenged with gamma-rays without or with concomitant exposure to gefitinib, a potent inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR). The outcome of treatment was determined from cell and colony count, cell cycle progression and DNA double-strand break formation and rejoining. Apoptosis was measured in parallel from hypodiploid DNA and using an annexin V assay. Gefitinib developed a cytostatic effect in all cell lines, with drug sensitivity correlating the level of EGFR expression. A weak cytotoxicity of gefitinib was observed in HeLa cells only, although the drug was unable to induce significant cell cycle redistribution in this cell line. In contrast, substantial G1 block and S-phase depletion was observed in A-431 and A-549 cells exposed to gefitinib. The drug brought about additive to subadditive interaction with radiation with regard to growth inhibition, clonogenic death and induction of apoptosis. Consistently, gefitinib did not hinder the rejoining of radiation-induced DNA double-strand breaks in any cell line. The results demonstrate that gefitinib may elicit cytotoxicity at high concentration, but does not act as a radiosensitiser in vitro in concomitant association with radiation.

Blind individuals are not only handicapped by their loss of vision, but are also affected because the loss of sight may have a secondary impact on functioning of their biological clock. The objective of the present study was to determine the impact of visual loss on sleep/wake disorders. A prospective 48-item questionnaire survey was distributed to blind individuals through the French Association Valentin Haüy, which serves blind persons. A control group matched by age, sex, geographical location and professional activity/non-activity was obtained from a panel of 20000 households representative of the French population, and this group also completed the questionnaire. From a potential blind population of 1500 subjects, 1073 questionnaires (71.5%) were completed and usable for analysis, and from a potential 1000 control subjects, 794 (79. 4%) of the questionnaires were returned and analysed. Criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, 4th revision, and the International Classification of Sleep/Wake Disorders (1990) were used to determine pathology. Individuals determined to be 'totally blind' and 'almost blind' (i.e. with less than 10% vision left in only one eye) presented a significantly higher occurrence of sleep/wake disorders than controls. Nocturnal sleep disruption, daytime somnolence, and (to a lesser degree) a 'free-running' condition are significantly more common in blind individuals. There is an increased use of sleeping pills, and a higher incidence of inappropriate involuntary daily naps. In conclusion, individuals with blindness report a significant curtailment of total sleep time and hence resulting daytime somnolence, which impacts on daytime activities. A 'free-running' condition is also a common sleep/wake impairment that may compound the handicap of blindness.

Purpose: To determine the prevalence and severity of sleep disturbance in blind subjects and its relation to the form and duration of visual loss., Methods: Of 403 blind subjects (visual acuity of less than 20/200 or a visual field of less than 5 degrees) recruited for the study, 15 were excluded because of affective disorder as identified by Montgomery Asberg Depression Scale. The remaining 388 subjects and a comparison group of 44 normally sighted individuals underwent an interview, and the Pittsburgh Sleep Quality Index questionnaire was administered. Sleep disturbance was classified as mild, moderate, or severe., Results: Disturbance of sleep was recorded in 189 (48.7%) of the blind subjects. The prevalence was higher and the sleep disturbance was more severe in those with no perception of light than in those with light perception or better visual acuity. In the comparison group, four (9.1%) had mild sleep disturbance only. The differences between blind subjects and normally sighted individuals were highly significant (P < .001). The most common sleep-related problem among the blind subjects was interrupted sleep, followed by increased sleep latency, short sleep duration, and daytime naps. Among the blind subjects, no correlation was found between the extent of sleep disturbance and the duration and pattern of visual loss., Conclusions: Blind subjects who retain light perception, as well as those with total loss of vision, have a high frequency of sleep disturbance, although disorder is more common and more severe in subjects with no light perception. Management of the sleep disturbance may improve the quality of life in the visually handicapped.

Increasing knowledge of the pharmacological effects of melatonin has suggested various possible therapeutic applications for the hormone. Because, as a natural substance, melatonin cannot be patented, melatonin-related compounds have been synthesized by industrial groups. The scope of such compounds is also to specifically target the recently discovered melatonin receptor subtypes. The sleep-inducing properties of melatonin are disputed, but are distinct from those of benzodiazepines. The observed effects on sleep latency or sleep efficiency, which remain to be confirmed, could be accounted for by the effects of melatonin on core body temperature and on circadian rhythms. There is also an urgent need for safety data, both in animals and in humans, particularly when long-term use is envisaged.

We studied the performance and adaptability of 40 nurses (median age 35 years), 20 on permanent day shift and 20 on permanent night shift with fast rotation of work and days off, matched for age, gender, and socio-familial responsibilities. For 15 days prior to the study, subjects maintained sleep logs and trained for performance tests. Questionnaires were administered to evaluate adaptability to shift work. During the experimental phase, sleep/wake patterns were monitored using sleep logs and activity/inactivity with wrist actigraphy. Performance levels were measured with the four choice reaction time and memory test for seven letters, eight times/day during the wake period, days on and off. On the last day of work and first day off, 6-sulfatoxy-melatonin levels were assayed from urine samples collected every 2 hours. Estimated total sleep time during the 15-day experimental period was not significantly different in the dayshift and nightshift nurses. Night nurses shifted regularly to daytime activities on days off and, as a group, were significantly sleep deprived on work days with napping on the job in 9 of the 20 night shift nurses (mean of 114+/-45 minutes per shift) and a significant performance decrement during the work period. Further analysis revealed two subgroups of night nurses: The majority (14 nurses) had a mean peak of 6-sulfatoxy-melatonin at 0718 hours on days off and no peak during night work while the other 6 night shift nurses presented a fast melatonin shift with two clear peaks on both work and days off. Comparison of performance scores revealed that all nurses performed similarly on days off. Daytime nurses and fast-shifting night nurses had similar scores on work days, while nonshifting night nurses had significantly lower scores at work. Despite similar gender, age, social conditions, and light exposure levels, a minority of the nurses studied possessed the physiological ability to adapt to a fast-shifting sleep-wake schedule of more than 8 hours and were able to perform appropriately in both conditions. This shift was associated with a change in the acrophase of 6-sulfatoxy-melatonin.

Melatonin rhythms were assessed in 49 registered blind individuals by measurement of the urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s). Subjects had different causes of visual loss and were classified as having light perception or better (LP; n = 19) or having no perception of light (NPL; n = 30). Subjects collected four-hourly urine samples (eight-hourly overnight) for 48 h at weekly intervals for 3-5 weeks. The majority of LP subjects (14 of 19) had normally entrained aMT6s rhythms (mean acrophase range, 2.4-6.2 h), 4 were abnormally entrained to 24 h (mean acrophase range, 8.9-1.0 h), and 1 was unclassified. Conversely, most NPL subjects had abnormal rhythms (23 of 30), the incidence of which was greater in uni- and bilaterally enucleated subjects. The majority of NPL subjects (17 of 30) had free-running aMT6s rhythms period range, 24.13-24.79 h), 5 were abnormally entrained to 24 h (acrophase range, 7.2-20.6 h), and 1 was unclassified. Output (micrograms of aMT6s per 24 h) and amplitude (micrograms per h) of aMT6s production did not vary between LP and NPL subjects (mean 24-h output +/- SD, 12.7 +/- 7.5 and 9.4 +/- 6.4 micrograms aMT6s/24 h, respectively; mean amplitude +/- SD, 0.6 +/- 0.4 and 0.5 +/- 0.3 microgram/h, respectively). These results indicate that a higher proportion of NPL subjects have abnormal melatonin rhythms compared to those with LP.

S-20098 has potent and specific agonist properties on melatonin receptors both in vitro and in vivo. Behavioral studies on rodents already showed that repeated intraperitoneal administration of S-20098 could dose-dependently alter the functioning of the circadian clock. To determine whether single administration of S-20098 could alter the circadian rhythms of rodents, we first used the phase-response curve (PRC) approach in two different species: Syrian hamsters and mice (C3H/HeJ). Our results show that the shape, circadian times and extent of the PRC to S-20098 look very similar in mice and hamsters. In both species, the phase advance portion of the PRC to S-20098 is limited to a 3 h window preceding the onset of locomotor activity, but the magnitude of phase shifts is larger in mice. We also tested the phase shifting effects of increasing doses of S-20098 during the interval of maximal sensitivity to this compound. Treatment with S-20098 induces dose-dependent phase shifts, with maximal shifts observed after injections of 20 and 25 mg/kg S-20098 i.p., respectively, in mice and hamsters. Those results are in agreement with the limited distribution of melatonin-binding sites within the circadian clock of adult Syrian hamsters, as compared to other rodents.

Daytime sleepiness is a common complaint in blind subjects. Abnormally timed melatonin has been invoked as a possible cause of both daytime sleepiness and nighttime awakening. In free-running blind individuals, there is an opportunity to assess the relationship between endogenous melatonin rhythms and subjective sleepiness and naps. The aim of this study was to characterize melatonin rhythms and simultaneously to evaluate subjective napping. A total of 15 subjects with no conscious light perception (NPL) were studied for 1 month. Prior to the study, sleep disorders were assessed using the Pittsburgh Sleep Quality Index. Cosinor and regression analysis revealed that 9 of the 15 NPL subjects had free-running 6-sulphatoxymelatonin (aMT6s) rhythms (period [tau] range = 24.34 to 24.79 h), 3 were entrained with an abnormal phase, and 3 were normally entrained. Most of the subjects (13 of 15) had daytime naps; the 2 individuals who did not made conscious efforts not to do so. Subjects with abnormal aMT6s rhythms had more naps of a longer duration than did those with normal rhythms. Free-running nap rhythms occurred only in subjects with free-running aMT6s rhythms. The 2 abnormally entrained subjects who napped did so at times that coincided with high levels of aMT6s (mean aMT6s acrophase [phi] +/- SD = 14.30 +/- 1.08 h, 20.30 +/- 0.62 h; mean nap time +/- SD = 14.01 +/- 3.60 h, 18.23 +/- 3.20 h, respectively). Regardless of aMT6s rhythm abnormality, significantly more naps occurred with a 4-h period before and after the estimated aMT6s acrophase. In 4 free-running subjects, aMT6s acrophase (phi) passed through an entire 24-h period. When aMT6s was in a normal phase position (24:00 to 06:00 h), night-sleep duration tended to increase with a significant reduction in the number and duration of naps. Sleep onset and offset times tended to advance and delay as the aMT6s rhythms advanced and delayed. Our results show a striking relationship between the timing of daytime production of melatonin and the timing of daytime naps. This suggests that abnormally timed endogenous melatonin may induce sleepiness in blind subjects.

Tolerance to shift work and adaptability to shifting schedules is an issue of growing importance in industrialized society. We studied 40 registered nurses, 20 on fixed day-shifts and 20 on fixed night-shifts, to assess whether workers with rapidly shifting schedules were able to adapt their melatonin secretion and sleep-wake cycles. The day-shift worked 5 days with 2 days off and the night-shift worked 3 nights with 2 off. All night-shift personnel acknowledged shifting back to daytime schedules on their days off. Sleep-wake was determined by sleep logs and actigraphy. To measure 6-sulfatoxymelatonin levels, urine was collected at 2-hour intervals on the last work day and on the last day off. Night-shift workers slept significantly more on days off. Napping on the job occurred in 9/20 night-shift workers (mean 114 minutes) between 3 and 6 a.m. The acrophase of 6-sulfatoxymelatonin in day-shift nurses occurred at similar times on workdays and off days. In night-shift nurses, the acrophase was about 7 a.m. on days off, but had a random distribution on workdays. Further analysis revealed two subgroups of night-shift nurses: six subjects (group A).demonstrated a rapid shift in melatonin secretion (acrophase at near 12 noon on work days and at near 7 a.m. on days off) while 14 nurses (group B) did not shift. Group A nurses slept more in the daytime on work days and their total sleep time was the same as day-shift nurses. Group A was slightly younger and was composed solely of women (there were nine women and five men in group B). Age may be a factor in the ability to adapt to rapidly shifting schedules.

A balanced 3 way cross-over study involving 12 young healthy volunteers (6 men and 6 women) was used to determine the pharmacokinetic parameters of the antidepressant tianeptine following a single dose administered by oral and intravenous route. The influence of alcohol on the pharmacokinetics of tianeptine when given per os was also investigated. Kinetic parameters of metabolite MC5, the C5 side chain beta-oxidation product of tianeptine, were simultaneously determined. Following intravenous administration total clearance and volume of distribution of tianeptine were 230 +/- 59 ml.min-1 and 0.47 +/- 0.14 l.kg-1 respectively. When given orally, tianeptine was absorbed rapidly (tmax = 0.94 +/- 0.47 h). The mean systemic availability was estimated to be 99 +/- 29%. Tianeptine was eliminated from plasma with a half-life of 2.5 +/- 1.1 h, mainly via extrarenal route since its renal clearance averaged 0.38 +/- 0.47 ml.min-1. Plasma levels of metabolite MC5 were lower than those of the parent drug but decreased with a longer half-life (7.2 +/- 5.7 h). Alcohol co-administration decreased tianeptine absorption rate and lowered tianeptine plasma levels by about 30% but did not affect those of the MC5 metabolite.

The effect of chronic alcoholism (with or without associated moderate cirrhosis) on the disposition of the antidepressant tianeptine, which is devoid of substantial first-pass metabolism, was examined in 21 patients and 11 age-matched controls. Pharmacokinetic parameters for tianeptine and its C5 acid analogue metabolite (MC5 metabolite) were estimated by non-compartmental analysis. The area under the curve (AUC) for tianeptine, following a 12.5mg single oral dose, was decreased by 31% in chronic alcoholics and increased by only 14% in cirrhotics, compared to controls. These changes did not attain statistical significance. The trend of changes in the AUC for the MC5 metabolite was similar to that observed for the parent drug. No statistical difference was found in the terminal half-life for both tianeptine and its MC5 metabolite between patients and controls. On the basis of this study, it appears unnecessary to modify the proposed dosage regimen used in clinical trials (tianeptine sodium salt 12.5mg 3 times daily) in chronic alcoholics with or without associated moderate cirrhosis.

The influence of a test meal on the absorption and disposition of tianeptine (Stablon), a new antidepressant, was investigated in 12 healthy subjects in a two-way, randomized, open cross-over study. Single 12.5-mg oral doses of tianeptine were administered following a night of fasting or immediately after a standardized breakfast. When subjects received tianeptine under fasting conditions the lag time before absorption onset, and the time of the maximum plasma concentration were 0.55 +/- 0.26 hours and 1.29 +/- 0.29 hours, respectively. The maximum plasma concentration was 322 +/- 44 ng/mL, and the total area under the curve 994 +/- 248 ng/hr/mL. When tianeptine was given at the end of the meal, several significant changes were found for tianeptine kinetic parameters; the lag time increased by 0.3 hour and the maximum plasma concentration was lowered (decreased by 25%) and occurred later (tmax increased by 0.5 hour). However, no significant change was found in the area under the plasma concentration-time curve. The trend and extent of changes in the MC5 metabolite parameters were similar to those observed for the parent drug. Absorption of tianeptine is slightly delayed and slowed down without modification of its extent when tianeptine is given at the end of a meal. These slight changes are not clinically relevant for an antidepressant administered three times a day. Despite the changes observed, tianeptine may be given at meal times to improve compliance with treatment.

129 chronic alcoholic patients, withdrawn from alcohol and presenting major depression or dysthymic disorder, were treated for 4-8 weeks under double-blind conditions either with a new antidepressant, tianeptine (37.5 mg per day), or with amitriptyline (75 mg per day). Both groups presented steady improvement of the symptoms of depression during treatment, as scored on the Montgomery and Asberg Depression Rating Scale and the Hopkins Symptom Checklist self-evaluation; for the latter scale, the improvement was significantly greater in the tianeptine group. In addition to the improvement of mood, tianeptine also produced significant reduction of the somatic complaints of the depressed patients. Furthermore, tianeptine possesses anxiolytic activity, as shown by the change of the Hamilton Anxiety Rating Scale global score, similar to that produced by amitriptyline. The anxiolytic activity of tianeptine was not accompanied by any impairment of vigilance, unlike that of amitriptyline. Tianeptine produced rare, mild anticholinergic effects. The results obtained show that tianeptine is an effective anxiolytic antidepressant, with better safety than amitriptyline, suitable for use in the treatment of mood disorders following alcohol withdrawal.

Tianeptine is a new antidepressant effective against anxiety accompanying mood disturbances. Its clinical properties have been assessed by double-blind controlled studies (versus imipramine, amitriptyline, nomifensine, viloxazine) in depressed patients fulfilling the diagnostic criteria of the DSM III: single recurrent major depressive episodes without melancholia or psychotic features, and dysthymic disorders. The authors have concluded that tianeptine is effective in depressive disorders as shown both by depression rating scales and subjective impressions of treated patients. This improvement increases regularly with time. Seventy-eight percent of patients were considered to be "responders" at the end of the treatment with tianeptine. Antidepressant activity of tianeptine is equally present in depressive states appearing after withdrawal from alcohol. In depressed patients with anxiety, the results also reveal the efficacy of tianeptine on anxiety symptoms. Tianeptine, in addition, shows a marked action on somatic complaints. These results have been confirmed by open long-term trials, particularly in the elderly. Tianeptine can be placed in a middle position in the bipolar classification, between the sedative and stimulant antidepressants. Its antidepressant and anxiolytic properties and its action on somatic complaints make the drug particularly suitable for the treatment of the entire range of depressive symptomatology.

The pharmacokinetics of the tricyclic antidepressant amineptine (Survector) and its main metabolite were studied in 12 young healthy adults (6 men, 6 women; mean age 35.8 yr). Plasma samples were taken over 24 h following a single oral dose of 100 mg amineptine chloryhdrate. Plasma levels of both compounds were determined by means of high performance liquid chromatography. Amineptine was rapidly absorbed. Mean peak plasma concentrations of amineptine and its metabolite occurred 1 h and 1.5 h, respectively, after product administration. The mean apparent volume of distribution was large: 2.4 l.kg-1. Elimination was rapid; the mean half-lives of the 2 compounds were short: 0.8 h for amineptine and 2.5 h for the metabolite. The mean apparent plasma clearance of amineptine was high (124.8 l.h-1). When the results were adjusted for body weight and surface area, no significant difference in pharmacokinetic parameters was found between men and women. Given its pharmacokinetic characteristics there is no risk of amineptine accumulation and thus it is a particularly easy drug to manage. A standard dosage of amineptine was defined for use in healthy young adults.