Juha Ellmen

Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer

Meta‐analysis of all clinical data was conducted to compare toremifene 40–60 mg/day (TOR) with tamoxifen 20–40 mg/day (TAM) in postmenopausal women with estrogen receptor (ER) positive or ER unknown advanced breast cancer and assess factors predicting treatment outcome. Data from five randomized parallel group studies (all studies) were combined. Efficacy variables were the response rate in all studies and also the time to treatment failure and survival in the three major studies (pivotal studies).Of the 1421 patients, 725 received TOR and 696 TAM. Response rates were 24.0 and 25.3, respectively (p=0.675) with 95 confidence interval (95 CI) for the difference −5.3 to 3.4. Of the 1157 patients in the pivotal studies, 75 had progressed and 50 expired. Median treatment times were 4.9 months in TOR and 5.3 months in TAM groups (p=0.762, hazard ratio 0.98 with 95 CI 0.87–1.11). Median survival times were 31.0 (TOR) and 33.1 (TAM) months (p=0.758, hazard ratio 0.98 with 95 CI 0.83–1.15). All results are consistent with the criteria of statistical equivalence between TOR and TAM. More patients in TAM (20) than in TOR (14, p=0.007) discontinued the treatment prematurely but overall the treatments were well tolerated. As the treatments were equally effective all data were analyzed together for predictive factors. High tumor ER concentration, long disease free time, soft tissue metastases, few metastatic sites, and good performance status all independently predicted longer survival (p<0.001). Previous adjuvant tamoxifen predicted shorter survival (p=0.008). Objective response to treatment or disease stabilization for at least 12 months both predicted prolonged survival (p=0.001).TOR 60 mg/day and TAM are equally effective and well tolerated in the treatment of advanced breast cancer in postmenopausal women. Probability of survival may be predicted based on patient characteristics and on the initial response to the treatment.

A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer

Efficacy and safety of toremifene 60 and 240mg daily (TOR60 and TOR240) are compared to40 mg tamoxifen daily (TAM40) in postmenopausal womenwith advanced estrogen receptor (ER) positive or ERunknown breast cancer. The study is randomized andopen label in three parallel groups. Primary efficacyvariables are response rate and time to progression.WHO and ECOG criteria were used for measurableand nonmeasurable disease assessment, respectively. Safety was reportedaccording to WHO criteria. Altogether 463 patients wererandomized (157 to TOR60, 157 to TOR240, and149 to TAM40). By data cut-off, after 20.5months median follow-up time, over 70% of thepatients had experienced disease progression. Response rates are20.4%, 28.7%, and 20.8% in TOR60, TOR240, andTAM40, respectively. TOR60 and TAM40 show statistically equivalentefficacy and the difference between TOR240 and TAM40is not significant (P=0.112). Median timesto progression are 4.9 (TOR60), 6.1 (TOR240), and5.0 (TAM40) months and the corresponding hazard ratios(TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40are statistically equivalent and the difference between TOR240and TAM40 is not significant (P=0.374).All treatments were well tolerated. As a conclusion,TOR60 and TAM40 show equivalent clinical efficacy andtolerability. The higher dose of toremifene slightly butnot statistically significantly improves response rate and timeto progression. In postmenopausal women, toremifene 60 mgdaily is an effective and safe treatment ofadvanced ER-positive or ER-unknown breast cancer.

Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients

Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and TAM20) were compared in a randomized clinical study in postmenopausal women with advanced breast cancer. The study was open label in three parallel groups. Variables for analysis were serum follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG), estradiol (E2), antithrombin III (AT III), aspartate aminotransferase (ASAT) and vaginal cytology. Clinical efficacy and safety have been reported earlier. A total of 648 patients were randomized (221 to TOR60, 212 to TOR200 and 215 to TAM20). Sera were available for the analysis from 148, 165 and 156 and for vaginal cytology from 98, 93 and 86 patients, respectively. All treatment regimens showed tissue-specific and dose-dependent estrogen agonist effect. In the primary measure of in vivo estrogenicity, effect on hypothalamus–pituitary-axis, all three treatment regimens decreased serum FSH (p < 0.001). TOR200 was more potent than the two other treatments (p < 0.05), but surprisingly, TAM20 was more estrogenic than TOR60 (p < 0.001). As could be expected in postmenopausal women, the treatments had no effect on mean serum E2 concentrations and decrease of serum LH was similar to that of FSH. Estrogenic effect on the liver was seen as dose-dependent increase of SHBG with statistically significant differences between the treatment groups (p < 0.001). Trends of transient ASAT elevations in TOR200 group (p = 0.07) and in all treatment groups AT III decrease (p = 0.1) were seen in the beginning of the treatment. TOR60 or TAM20 did not have an effect on mean ASAT values, and AT III decreased in TAM20 group more than in the two other groups (p = 0.1 compared to TOR60 and p < 0.05 compared to TOR200). Estrogenic effects on vaginal superficial cells were higher in TOR60 and TOR200 groups when compared to TAM20 (p < 0.05). Toremifene and tamoxifen had tissue-specific and partially dose-dependent estrogenic effects in hypothalamus–pituitary-axis, in the liver and in the vaginal epithelium of postmenopausal women. In some tissues tamoxifen 20 may be more estrogenic than toremifene 60 mg/day.

High-dose toremifene in advanced renal-cell carcinoma

Abstract Toremifene (Fareston) – a novel antiestro-genic drug with a triphenylethylene structure – is effective in the treatment of postmenopausal breast cancer patients. It can be safely given even at high doses of up to 300 mg/day. The purpose of the present study was to investigate the effect and tolerability of high-dose toremifene in the treatment of patients with advanced renal-cell carcinoma (RCC). A total of 36 patients started treatment with toremifene at 300 mg/day, including 26 men and 10 women. Their mean age was 56 years (range 35–75 years). In all, 19 patients were nephrectomized. One patient was not evaluable for response because of insufficient treatment time. The response rate was 17%, including one complete response (CR, 3%) lasting for 121+ weeks and five partial responses (PRs, 14%) with a mean duration of 40+ weeks. Ten cases of no change (NC, 28%) had a mean duration of 24 weeks. There was no significant difference in the response rate when patients with lung metastases alone were compared with patients showing metastases of other sites with or without lung metastases. Total pain control was achieved in 45% of the patients who had pain at the beginning of the treatment, and partial control was attained in 20%. Ten patients (28%) developed adverse reactions, which led to discontinuation of the treatment in one case. Blood samples were taken from 16 patients on days 0, 1, 3, 7, 14, and 28 for drug analyses. The concentration of toremifene and its main metabolites measured in serum were about 1.5 times that detected after a conventional dose of 60 mg/day. It can be concluded that high-dose toremifene is an effective and safe palliative treatment in advanced RCC.

Treatment of restless legs syndrome

OBJETIVO: A sindrome das pernas inquietas e um transtorno neurologico caracterizado por um desejo incontrolavel de mover os membros, que comumente esta somente presente ou piora ao descanso ou a noite. O objetivo do trabalho foi a revisao da literatura disponivel sobre o tratamento farmacologico para a sindrome das pernas inquietas. METODO: Pesquisa da literatura recente realizada em bases de dados eletronicas (Medline, Pubmed, Scielo e Lilacs). RESULTADOS: Quinhentos e dois artigos foram encontrados, dos quais 30 foram selecionados. Os agentes dopaminergicos, os anticonvulsantes, os opioides, os benzodiazepinicos, o zolpidem, o entacapone e a ketamina foram eficazes no tratamento da sindrome das pernas inquietas. Um estudo mostrou que o ferro nao foi eficaz. CONCLUSOES: Baseado nos poucos estudos duplo-cegos, randomizados e controlados, parece que as melhores opcoes para tratar os pacientes com sindrome das pernas inquietas sao a gabapentina e L-dopa associada a sua formulacao de liberacao lenta.

Dose-dependent hormonal effects of toremifene in postmenopausal breast cancer patients

Purpose: The purpose of the study was to compare hormonal effects of three toremifene doses, 20 mg (TOR20), 40 mg (TOR40) and 60 mg (TOR60) administered daily, in postmenopausal women with advanced breast cancer. Methods: The study was randomized and open label in three parallel groups. Biochemical variables were identified as the serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone binding globulin (SHBG). The changes were compared with objective clinical responses and to progression-free time. Adverse reactions and liver function test (aspartate aminotransferase, ASAT) were assessed for safety. Results: A total of 260 patients were randomly grouped (90 to TOR20, 81 to TOR40 and 89 to TOR60). Of these patients 29, 29 and 22 completed at least 3 months of treatment and the results were analyzed for biochemical variables. All treatments had intrinsic estrogen agonist activity by decreasing of serum FSH and LH and by increasing of SHBG during the first 3 months (P < 0.01). Dose TOR20 showed slightly longer times to exert maximum estrogenic effects than did the two higher doses. No increases in liver function tests were seen in any of the groups. Objective response rates were 24.4, 39.5 and 32.6% (P = 0.01) and median times-to-progression were 206, 189 and 196 days in TOR20, TOR40 and TOR60, respectively (P = 0.913). Fewer responses were observed in the TOR20 group than in TOR40 (P = 0.05). Adverse events were reported in 19, 23 and 30 patients in the treatment groups (P = 0.20). The most frequently reported events were hot flushes and nausea. These were mostly mild or moderate, and only 1.5% of treatments was discontinued due to toxicity. Conclusions: Toremifene doses of 40 and 60 mg daily were effective and safe treatments of breast cancer in postmenopausal women, and no differences in their biochemical or clinical effects were seen. Toremifene at 20 mg/day had similar but slightly less potent antiestrogenic and estrogenic effects than the two higher doses.

Entacapone Prolongs the Reduction of PLM by Levodopa/Carbidopa in Restless Legs Syndrome

Objectives: Levodopa is effective in the treatment of restless legs syndrome (RLS). However, due to the short duration of action of conventional levodopa/decarboxylase inhibitor formulations, multiple dosing may be required in individual patients with persisting symptoms. We assessed whether a new levodopa formulation containing levodopa, carbidopa, and entacapone (LCE) improves levodopa action in RLS. Methods: Twenty-eight RLS patients with periodic limb movement (PLM) received single doses of Stalevo 50 (LCE50; 50/12.5/200 mg), Stalevo 100 (LCE100; 100/25/200 mg), Stalevo 150 (LCE150; 150/37.5/200 mg), Sinemet 100 (LC100; 100/25 mg), or placebo in a randomized, double-blind, crossover study with polysomnography. Periodic limb movements per hour (PLM/h) during total sleep time and PLM during total time in bed were the primary and secondary variables, respectively. Results: Mean PLM/h during total sleep time after Stalevo 50 (12.6/h, P < 0.05), LCE100, LCE150, and LC100 (6.4/h, 3.5/h and 9.5/h, respectively; P < 0.01) were significantly reduced compared with placebo (25.7/h). Improvement was also observed in PLM/h during total time in bed for all treatments (P < 0.01) and a significant dose response observed between LCE doses (P < 0.05). Compared with LC100, LCE100 and LCE150 reduced PLMs during the second half (P = 0.06 and P < 0.001, respectively) or during the last 3 early morning hours (hours 5-7 from the start of recording) of the night (P < 0.05 and P < 0.01, respectively). All formulations were well tolerated. Conclusions: Single doses of LCE tablets decreased PLMs in a dose-related manner in RLS patients. Prolonged effects of levodopa on PLMs suggest that, compared with standard levodopa, this new levodopa formulation provides longer symptom control throughout the night in patients with previously untreated RLS.

Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

Background Intravenous levosimendan is indicated for acute heart failure. The compound has shown promising beneficial effects in ischemic stroke models. Objective We evaluated the efficacy and safety of oral levosimendan in patients with a history of cerebral ischemia. Methods In a randomized, double-blind, placebo-controlled, parallel-group study, 16 patients with a history of ischemic stroke/transient ischemic attack received oral levosimendan in 5 escalating doses from 0.125 to 2.0 mg daily for 18-day intervals of each dose; 5 patients received placebo. Twenty-four-hour ambulatory ECG and cerebral blood flow velocities using transcranial Doppler ultrasound were recorded at baseline and at the end of each dosing period. Vasomotor reactivity was assessed via the breath holding index. In addition, plasma levels of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and the metabolites of levosimendan were determined. Results Levosimendan induced an increase in cerebral blood flow velocities and a decrease in NT-pro-BNP compared with placebo. There was no significant effect on breath holding index. Doses ≥0.5 mg increased heart rate by 5 to 9 beats/min. The dose level of 2.0 mg exceeded the preset safety margin of ventricular extrasystoles per hour (ie, upper 90% CI of the ratio of levosimendan to placebo above 2) with an estimate of 3.10 (90% CI, 0.95–10.07). Conclusions Oral levosimendan increases cerebral blood flow velocities and diminishes NT-pro-BNP levels in patients with earlier ischemic cerebrovascular event. Daily doses up to 1.0 mg were well tolerated, whereas the 2.0 mg dose level induced an increase in ventricular extrasystoles. ClinicalTrials.gov identifier: NCT00698763.

Pooled analysis of phase III with entacapone in Parkinson's disease

To investigate efficacy and safety of entacapone across phase III studies in Parkinsons disease (PD) with wearing‐off symptoms.

Toremifene concentration and multidrug resistance in lung tumors

Abstract In this pharmacokinetics study, concentrations of toremifene (TOR), a new antiestrogen, were measured after a 7-day oral treatment in serum, lung, and tumor tissue to determine the optimal dose of TOR for the modulation of clinical multidrug resistance in patients with lung cancer. Target levels of the antiestrogen were based on previous in vitro studies. Altogether, 18 patients with operable lung tumors were studied. TOR was given in an open, nonrandomized, phase I study at three different dose levels. The medication consisted of oral TOR given for 7 days at either 240, 480, or 600 mg/day before surgical removal of the tumor. At least five patients were scheduled to be included at each dose level, with all five receiving the full course of therapy before escalation of the dose. Blood samples for serum TOR concentration measurements were taken on days 0 and 7. Specimens of tumor and normal lung tissue of approximately 0.5 g were taken on day 7. The concentrations of TOR and its metabolites were determined in serum, lung, and tumor tissue at different dose levels. Altogether, 12 evaluable patients completed the scheduled treatment. The concentrations measured in serum, lung, and tumor tissue increased along with the dose used, such that the highest TOR values were achieved at 600 mg/day, with mean values being 4.9 μmol/l, 175.0 μmol/g, and 122.7 μmol/g, respectively. The concentrations of TOR and its metabolite N-demethyltoremifene were highest in lung tissue, but the values measured in tumor specimens were also well above the respective concentrations detected in serum samples. The TOR doses of 240 and 480 mg/day were well tolerated. One patient in the group treated at 600 mg/day had to discontinue the treatment because of headache and nausea. TOR given at doses ranging from 480 to 600 mg/day for 7 days will produce serum, lung, and tumor concentrations of the parent drug and its metabolites that have been shown to reverse multidrug resistance of cancer cells in vitro. As the 480-mg/day dose of TOR produced tumor concentrations high enough to reverse multidrug resistance without producing adverse drug reactions, the dose recommended for the foreseen clinical trials in the reversal of multidrug resistance would be 480 mg/day for 7 days.