Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer

CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.     

Treatment of newly diagnosed state D2 prostate cancer with leuprolide and flutamide or leuprolide alone, phase III, intergroup study 0036

In order to test the hypothesis of complete androgen blockade for advanced prostate cancer (D₂CaP), an intergroup trial was instituted in 1985 comparing leuprolide (L) alone to the combination of L with flutamide (F). Eligibility requirements included previously untreated histologically confirmed stage D₂CaP, measurable bone or soft tissue metastases, performance status (PS) of 3 or better, acceptable renal and hepatic function, no severe cardiac disease, and no prior or concomitant endocrine therapy. Stratification at entry was on the basis of PS and none or minimal disease (MD) versus severe degree (SD) of bone metastases. Six hundred and seventeen patients were entered into this study between March 1985 and April 1986. At the present time, there is a 3-month difference in the median progression-free survival (13.9 vs 16.9 months; P = 0.039) and a 7.1-month difference in survival (27.9 vs 35.01 months; P = 0.035) favoring L + F. In L + F-treated patients with good PS-MD, the median survival recently has been reached and is 51.9 months vs 39.6 months for L + P patients. The 107 black patients in the study had median survival of 26.4 months vs 33.3 months for whites. Discussions of racial differences in survival as well as other prognostic factors will be presented. The combination of L + F is superior to treatment with L alone. The benefits appear greatest in patients with minimal disease.     

Radiopotentiation of enzalutamide over human prostate cancer cells as assessed by real-time cell monitoring

AimTo evaluate the radiopotentiation of enzalutamide in human prostate cancer cells.BackgroundWhile radiotherapy is the first line of treatment for prostate cancer, androgen blockade therapies are demonstrating significant survival benefit as monotherapies. As androgen blockade can cause cell death by apoptosis, it is likely that androgen blockade will potentiate the cytotoxic activities of radiotherapy.Materials and methodsHere, we tested the potential synergistic effects of these two treatments over two human metastatic prostate cancer cells by real-time cell analysis (RTCA), androgen-sensitive LNCaP cells (Lymph Node Carcinoma of the Prostate) and androgen-independent PC-3. Both cell lines were highly resistant to high doses of radiotherapy.ResultsA pre-treatment of LNCaP cells with IC50 concentrations of enzalutamide significantly sensitized them to radiotherapy through enhanced apoptosis. In contrast, enzalutamide resistant PC-3 cells were not sensitized to radiotherapy by androgen blockade.ConclusionsThese results provide evidence that the enzalutamide/radiotherapy combination could maximize therapeutic responses in patients with enzalutamide-sensitive prostate cancer.     

Effect of L-arginine supplement on liver regeneration after partial hepatectomy in rats

Background

To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa).

Methods

Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m²) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed.

Results

No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease.

Conclusion

We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.     

Phase II clinical study of toremifene in patients with metastatic breast cancer. Preliminary communication

Twelve postmenopausal women with inoperable or metastatic breast cancer were given toremifene at a daily dose of 60 mg. The patients had no prior endocrine or cytotoxic therapy and further inclusion criteria were bidimensionally measurable disease, performance status above 50, expected survival of more than 3 months and estrogen receptor status positive or undetermined. Objective response [complete remission (CR) + partial remission (PR)] was achieved in 6 patients (50%) and stable disease was obtained in 5 patients. No side effects of the treatment were noted.     

Phase II trial of recombinant interferon alpha-2C in metastatic renal cell carcinoma

A total of 18 patients with advanced metastatic renal cell cancer were treated with recombinant interferon alpha-2C (rIFN alpha-2C) at daily doses of 10 X 10(6) IU by intramuscular injection. All patients had evaluable metastatic lung, liver, or abdominal disease as measured by radiographic or computerized tomographic scans. In 2 of the 18 patients an objective response (1 CR, 1 PR) with a duration of +28 and 12 months, respectively was achieved. A 25$ to 50$ decrease in tumor measurements (MR) was seen in 2 additional patients; in 3 cases a stabilisation of the disease (SD) was observed, whereas it progressed in 11. 3/4 responding patients (including MR) and all 3 cases with SD had measurable disease in the lungs as predominant site of metastatic disease. Additional clinical characteristics of patients exhibiting response or SD to IFN therapy included prior nephrectomy, favourable initial performance status and limited metastatic disease. No serious haematologic or irreversible organ toxic effects were attributed to interferon. Several patients, however, had constitutional symptoms, and major dose reductions due to CNS toxicity became necessary in two. Further studies are warranted to evaluate the use of interferons in combination with cytotoxic drugs or other biologic response modifiers.     

Prostate cancer: Re-focusing on androgen receptor signaling

Prostate cancer is the most common, non-dermatologic cancer in men. Since prostate cancer is highly associated with increased age, the incidence of this disease is expected to increase as the population ages. In its initial stages prostate cancer depends upon the actions of androgen, and androgen deprivation therapy induces tumor regression. Currently, androgen deprivation is achieved by either surgical or chemical androgen blockade. Unfortunately, nearly all prostate cancer patients develop tumors that grow despite androgen blockade and ultimately relapse. Many alterations in prostate cancer cells contribute to this state. Although chemotherapy induces short remissions in some patients, there are no curative therapies for metastatic disease. This review summarizes our current understanding in androgen signaling and the mechanisms that allow tumor cells to bypass androgen manipulation therapy. The identification of novel survival pathways and effector molecules that drive androgen independent growth is necessary to develop effective therapies for advanced prostate cancers.     

A multicenter,randomized, placebo controlled,multiple-dose,safety and pharmacokinetic study of AIT-082 (Neotrofin) in mild Alzheimer's disease patients

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study of the purine derivative, AIT-082 (Neotrofin, NeoTherapeutics) was conducted in mild Alzheimer's disease (AD) patients to evaluate multiple-dose safety, tolerability, and pharmacokinetics. Possible short-term effects of AIT-082 on cognition and memory were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimer's disease and other neurological disorders. Pre-clinical studies indicate that AIT-082 has memory enhancing properties, stimulates neuritogenesis and the production of neurotrophic factors. Patients received an oral dose of AIT-082 or placebo daily for one week. Thirty-six AD patients were divided into three dose cohorts; each dose cohort consisted of twelve patients with 8 patients randomized to AIT-082 and 4 to placebo. The 3 doses of AIT-082 evaluated in this study were 100 mg/day, 500 mg/day, and 2,000 mg/day. There were no serious adverse events at any dose and the drug was well tolerated without significant side effects. AIT-082 was orally and rapidly absorbed, resulting in peak serum concentrations within 2 hours with an elimination half-life of approximately 20 hours. Higher doses resulted in corresponding increases in peak concentrations and areas under the curve (AUC). There was an approximate 2-fold accumulation in AIT-082 with daily dosing (as reflected by the AUC) at steady state. There were no significant differences by treatment arm on the clinical or neuropsychological evaluations. AIT-082 was rapidly absorbed by the oral route with a half-life suitable for dosing once or twice daily. No problems with tolerability or safety were found. AIT-082 appears suitable for testing in larger clinical trials for the treatment of AD and other neurologic disorders.     

Letrozole versus tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy

Letrozole, a third generation aromatase inhibitor, has been compared with tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. In a first-line trial in advanced disease, 939 post menopausal women were randomised double blind to receive treatment with letrozole 2.5 mg daily or tamoxifen 20 mg daily. Letrozole was significantly superior in terms of median time to progression (9.4 months versus 6.1 months, P = 0.0001), objective response (30% versus 20%, P = 0.0006), and clinical benefit (49% versus 38%, P = 0.0001). Superiority of letrozole was independent of disease site, receptor status, or prior adjuvant anti-oestrogen therapy. In an extended phase of this trial, 200 patients were crossed over to tamoxifen after letrozole, compared with 197 crossed over to letrozole after tamoxifen. Median overall survival was 34 months for letrozole versus 30 months for tamoxifen (not significant).

In a similar randomised double-blind neoadjuvant trial, 337 post menopausal patients with large ER/or PgR positive T2–T4 cancers, either requiring mastectomy or locally advanced, were randomised to preoperative letrozole or tamoxifen for 4 months prior to surgery. Overall response was 55% for letrozole versus 36% for tamoxifen (P < 0.001). Conservative surgery was possible in 45% of patients treated with letrozole versus 35% with tamoxifen (P = 0.022).

In both trials, both treatments were well tolerated with no significant differences in side effects.

These results indicate that letrozole is more active than tamoxifen both as neoadjuvant therapy and as first-line treatment in advanced disease. They support the importance of current adjuvant trials comparing the two treatments.     

Apomorphine in Huntington's chorea: clinical observations and theoretical considerations

Five patients, four definitively diagnosed as suffering from Huntington's disease and the fifth with abnormal involuntary movements (AIM) and dementia but no apparent family history of the disease, were administered apomorphine. Although the short duration of action and stressful side-effects produced by apomorphine limited its use regarding a complete dose- and time-response evaluation, slight to marked diminution of AIM was seen in all patients. Optimal doses ranged from 1–2 mg across patients, producing a significant reduction in AIM for the entire hour of observations. Theoretical interpretations of these effects regarding dopaminergic receptor stimulation and/or blockade by apomorphine are discussed.     

Endocrine treatment of prostate cancer

Although androgen deprivation as a treatment for patients with prostate cancer was described more than 60 years ago its optimal use remains controversial. The widespread use of prostate-specific (PSA) assay has lead to earlier diagnosis and earlier detection of recurrent disease. This means that the systemic side effects of androgen deprivation and quality of life have become more important. Debates continue regarding the proper use and timing of endocrine therapy with orchiectomy, oestrogen agonists, gonadotropin hormone-releasing hormone (GnRH) agonists, GnRH antagonists, and androgen antagonists. A critical review of the literature was performed. Data support that androgen deprivation is an effective treatment for patients with advanced prostate cancer. However, although it improves survival, it is not curative, and creates a spectrum of unwanted effects that influence quality of life. Castration remains the frontline treatment for metastatic prostate cancer, where orchiectomy, oestrogen agonists and GnRH agonists produce equivalent clinical responses. Maximum androgen blockade (MAB) is not significantly more effective than single agent GnRH agonist or orchiectomy. Nonsteroidal antiandrogen monotherapy is as effective as castration in treatment of locally advanced prostate cancer offering quality of life benefits. Adjuvant endocrine treatment is able to delay disease progression at any stage. There is, however, controversy of the possible survival benefit of such treatment, including patients having PSA relapse after definitive local treatment for prostate cancer. Neoadjuvant endocrine treatment has its place mainly in the external beam radiotherapy setting. Intermittent androgen blockade is still considered experimental. The decision regarding the type of androgen deprivation should be made individually after informing the patient of all available treatment options, including watchful waiting, and on the basis of potential benefits and adverse effects. Several large studies are under way to investigate the role of adjuvant endocrine treatment in the field of early prostate cancer, intermittent androgen deprivation and endocrine therapy alone compared with endocrine therapy with radiotherapy. The real challenge, however, is to develop better means to avert hormone-refractory prostate cancer and better treatments for patients with hormone-refractory disease when it occurs.     

Effectiveness of carboplatin and paclitaxel as first- and second-line treatment in 61 patients with metastatic melanoma

Background

Patients with metastatic melanoma have a very unfavorable prognosis with few therapeutic options. Based on previous promising experiences within a clinical trial involving carboplatin and paclitaxel a series of advanced metastatic melanoma patients were treated with this combination.

Methods

Data of all patients with cutaneous metastatic melanoma treated with carboplatin and paclitaxel (CP) at our institution between October 2005 and December 2007 were retrospectively evaluated. For all patients a once-every-3-weeks dose-intensified regimen was used. Overall and progression free survival were calculated using the method of Kaplan and Meier. Tumour response was evaluated according to RECIST criteria.

Results

61 patients with cutaneous metastatic melanoma were treated with CP. 20 patients (85% M1c) received CP as first-line treatment, 41 patients (90.2% M1c) had received at least one prior systemic therapy for metastatic disease. Main toxicities were myelosuppression, fatigue and peripheral neuropathy. Partial responses were noted in 4.9% of patients, stable disease in 23% of patients. No complete response was observed. Median progression free survival was 10 weeks. Median overall survival was 31 weeks. Response, progression-free and overall survival were equivalent in first- and second-line patients. 60 patients of 61 died after a median follow up of 7 months. Median overall survival differed for patients with controlled disease (PR+SD) (49 weeks) compared to patients with progressive disease (18 weeks).

Conclusions

Among patients with metastatic melanoma a subgroup achieved disease control under CP therapy which may be associated with a survival benefit. This potential advantage has to be weighed against considerable toxicity. Since response rates and survival were not improved in previously untreated patients compared to pretreated patients, CP should thus not be applied as first-line treatment.     

Improvement in prognosis of myocardial infarction by long-term beta-adrenoreceptor blockade using practolol. A multicentre international study.

In a large-scale double-blind controlled trial of practolol (200 mg twice daily) in the long-term prophylactic treatment of 3038 patients recovering from acute myocardial infarction treatment was started one to four weeks after the acute attack. The trial was originally planned to include 4000 patients treated for at least a year but had to be terminated prematurely because of the serious oculocutaneous and peritoneal reactions reported elsewhere. Nevertheless, important findings, probably applicable to other beta-adrenoreceptor antagonists, have emerged in relation to mortality and morbidity. (1) The practolol-treated group showed a significant reduction in overall mortality and in sudden deaths; (2) there was a highly significant reduction in "all cardiac events"; (3) the reduction in overall mortality was virtually confined to patients whose original pre-entry infarcts were sited anteriorly; (4) the protective effect of practolol was most evident in those patients with pre-entry anterior infarcts whose blood pressures at entry were below the mean for the trial as a whole; (5) there were highly significant group differences in favour of the drug relating to the incidence of angina pectoris and cardiac arrhythmias, and to the numbers of patients who had to be withdrawn from the trial because of these conditions; (6) significantly more patients were withdrawn from the treatment group because of suspected adverse reactions. It is concluded that practolol used in the long-term treatment of patients who have survived the acute phase of myocardial infarction reduces the death rate when the original infarct is sited anteriorly. It is postulated that the favourable results of the trial were due to beta-adrenoreceptor blockade rather than to some other property specific to practolol itself. Since practolol produces severe side effects in long-term use it is recommended that an alternative beta-adrenoreceptor blocking agent should be used.     

Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy

Current systemic treatments for metastatic uveal melanoma (UM) have not improved overall survival (OS). The fully human anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, ipilimumab, improved OS of patients with advanced cutaneous melanoma in a phase 3 trial; however, UM patients were excluded. The aim of this subanalysis, performed by the ipilimumab-ocular melanoma expanded access program (I-OMEAP) study group, was to assess the activity and safety of ipilimumab in patients with UM in a setting similar to daily clinical practice. Patients participating in a multicenter expanded access program (EAP) received induction treatment with ipilimumab 10 mg/kg. Maintenance doses were administered in patients who experienced clinical benefit or at physicians' discretion. Tumor assessment was evaluated per modified World Health Organization criteria at baseline, Week 12, Week 24, and Week 36. Adverse events (AEs) and immune-related AEs (irAEs) were collected according to Common Terminology Criteria for Adverse Events version 3.0. Thirteen pretreated patients with metastatic UM were treated at 6 European institutions. All patients received at least one dose of ipilimumab. Overall, no objective responses were observed; however, two patients had stable disease (SD), with a third patient achieving SD after initial progressive disease. Median OS as of July 1, 2011, was 36 weeks (range 2-172+?weeks). No grade 3/4 AEs of non-immune origin were reported. Three patients (23%) experienced grade 3 irAEs (1 thrombocytopenia, 1 diarrhea, and 1 alanine/aspartate aminotransferase elevation) that resolved with steroid therapy. The results indicate UM is a potential indication for ipilimumab treatment that should be further investigated in clinical trials.     

A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients

Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.     

Effect of tetrahydroaminoacridine on cognition,function and behaviour in Alzheimer's disease.

OBJECTIVE: To determine the efficacy of tetrahydroaminoacridine (THA) in Alzheimer''s disease. DESIGN: Randomized, double-blind, multiple crossover trial with three treatment periods, each consisting of 3 weeks of active drug therapy and 3 weeks of placebo administration. SETTING: Referral-based geriatric practice in a community hospital. PATIENTS: Thirty-four patients with moderate to severe Alzheimer''s disease. Subjects were included if they had stage 3 to 6 disease (as determined by the Reisberg scale) and had not been taking psychotropic drugs for at least 1 month and if informed consent had been obtained from the patients and their next of kin. INTERVENTIONS: Fifty to 100 mg of THA daily and matched placebo. RESULTS: Of the initial 34 patients 14 experienced liver toxicity and 3 gastrointestinal side effects during the study; however, all 22 who completed the study were able to tolerate at least the minimum dose. For the 22 patients there was no clinically or statistically significant effect of THA on cognition, functional status or behaviour. The results for individual patients showed no subgroup of THA-responsive patients. CONCLUSION: THA has no clinically important benefits in Alzheimer''s disease and is associated with appreciable toxic effects.     

Effect of injection of gonadotrophin-releasing hormone on testicular steroidogenesis in the hypogonadal (hpg) mouse

Hypogonadal (hpg) mice were injected once daily with 10 ng, 50 ng or 1 microgram GnRH for 5, 10 or 20 days or 12 times daily with 4.2 ng GnRH for 5 days. Basal and hCG-stimulated production in vitro of androstenedione, testosterone and 5 alpha-androstane-3 alpha,17 beta-diol (androstanediol) were measured by radioimmunoassay. All doses of GnRH increased testicular weight and in-vitro androgen production although seminal vesicle weights were unchanged and serum testosterone concentrations remained undetectable. After 5 days' treatment androstenedione and androstanediol were the dominant androgens produced, the latter indicating the presence of high levels of 5 alpha-reductase. By 20 days testosterone production was predominant after treatment with higher doses of GnRH. Total androgen production (androstenedione + testosterone + androstanediol) after 5 and 10 days was similar at all concentrations of GnRH used. After 20 days' treatment total androgen production was significantly greater with 50 ng GnRH/day than with 10 or 1000 ng/day. Multiple daily injections of 4.2 ng GnRH (total dose 50 ng/day) had no greater effect on androgen production in vitro compared to single daily injections of 50 ng. This suggests that under the conditions used in this study the testis does not require pulsatile release of the gonadotrophins. The pattern of [3H]pregnenolone metabolism was measured after 5 days injection of 50 ng GnRH/day. Compared to control hpg animals there was a significant increase in formation of C19 steroids, synthesis being solely through the 4-ene pathway. These results show that GnRH treatment of hpg mice will induce testicular steroidogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial

The aim of this study was to evaluate the efficacy and safety of mycophenolate sodium (MPS) in patients with primary Sjögren syndrome (pSS) refractory to other immunosuppressive agents. Eleven patients with pSS were treated with MPS up to 1,440 mg daily for an observation period of 6 months in this single-center, open-label pilot trial. At baseline, after 3 months, and after 6 months, we examined the clinical status, including glandular function tests, as well as different laboratory parameters associated with pSS. In addition, subjective parameters were determined on the basis of different questionnaires. Treatment with MPS was well tolerated in 8 of 11 patients. Due to vertigo or gastrointestinal discomfort, two patients did not complete the trial. One patient developed pneumonia 2 weeks after treatment and was withdrawn. In the remaining patients, MPS treatment resulted in subjective improvement of ocular dryness on a visual analogue scale and a reduced demand for artificial tear supplementations. However, no significant alterations of objective parameters for dryness of eyes and mouth were observed, although a substantial improvement of glandular functions occurred in two patients with short disease duration. In addition, treatment with MPS resulted in significant reduction of hypergammaglobulinemia and rheumatoid factors as well as an increase of complement levels and white blood cells. MPS promises to be an additional therapeutic option for patients with pSS, at least in those with shorter disease duration. Further investigations about the efficacy and safety of MPS in pSS have to be performed in larger numbers of patients.     

Phase I evaluation of coumarin (1,2-benzopyrone) and cimetidine in patients with advanced malignancies.

Fifty-four patients with advanced malignancies were treated on this phase I trial of coumarin and cimetidine. The dose of coumarin was escalated, with three patients treated at each dose level, while the cimetidine dose was held constant at 300 mg four times daily. Patients received coumarin alone as a single daily oral dose for 14 days; on day 15, cimetidine was added and both drugs were continued until progression of disease. This trial was initiated with patients receiving coumarin at 400 mg daily and closed at 7 g daily with four of five patients on this dose experiencing nausea and vomiting. Treatment was generally well tolerated over a wide range of coumarin doses. Symptomatic side effects were few, mild, and usually self limited. Side effects included insomnia, nausea, vomiting, diarrhea, and dizziness. Two patients withdrew from therapy because of daily nausea and vomiting. Typically, nausea, vomiting, and dizziness occurred 2.5-3 hours after a dose of coumarin. In most patients, these side effects abated spontaneously with continuation of therapy. There was no significant hematologic or renal toxicity. Hepatotoxicity occurred in only one patient and was manifested by asymptomatic abnormal elevations of serum hepatic transaminases. This toxicity was reversible upon interruption of therapy. Objective tumor regressions were observed in six patients with renal cell carcinoma. Responses occurred at coumarin doses ranging from 600 mg to 5 g daily. Coumarin is a relatively nontoxic, oral, outpatient therapy that warrants further investigations for the treatment of human malignancies. Because of its low toxicity, there is potential for combining coumarin with chemotherapeutic and/or biological agents in an attempt to improve on efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early,mild Parkinson's disease. Parkinson's Disease Research Group of the United Kingdom.

OBJECTIVE: To compare effectiveness of levodopa and levodopa combined with selegiline in treating early, mild Parkinson''s disease. DESIGN: Open, long term, prospective randomised trial. SETTING: 93 hospitals throughout United Kingdom. SUBJECTS: 520 patients with early Parkinson''s disease who were not receiving dopaminergic treatment. INTERVENTIONS: Treatment with levodopa and dopa decarboxylase inhibitor (arm 1) or levodopa and decarboxylase inhibitor in combination with selegiline (arm 2). MAIN OUTCOME MEASURES: Assessments of serial disability, frequency and severity of adverse events, and deaths from all causes. RESULTS: After average of 5-6 years'' follow up, mortality ratio in arm 2 compared with arm 1 was 1.57 (95% confidence interval 1.09 to 2.30), and difference in survival between the two arms was significant (log rank test, P = 0.015). Hazard ratio adjusted for age and sex was 1.49 (1.02 to 2.16), and after adjustment for other baseline factors it increased to 1.57 (1.07 to 2.31). Patients in arm 1 had slightly worse disability scores than those in arm 2, but differences were not significant. Functionally disabling peak dose dyskinesias and on/off fluctuations were more frequent in arm 2 than arm 1. During the trial the dose of levodopa required to produce optimum motor control steadily increased in arm 1 (median daily dose 375 mg at 1 year and 625 mg at 4 years), but median dose in arm 2 did not change (375 mg). CONCLUSIONS: Levodopa in combination with selegiline seemed to confer no clinical benefit over levodopa alone in treating early, mild Parkinson''s disease. Moreover mortality was significantly higher with combination treatment, casting doubts on its chronic use in Parkinson''s disease.