Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
A pilot phase II study of digitoxin for Androgen-Independent Prostate Cancer (AIPC) Principal Investigators: Johan Haux and Hans Hedelin Departments of Medicine and Surgery KSS SE-541 85 Skövde Sweden Table of contents 1. 1.1. 1.2. 1.3. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Introduction Background Digitalis and cancer Rationale Objective Study design Inclusion criteria Exclusion criteria Concurrent medication Precautions Study drug Objective response Primary endpoint Secondary endpoint Statistical considerations Criteria for removal from protocol treatment Adverse events Patient information and informed consent References Flow chart Clinical Research File 1. Introduction 1.1. Background Prostate cancer is the most common cancer among men in Sweden. Every year about 7600 men are diagnosed with prostate cancer. The incidence has increased the last years mainly due to increased diagnostic activity and an increased life span of the population (1). Since more than 50 years androgen ablation has been a cornerstone in the treatment. Most patients with metastatic disease will initially respond to endocrine therapy, however, the effect is temporary and the median time of duration of response is about 18 months. Survival time after secondary progress, i.e. when the disease has become androgen independent, is approximately 1 year (1). Until recently no clinical studies had shown any impact on survival that could be attributed to second line therapy. In 2004 it was reported from two studies, TAX 327 and SWOG 9916, that taxotere has significant effects in men with hormone independent prostate cancer. Prior to taxotere, no chemotherapy drug has ever shown a survival benefit for men with prostate cancer resistant to hormone therapy. The TAX 327 study showed that the median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel (2). In the SWOG 9916 study it was shown that in an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test (3). Thus, we have a lot more to wish concerning effectiveness of drugs for this disease. Most often patients with AIPC present without measurable disease. Thus, conventional criteria for objective response are frequently not applicable. On the other hand biochemical response can be assessed by repeated serum PSA (S-PSA) measurements. Actually, eligibility and response guidelines for phase II clinical trials in these patients have been developed by the Prostate-Specific Antigen (PSA) Working group (4). PSA has been shown to be useful in this setting when new treatments are evaluated in patients with AIPC. 1.2. Digitalis and cancer During our work on anti-cancer molecules utilized by the innate immune system in humans, we found a rationale to examine the effects of digitalis on malignant cells (5,6,7). Since ancient times reports have indicated that digitalis may have anti-cancer effects and in our laboratory studies digitalis induced apoptosis in different types of cancer cells in clinically relevant concentrations (8,9). For prostate cancer we used 4 different human cell lines, three androgen independent (DU-145, PC-3 and TSU – prl) and one androgen dependent LNCaP. These four cell lines were sensitive for digitoxin (10). The digitoxin treated prostate cancer cells that survived also accumulated in the G2M phase of the cell cycle. That might indicate that they will be more sensitive for irradiation as we have shown for breast cancer cell lines (11). The cell death induction by digitoxin is not dependent on functional p53. Subsequent studies from several different institutes, among them the MD Anderson Cancer Center in Texas, have confirmed that prostate cancer cells are sensitive for digitalis (12,13,14) Further, we found that digitoxin seems to be the most potent of the clinically used digitalis derivatives concerning the anti-cancer effects. That has also been supported by other studies (15). Since several decades the inhibition of the ubiquitous Na+/K+ATP:ase has been the well known working mechanism of digitalis (16). Interestingly, already in 1993 it was proposed that the Na+/K+ATP:ase might be the actual androgen receptor of the prostate (17). It is evident that not just the inhibition of the Na+/K+ATP:ase can explain all the anticancer effects (18). Recently we have learnt much more concerning mechanisms of action of digitalis. Digitoxin is a potent inhibitor of the transcription factor NF-kB and inhibits production of pro-inflammatory cytokines such as TNF-a and IL-8 (19,20). The last years we have learnt that infection/inflammation and the associated proinflammatory cytokines have great impact, not only on well known inflammatory diseases such as Mb. Crohn, ulcerative colitis, but also on cancer (21,22). Inhibition of these pro-inflammatory cytokines also inhibit angiogenesis (23). Thus, drugs that inhibit NF-kB, such as thalidomide, and now digitoxin, are of interest for several, seemingly diverse diseases, but on the molecular level dependent on some of the same mechanisms (24). The latest screening procedures on gene level for potential anti-cancer drugs also point out digitoxin (25). The common picture is that drug candidates that exhibit anti-cancer effects in vitro fail in clinical cancer studies. Thus, to learn more about eventual impact on cancer we performed a study to examine cancer in a population taking digitoxin for cardiac conditions. However, the age is high and the morbidity and mortality due to cardiac disease are high in the population taking digitoxin. Eventual anti-cancer effects would easily “drown” in this study set-up. Despite that, an anti-cancer effect of digitoxin was detected for kidney/urinary tract cancers and leukemia/lymphoma (26). The indications for digitoxin treatments today are cardiac congestion and supraventricular tachyarrhtmias. Studies on healthy volunteers that take digitoxin show a decrease of diastolic blood pressure and heart rate, especially during rest (27). Thus, digitoxin in doses used for the cardiac indications seems not to give any alarming side effects in humans without cardiac problems (28). The anti-cancer effects of digitoxin are dose-dependent; the higher the dose, the more potent the anti-cancer effects. Thus, for cancer treatment as high concentrations as possible, without inducing toxic symptoms, should be used. For practical reasons one should aim at a concentration just beneath the recommended upper limit for treatment of cardiac disease (about 25 ng/l) (29). 1.3. Rationale There are no curative therapies for patients with androgen independent prostate cancer (AIPC). New therapies for these patients are urgently needed. Digitoxin shows potent anti-cancer activities in androgen dependent and independent prostate cancer cell lines. Digitoxin targets many of the mechanisms of interest for new anti-cancer agents and may represent a novel type of drug therapy for prostate cancer that should be evaluated in clinical studies. 2. Objective Investigate if digitoxin has an effect on hormonal refractory carcinoma of the prostate. The primary endpoint is the proportion of complete or partial responders as determined by repeated S-PSA assessments. 3. Study design This is a pilot phase II, non-randomized, single-arm study of digitoxin for AndrogenIndependent Prostate Cancer (AIPC). In the first stage we plan to accrue 15 patients. If no responder is found among these, the study is closed and the drug is regarded as inactive for this indication. If one or more patients respond, additional 15 patients will be accrued, see section 12 for statistical considerations. The patients will start with the same dose of digitoxin. Digitoxin tablets, 0.1 mg, will be taken two tablets in the morning and three in the evening day one and day two, thus a total amount of 1.0 mg digitoxin the first two days. On day three a daily maintenance dose of 0.1 mg will be started. If at four weeks there is no evidence of digitalis toxicity and the blood concentration is < 20 ng/ml, the maintenance dose may be increased to aim at a steady-state concentration just below the upper recommended limit, 25 ng/ml. Serum digitoxin levels will be obtained just before daily dose every four weeks or whenever there is any sign of digitalis toxicity. Therapeutic plasma concentration of digitoxin is 15-25 ng/ml (29). There will be one scheduled visit to nurse or physician every 4th week, and whenever needed. Physical examination will performed at all visits and according to standard routines. Laboratory studies included a complete blood count, electrolytes, creatinine, glucose, albumin, calcium, alkaline phosphatase, bilirubin, ASAT, ALAT, S-PSA and S-digitoxin will be checked during the study at different time intervals, see section 17, flow chart. The patients will be treated with digitoxin according to the schedule until progression of the AIPC, unacceptable side effects occur, or until death, whatever comes first. Efficacy assessments will include analysis of S-PSA, evaluation of eventual measurable tumors clinically and with radiological examinations, the patients’ performance status and weight. Pain medication will be analyzed. Eventual effects on skeletal lesions will also be followed by diagnostic radiology. 4. Inclusion criteria 4.1. Age 50-80 years 4.2. Life expectancy greater than 3 months 4.3. Histologically proven carcinoma of the prostate (any T or N category) with evidence of progression following primary hormonal treatment, i.e. hormone resistant. 4.4. S-PSA level at trial entry should be greater than or equal to 5 ng/ml. S-PSA progression should be documented by two consecutive increases in S-PSA before enrollment. Each increase in S-PSA should be at least one unit and it should be at least 4 weeks between the samples. 4.5. The patient has WHO performance status 0-2, for definition see Appendix. 4.6. Patient is receiving hormone therapy (i.e. an LHRH agonist and/or anti-androgen) and/or orchiectomy has been performed. Ongoing endocrine treatment should continue. 4.7. Patients must be physically, mentally and emotionally able to give informed consent. 4.8. Signed informed consent has been given. 4.9. Prior radiation therapy will be allowed, but radiotherapy during the study is not allowed. No concurrent other chemotherapy is given in the study. 5. Exclusion criteria 5.1. The patient has a relevant concurrent disease or baseline laboratory results, which put the patient at risk to take digitoxin. 5.2. Patients with heart disease already on a cardiac glycoside are not eligible. 5.3. No other prior malignancy is allowed except for adequately treated basal cell cancer. 6. Concurrent medication All concomitant medications will be recorded in the patient file from dosing day 1 until the end of treatment. Anti-androgen therapy that the patient is on at study entrance should be continued. No new drugs should be given, except analgesics, chronic treatments for concomitant medical conditions, or agents required for life-threatening medical problems. The hormonal treatment the patient is on at study entrance should be continued. 7. Precautions 7.1. Electrolyte imbalance: Calcium; Hypocalcaemia from any cause predisposes the patient to digitalis toxicity. Potassium; Hypokalemia sensitizes the myocardium to digitalis. Therefore, it is important to maintain normal serum potassium levels. In general avoid rapid shifts in serum potassium or other electrolytes. Magnesium; Hypomagnesaemia may predispose to digitalis toxicity. 7.2. Cardiac Problems Patients with incomplete AV block may develop advanced or complete heart block. Patients with acute myocardial infarction, severe pulmonary disease, or advanced heart failure may be more sensitive to digitalis and prone to rhythm disturbances. 7.3. Contraindications Previous toxic responses to digitalis preparations, ventricular fibrillation, ventricular tachycardia, or allergy to digitalis are contraindications. 7.4. Drug Interactions A variety of drugs may affect the serum concentration of cardiac glycosides via various mechanisms; Beta blockers: These drugs may inhibit AV nodal conduction and can result in complete heart block. Potassium-sparing diuretics: Spironolactone may increase or decrease toxic effects of digitalis glycosides. Changes cannot be predicted and patients should be carefully monitored. Sympathomimetics: Concomitant use with digitoxin can increase the risk of cardiac arrhythmias because enhanced ectopic pacemaker activity. Thiazide and loop diuretics and amphotheracin B increase potassium loss, possibly resulting in hypokalemia and will be used with caution. Thyroid hormones: Thyroid hormones may decrease the therapeutic effectiveness of cardiac glycosides. 8. Study Drug 8.1. Digitoxin is a single cardiac glycoside extracted from the leaves of Digitalis purpurea. Digitoxin is 8.2. Structural formula 8.3. Source of Drug: We purchase it from Nycomed. 8.4. Pharmacology More than 200 years ago, William Withering introduced the rationale use of Foxglove extracts, digitalis for cardiac conditions. Digitoxin is extracted from Digitalis purpurea. The activity of digitoxin on the myocardium is dose-related and involves a direct action on myocardium, the specialized conduction system, and indirect actions mediated by the autonomic nervous system. These indirect actions involve a vagomimetic action that results in increased carotid sinus nerve activity. Digitoxin has a direct inotropic effect on the myocardium The cellular basis for the inotropic effects appears to be inhibition of sodium and potassium ATPase that increase calcium available to activate the contractile proteins, actin and myosin. The mechanism behind the anti-cancer effects of digitalis is currently under investigation. However, we already know that digitalis interacts with signaling mechanism involving tyrosinase receptors in a complex way, and inhibit the transcription factor NF-kB. Apoptosis is induced in an array of different human cancer cells and angiogenesis is inhibited. Digitoxin is greater than 90% absorbed following oral administration. Concurrent food intake slows absorption of digitoxin but is complete, except when taken with meals high in bran fiber. Cardiac glycosides are widely distributed in tissues. High digitoxin concentrations are found in the myocardium, skeletal muscle, liver, brain and kidneys. 50-80% of administered digitoxin is degraded by the liver to inactive metabolites that are excreted by the kidneys. About 8% is converted to digoxin. Digitoxin has a serum half life of 7-9 days. As a result, clinical effects do not fully develop until steady state levels (approximately 5 half lives) are achieved, and 3-5 weeks are needed for complete dissipation of digitoxin effects following discontinuation. Digitoxin is greater than 95% bound to plasma proteins. The bound drug is in equilibrium with the unbound fraction. At equilibrium, the concentrations in cardiac tissue are 15 to 30 times those in the plasma; the concentration in skeletal muscle is about half that in the heart. 9. Objective response Responses will be categorized according to biochemical response by PSA assessments. The event of progression and time to progression are defined based on PSA progression (biochemical progression), objective progression (new metastases) or subjective progression whatever comes first. Any response has to be confirmed after 4 weeks. A. Biochemical response Complete S-PSA response (CR) Normalisation of PSA (less than 5 ng/ml) on two successive evaluations (minimum interval of 4 weeks). Partial response (PR) Decrease from baseline S-PSA value by 50% or more, but without normalization on two consecutive evaluations with 4 weeks interval. Progression (PD) Increase from nadir S-PSA during digitoxin treatment by ≥ 50% at two consecutive evaluations with 4 weeks interval. Stable disease (SD) S-PSA change which does not qualify for CR, PR or progression. B. Subjective effect At each clinical visit WHO performance status is assessed. Subjective response: increase of performance status Subjective progression: deterioration of the performance status The type and amount of analgetics are recorded and will also be analyzed. 10. Primary endpoints The primary endpoints are; A. The proportion of complete or partial responders as determined by S-PSA assessments, i.e. response rate: That proportion of patients who responded to treatment with complete response (CR) or partial response (PR). B. Survival; time to death: from date of registration to date of death due to any cause. 11. Secondary endpoints Time to response: from date of registration to date of first observation of response of disease. Time to progression; from date of registration to date of first observation of progressive disease. 12. Statistical Considerations This is a pilot phase II, non-randomized, single-arm study. The purpose is to assess the eventual anti-tumor activity of digitoxin in a population of patients with AIPC. A two-stage design is used to minimize the expected number of patients treated in the event that the regimen proved to be successful or disappointing (30). The regimen should be rejected if the estimated true response rate is less than 5 % and would be accepted as active if the true response rate is greater than 20%. In the first stage we accrue 15 patients. If no responder is found among these, the study is closed and the drug is regarded as inactive for AIPC. If one or more patients respond, additional 15 patients will be accrued. If three or fewer patients among these 30 respond, the drug will be regarded as inactive, if four or more respond we consider the drug is promising. An alpha error of 0.05 and a beta error of 0.10 are used; thus, the null hypothesis is that the true response rate is ≤5% versus the alternative hypothesis that the true response is ≥20%. With this design, the probability of rejecting the null hypothesis when it is true is 0.058 and the power is 0.865 when the response probability is 20 %. Kaplan-Meier estimates of time to progression and overall survival will also be determined. 13. Criteria for removal from protocol treatment. 13.1. Progression of disease. 13.2. Unacceptable toxicity requiring discontinuation of digitoxin. 13.3. The patient may withdraw from the study at any time for any reason. All reasons for discontinuation of treatment must be documented in the patient record. 14. Adverse events 14.1. Definition of adverse event An adverse event (AE) is any unintended symptom or medical complaint or clinically relevant change in a laboratory test that is considered drug related or not. Progression of the prostate cancer is not considered AE and should not be entered on the AE form, however, clinical symptoms, whether or not related to AIPC are considered as AE:s. Serious Adverse Event (SAE) definition; 1. Death 2. Permanent or severe disability 3. In-patient hospitalization (hospitalization for study purposes is not to be considered a serious adverse event.) The investigator shall report all Serious Adverse Events (SAE:s) immediately. The initial report shall be promptly followed by detailed, written reports. The investigator is responsible for the prompt notification to the competent Authority (Pharmacovigilance Unit, Medicinal Product Agency, P.O. Box 26, S-751 03 Uppsala, Sweden, phone: +46 18175600, fax: +46 185485666) and the Ethics Committee (Regionala etikprövningsnämnden i Göteborg, Box 100, 405 30 Göteborg). The investigator has to keep detailed records of all Adverse Events (AE:s) reported to him and to perform an evaluation with respect to seriousness, causality and expectedness. By the question “Have you had any health problems since your previous visit?” adverse events may be obtained. Adverse events will be recorded with information about seriousness, date of onset, duration, maximum intensity, action taken and outcome. The causal relationship with the study drug will be assessed, and classified as; 1. Probable: Time relationship exists. No other causative factors. 2. Possible: Time relationship exists, but other causative factors may exist. 3. Unlikely: Time relationship non-existent or other factors certain or probable to have been causative. 4. Cannot be classified: Insufficient information available for evaluation. 5. Overdose: The symptoms are related to overdose of the drug. All changes in the patients´ medication such as change of dose or new medication should be recorded in the patient record. Serious Adverse Events, SAE: Serious adverse events should be reported by the investigator to the competent authority within 1 working day, by phone, fax or e-mail, se above for addresses. 15. Patient information and informed consent Patient information och informerat samtycke. Digitoxin är en form av digitalis som ursprungligen kommer från Digitalis purpurea (Fingerborgsblomman). Preparatet används vid hjärtsvikt och hjärtrytmrubbningar. Det finns beskrivningar alltsedan medeltiden som tyder att digitalis kan ha effekt vid cancersjukdomar. De senaste åren har vi och andra också visat att prostata cancer celler är känsliga för digitoxin i koncentrationer som inte har några negativa effekter på kroppen i övrigt. Dessa försök är gjorda i laboratorium i cellkulturer. Ett tidigt tecken på att prostata cancer cellerna blir motståndskraftiga mot hormonell behandlingen är att PSA (prostata specifikt antigen) värdet stiger. I den situationen finns det idag ingen etablerad behandling som visat sig vara effektiv. Avsikten med denna studie är därför att undersöka om behandling med digitoxin i tablett form kan motverka prostatacancern. För att undersöka om digitoxin har denna effekt kommer halten av PSA i serum att regelbundet följas. Den pågående hormonella behandlingen kommer inte att avbrytas Om man inte har någon hjärtsjukdom och normala salthalter i blodet ger digitoxin sällan några biverkningar. Alla som ingår i studien kommer också att noga undersökas (inklusive EKG, elektrokardiogram) för att se att det inte föreligger några risker med att ta digitoxin. Blodprover (koncentrationen av digitoxin och PSA-värdet) kommer att undersökas med 4 veckors mellanrum. Laboratorieförsöken har visat att ju högre digitoxin koncentration desto starkare är effekten mot cancer cellerna. För höga koncentrationer digitoxin i blodet ger allvarliga biverkningar. Digitoxin koncentrationen i blodet skall därför helst hållas högt inom det terapeutiska intervallet, alltså mellan 20-25 ng/ml, därför görs upprepade mätningar av digitoxin koncentrationen och dosen digitioxin som tas justeras. Om PSA värdet stiger eller om det finns andra tecken på att prostatacancern växer, avbryts behandlingen Samma symptomlindrande behandling som om man inte var med i studien kommer att ges vid behov. All information som samlas in under studien kommer att bevaras med samma sekretessregler som gäller för den vanliga sjukhusjournalen. Informationen kommer att avidentifieras när den presenteras. Huvudansvarig Johan Haux, leg.läk., med.dr. KSS Tel:0500-431000 Informerat samtycke "Digitoxin behandling som prostata cancer behandling." Jag har fått muntlig information och läst igenom den skriftliga informationen och förstått vad studien går ut på. Jag ger härmed mitt samtycke till att deltaga i studien. Mitt deltagande är helt frivilligt och jag kan när som helst dra mig ur utan att behöva ange skäl till det. Ort och datum Namnteckning 16. References 1. Vårdprogram för Prostatacancer, 2004 (PDF-format), Onkologist centrum södra sjukvårdsregionen. http://www.ocsyd.lu.se/Vardprog/vardmeny.html 2. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. 3. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. 4. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Wilding G, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 1999 Nov;17(11):3461-7. 5. Medvedev AE, Johnsen AC, Haux J, Steinkjer B, Egeberg K, Lynch DH, Sundan A, Espevik T. Regulation of Fas and Fas-ligand expression in NK cells by cytokines and the involvement of Fas-ligand in NK/LAK cell-mediated cytotoxicity. Cytokine. 1997 Jun;9(6):394-404. 6. Johnsen AC, Haux J, Steinkjer B, Nonstad U, Egeberg K, Sundan A, Ashkenazi A, Espevik T. Regulation of APO-2 ligand/trail expression in NK cells-involvement in NK cell-mediated cytotoxicity. Cytokine. 1999 Sep;11(9):664-72. 7. Haux J, Johnsen AC, Steinkjer B, Egeberg K, Sundan A, Espevik T. The role of interleukin-2 in regulating the sensitivity of natural killer cells for Fas-mediated apoptosis. Cancer Immunol Immunother. 1999 May-Jun;48(2-3):139-46. 8.Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses. 1999 Dec;53(6):543-8. Review. 9. Haux J, Lam M, Marthinsen ABL, Strickert T, Lundgren S. Digitoxin, in non toxic concentrations, induces apoptotic cell death in Jurkat T cells in vitro. Z-ONKOL. Zeitschrift für Onkologie. 1999; 31/1 (14-20). 10. Haux J, Solheim O, Isaksen T, Angelsen A. Digitoxin, in non-toxic concentrations, inhibits proliferation and induces cell death in prostate cancer cell lines. Z-ONKOL. Zeitschrift für Onkologie. 2000; 32/1 (11-16) 11. Haux J, Marthinsen ABL, Gulbrandsen M, Alfredsen AS, Johansen H, Strickert. Digitoxin sensitizes malignant breast cancer cells for radiation in vitro. Z Onkol 1999;31: 61-65 12. McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA. Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res. 2000 Jul 15;60(14):3807-12. 13. Yeh JY, Huang WJ, Kan SF, Wang PS. Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J Urol. 2001 Nov;166(5):1937-42. 14. Smith JA, Madden T, Vijjeswarapu M, Newman RA. Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochem Pharmacol. 2001 Aug 15;62(4):469-72. 15. Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Claeson P. Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs. 2001 Jun;12(5):475-83. 16. Pharmacotherapy: “A Pathophysiologic Approach” Joseph T. Dipiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey Appleton & Lange; 3rd edition 1998 17. Farnsworth WE. Na+,K(+)-ATPase: the actual androgen receptor of the prostate? Med Hypotheses. 1993 Oct;41(4):358-62. Review. 18. Haux J. Digitalis; impinges on more than just the (ion-) pump. Med Hypotheses. 2002 Dec;59(6):781-2. 19. Srivastava M, Eidelman O, Zhang J, Paweletz C, Caohuy H, Yang Q, Jacobson KA, Heldman E, Huang W, Jozwik C, Pollard BS, Pollard HB. Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7693-8. 20. Yang Q, Huang W, Jozwik C, Lin Y, Glasman M, Caohuy H, Srivastava M, Esposito D, Gillette W, Hartley J, Pollard HB. Cardiac glycosides inhibit TNF{alpha}/NF-{kappa}B signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9631-6. 21. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001 Feb 17;357(9255):539-45. Review. 22. Haux J. Infection and cancer. Lancet. 2001 Jul 14;358(9276):155-6. 23. Gordon JN, Goggin PM. Thalidomide and its derivatives: emerging from the wilderness. Postgrad Med J. 2003 Mar;79(929):127-32. Review. 24. Haux J Old drugs – new uses http://pmj.bmjjournals.com/cgi/eletters/79/929/127#233 25. Johnson PH, Walker RP, Jones SW, Stephens K, Meurer J, Zajchowski DA, Luke MM, Eeckman F, Tan Y, Wong L, Parry G, Morgan TK Jr, McCarrick MA, Monforte J. Multiplex gene expression analysis for high-throughput drug discovery: screening and analysis of compounds affecting genes overexpressed in cancer cells. Mol Cancer Ther. 2002 Dec;1(14):1293-304. 26. Haux J, Klepp O, Spigset O, Tretli S. Digitoxin medication and cancer; case control and internal dose-response studies. BMC Cancer. 2001;1(1):11. 27. Grossmann M, Jamieson MJ, Kirch W. Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers. Eur J Clin Invest. 1998 Sep;28(9):701-6. 28. Grossmann M. Effects of cardiac glycosides on 24-h ambulatory blood pressure in healthy volunteers and patients with heart failure. Eur J Clin Invest. 2001;31 Suppl 2:26-30. Review. 29. http://www.felleskatalogen.no 30. Gehan EA. Update on planning of phase II clinical trials. Drugs Exp Clin Res. 1986;12(1-3):43-50. 18. CRF Clinical Research File ”En fas 2 studie av tablett behandling med digitoxin för hormonrefraktär prostata cancer.” Besöks nummer: dato: WHO perfomance status (märk av); 0.Fully active, able to carry out all pre-disease activities without restriction. 1. Restricted in strenuous activity but ambulatory and able to carry out any light work or pursue sedentary occupation. 2. Ambulatory and capable of all self-care but unable to carry out any light work. Up and about more than 50% of waking hours. 3. Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 4. Completely disabled. Unable to carry out any self-care and confined totally to bed or chair Vikt: Blodtryck: Lab. status (se ”flow chart”): PSA värde: Digitoxin koncentration: Eftersök eventuella ”adverse events”; ”Har du haft några hälsoproblem sedan förra besöket?”