Tadalafil gehört zur Gruppe der PDE5-Hemmer und wirkt über eine hochselektive Blockade des Enzyms Phosphodiesterase Typ 5. Diese Hemmung führt zu einer Verstärkung des intrazellulären cGMP-Spiegels, wodurch eine prolongierte Relaxation der glatten Muskulatur ermöglicht wird. Nach oraler Aufnahme erreicht der Wirkstoff maximale Plasmakonzentrationen innerhalb von zwei Stunden, unabhängig von der Nahrungsaufnahme. Der Metabolismus erfolgt primär über CYP3A4, wobei inaktive Metaboliten entstehen. Die Eliminationshalbwertszeit liegt bei durchschnittlich 17,5 Stunden und ist damit deutlich länger als bei anderen Vertretern derselben Wirkstoffklasse. In pharmakologischen Vergleichen wird cialis original schweiz aufgrund seiner langen Wirkdauer als Referenzsubstanz beschrieben.
Treatment policy prepared by
Polycythemia Vera Dr. Jeannie Callum Updated May 2003 Introduction
PV is a chronic, clonal, myeloproliferative disorder, classically associated with an increase in red cellmass, leukocytosis, thrombocytosis, splenomegaly, thrombosis and bleeding.
2 in 100 000 incidence with peak age of 60.
20% of patients present with thrombosis and 30% develop in follow-up despite control of disease in along-term follow-up study of 1213 patients over a 20-year period, followed for a median of 6 years [1].
Thrombosis sites – stroke/TIA > AMI > DVT/PE > Peripheral arterial thrombosis > hepatic /portal vein
- Patients < 60 years AND no history of prior thrombosis – 20%/15 years (1%/yr)
- Patients > 60 years OR history of thrombosis – 40%/15 years (3%/yr)
Cause of death: 50% related to PV (24% arterial thrombosis, 15% AML, 5% venous thrombosis, 3%
major hemorrhage, 2% spent phase complications)
Highest rates of thrombosis = age > 70, history of thrombosis, active disease (> 6 phlebotomies/yr) [2]
Hepatic and portal vein thrombosis can be the first manifestation of the disease before rise in red
5% of patients with ET eventually fulfill the criteria for PV [4]
Symptoms
(a) Hyperviscosity – headache, dizziness, tinnitus, dyspnea, weakness, chest pain (b) Ruddy skin(c) Hemorrhage(d) Splenomegaly – 66%(e) Cyanotic extremities(f) Aquagenic pruritus(g) Erythromelalgia (esp. with extreme thrombocytosis)(h) Arterial & Venous thrombosis(i) Hypertension(j) Gastric and duodenal erosions and ulcers
Median survival of untreated PV is 18 months
15% will progress to myelofibrosis at 10 years, with median life-expectancy after the diagnosis of the
TSRCC Hematology Site Group Treatment Policies Definitions [5] The following criteria are used to make diagnosis of PV: A Criteria
1. Raised RBC mass (male > 36 ml/kg: females > 32 ml/kg)2. Absence of any secondary cause of erythrocytosis3. Bone marrow biopsy – increased cellularity, enlarged megakaryocytes with hyperploid nuclei or
clusters of megakaryocytes, increase reticulin (optional)
B Criteria
1. Platelet count > 4002. Granulocytes > 103. Splenomegaly by palpation or ultrasound4. Spontaneous EEC in absence of epo
A123 – early PV A123 + any B – overt PV A3 + B1 – Essential thrombocythemia Baseline Investigations
CBC and blood film Ferritin Creatinine Peripheral blood or BM for PCR for BCR-ABL to exclude CML Oxygen saturation RBC mass Ultrasound abdomen – if spleen not palpable BM – Confirmatory marrow histology should be established before embarking on cytoreductive therapy.
- BM shows hyperplasia of the myeloid, erythroid and megakaryocyte lineages, enlarged
megakaryocytes with hyperploid nuclei or clusters of megakaryocytes, increase reticulin
- Cytogenetics – 30% have a detectable clonal abnormality; del 20q is the most common
Management (Chemotherapy) Treatment Objectives
1. Longest survival2. Fewest complications of disease – thrombosis, bleeding, and myelofibrosis (MF)3. Fewest complications of treatment – AML, MDS, NHL, other malignancies
Goal – HCT > 0.45 Hazardous to aggressively phlebotomize at diagnosis – therefore isovolemic therapy for extreme erythrocytosis (Hct > 0.60) at diagnosis Important Studies 1. PVSG-01 RCT – phlebotomy vs. 32-P vs. chlorambucil [6]
Patients in the phlebotomy alone arm had an unacceptable risk of thrombosis vs. patients on 32-P or
chlorambucil had higher rates of AML, NHL, and carcinomas of the GI tract & skin; no differences inthe myelofibrosis rates between the three arms.
30% of all deaths were due to thrombosis;1/3 of all thrombotic events were fatal
Polycythemia Vera
A subsequent publication regarding this cohort was published in 1994 [7]
- Chlorambucil – 22/42 died due to malignancies - P32 – 60 patients; @ 15 years 78% alive @ 20 years 55% alive (risk of MF 19% at 15 yrs, 53%
- Phlebotomy – 56 patients; only 37/56 still on phlebotomy alone at 3 yrs due to
intolerance/thrombosis/thrombocytosis; at 9 yrs only 7/56 on phlebotomy alone (6 of 7 have MF)
2. PVSG-05 RCT – phlebotomy + 900 mg/d ASA + persantine 225 mg/d vs. 32-P – addition of antithrombotic agents failed to protect patients from thrombosis and increased the rate of life- threatening hemorrhage (20% vs. 5% at 2 yrs) [8] 3. PVSG-08 Cohort Study [9] – 51 patients with PV treated with hydroxyurea; in 80% Hct was controlled by 12 weeks and 88% control of thrombocytosis by 12 weeks, followed for 12 years (range 9-15 yrs), average dose 500-1000 mg/d
PVSG-08 compared to PVSG-01 (phlebotomy arm) – patients in the PVSG-08 cohort had a higher
rate of previous thrombosis (35% vs. 14%); reduced thrombosis rate in HU group with 8 years of f/ufrom 38% to 13%; trend toward an increased AML/MDS rate in HU arm (5.9% vs.1.5%)
4. Interferon Studies (three published studies):
54 patients treated with IFN mIU/d until response then 2.5 mIU/d – at 4 yrs, 72% maintained
response even after drug stopped (median follow-up 39 weeks); 13 % had to stop due to adverseeffects [10]
38 patients with PV 9 mIU/wk – 30% CR; 25% flu like symptoms, 13% had to stop due to late
32 patients with PV – 12 mU/wk x 1 yr, 9 mU/wk x 1 yr, then 12 mU/wk thereafter – reduced
thrombosis (1.8%/yr vs. 3.6% before treatment); reduced frequency of phlebotomy (0.49/month to0.19/month) [12]
5. Patients age > 65 [13] – study by the French PSG randomized patients to HU (10 mg/kg/d) or no HU after clinical remission induced by P-32 in 461 patients
OAS – trend toward a reduction in those patients on HU (9.1 vs. 11.2 years) vs. 11.4 for age matched
No difference in thrombosis rate (25% at 10 years) Greater risk of MDS/AML after 10 years in the HU arm (21% vs. 14%) No reduction in myelofibrosis – 30% at 15 years
6. Patients age < 65 [14] – n = 292 patients, randomized to HU (25 mg/kg then 10 mg/kg) vs. pipobroman (1.2 mg/kg then 0.5 mg/kg)
No difference in thrombosis rate (15% at 10 yrs), AML rate 20% at 15 yrs, or survival Better hematologic control with pipobroman and less MF with pipobroman (40 vs. 17% at 15 years) Higher mortality than age matched controls Drug not available in Canada or USA
7. Anagrelide [15] – n = 113 patients with PV; 70% response rate (plt < 600); average dose 2.4 mg/d; time to response 20 days; adverse: headache 25%, palpitations 15%, diarrhea 25%, fluid retention 15%, intolerance rate 13%; rate of bleeding/thrombocytopenia was 9/942 patients (1%)
Insufficient data on the impact of anagrelide on thrombosis rate in PV
TSRCC Hematology Site Group Treatment Policies TSRCC Policy < 70 YRS > 70 yrs
1. Hydroxyurea 15 mg/kg starting dose; increase by 5 mg/kg q6 wks as needed to maintain hematocrit <
2. Interferon 3 mU sc qMWF; commence at 1 mU sc qMWF and titrate up to 3 mU sc qMWF over 1
month; increase dose if required q8wks; maximum dose 5 mU/M2/d
3. Phlebotomy – start qwk until Hct < 0.45; then as needed4. Anagrelide 0.5 mg po qid; can titrate up to a maximum of 1.0 mg po qid; (Patients with renal and
hepatic dysfunction should be closely monitored during the start of therapy)
Perioperative Management
Patients should have good hematologic control of disease, if possible, for 6 weeks preop Bleeding time is not accurate in identifying patient at risk of perioperative bleeding [16] Preop ensure DIC work-up is negative (D-Dimers/Fibrinogen) – patients with evidence of DIC have a
higher incidence of perioperative bleeding. If possible surgery should be delayed until evidence ofDIC resolves. DIC may be responsive to hydroxyurea. Anticoagulants/Antiplatelet Agents
GISP Trial – Low dose ASA has been shown to be safe at 40 mg/d in safety trial of 112 patients
compared to placebo; no difference in thrombosis rate at 1 year follow-up [17]
Efficacy of low dose ASA un-proven – ongoing European ECLAP trial (dose 40 mg/d) High dose ASA – see PVSG-05 above, not useful
Recommendation:
Venous thrombosis – warfarin for 3 months minimum, may consider stopping warfarin once Hct
controlled; consider hypercoagulable assessment
Arterial thrombosis or ischemic heart disease – ASA 40-80 mg/d; rule out other causes of stroke
(perform dopplers or echocardiogram as needed)
Management of the Spent Phase
TRANSFUSIONS – no manipulation of cellular products required (i.e. irradiation or CMV-negative
SPLENOMEGALY – therapeutic options include – IFN, Hydroxyurea; splenectomy may result in an
increased risk of AL transformation (Although not confirmed by all investigators); splenic irradiation(200-300 cGy in 10-15 daily fractions) usually results in only temporary benefit (3-6 months) and maypreclude future splenectomy due to scarring
EXTRAMEDULLARY HEMATOPOEISIS (spinal cord, peritoneal or pleural cavities) – radiation Polycythemia Vera Outcome Data
(Managed with phlebotomy and/or hydrea; estimates based on all the reported studies referred below)
10 yrs (%) 15 yrs (%) Thromboembolism Myelofibrosis Acute Leukemia AML with HU tx Monitoring
Hydroxyurea – q2wkly blood counts x 8 weeks then q8 weeks Interferon –q2wkly blood counts x 8 weeks then q8 weeks Anagrelide – q2wks blood counts x 6 weeks then q8 weeks Phlebotomy alone – hematocrit q8 weeks
References Polycythemia vera: the natural history of 1213 patients followed for 20 years. Gruppo Italiano Studio Policitemia. Ann Intern Med, 1995. 123(9): p. 656-64.
Berk, P.D., et al., Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol, 1986. 23(2): p. 132-43.
Valla, D., et al., Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med, 1985. 103(3): p. 329-34.
Murphy, S., et al., Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol, 1997. 34(1): p. 29-39.
Michiels, J.J. and E. Juvonen, Proposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group. Semin Thromb Hemost, 1997. 23(4): p. 339-47.
Berk, P., et al., Treatment of polycythemia vera: a summary of clinical trials conducted by thePolycythemia Vera Study Group, in Wasserman LR, et al. (eds): Polycythemia vera and themyeloproliferative disorders. 1995, Saunders: Philadelphia, PA. p. 166-194.
Najean, Y. and J.D. Rain, The very long-term evolution of polycythemia vera: an analysis of 318 patients initially treated by phlebotomy or 32P between 1969 and 1981. Semin Hematol, 1997. 34(1): p. 6-16.
Tartaglia, A., et al., Aspirin and persantine do not prevent thrombotic complications in patients with polycythemia vera treated with phlebotomy. Blood, 1981. 58(suppl 1, abstract 872): p. 240a.
Donovan, P.B., et al., Treatment of polycythemia vera with hydroxyurea. Am J Hematol, 1984. 17(4): p. 329-34.
Gilbert, H.S., Long term treatment of myeloproliferative disease with interferon-alpha- 2b: feasibility and efficacy. Cancer, 1998. 83(6): p. 1205-13.
Foa, P., et al., Long-term therapeutic efficacy and toxicity of recombinant interferon- alpha 2a in polycythaemia vera. Eur J Haematol, 1998. 60(5): p. 273-7.
Heis, N., et al., The effect of interferon alpha on myeloproliferation and vascular complications in polycythemia vera. Eur J Haematol, 1999. 62(1): p. 27-31.
Najean, Y. and J.D. Rain, Treatment of polycythemia vera: use of 32P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. The French Polycythemia Study Group. Blood, 1997. 89(7): p. 2319-27.
Najean, Y. and J.D. Rain, Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood, 1997. 90(9): p. 3370-7.
Petitt, R.M., M.N. Silverstein, and M.E. Petrone, Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders. Semin Hematol, 1997. 34(1): p. 51-4.
Murphy, S., et al., Template bleeding time and clinical hemorrhage in myeloproliferative disease. Arch Intern Med, 1978. 138(8): p. 1251-3. Low-dose aspirin in polycythaemia vera: a pilot study. Gruppo Italiano Studio Policitemia (GISP). Br J Haematol, 1997. 97(2): p. 453-6. TSRCC Hematology Site Group Treatment Policies
Pediatric Pulmonology 34:384–387 (2002)Pulmonary Alveolar Microlithiasis in Childhood:Stipan Jankovic, MD, PhD,1* Neven Pavlov, MD, PhD,2 Ante Ivkosic, MD,3 Ivana Erceg, MD,3Meri Glavina-Durdov, MD, PhD,4 Jadranka Tocilj, MD, PhD,5 Slavica Dragisic-Ivulic, MD,2Summary. This report describes a case of pulmonary alveolar microlithiasis that was diagnosed inan 8.5-year-old girl by high-resoluti
CURRICULUM VITAE Name Alexandre Valério de Mendonça Institutional address Laboratory of Neurosciences, Faculty of Medicine, 1649-028 Lisbon Telephone (351)217985183 Telefax (351)217999454 Email [email protected] Present position, institution, starting date Previous positions, institutions, dates Other scientific areas of interest Recent organization of scientific meeti