Archive.tsu.edu

A Glimpse at Avandia
(rosiglitazone)
Drug Information Resident
Ketal Patel Pharm.D. Drug Information Resident Texas Southern University’s Drug Information Center has a Rosiglitazone (Avandia®), a thiazolidinedione on the market new Drug Information Resident for the 2010-2011 year. Dr. since 1999, is FDA indicated for monotherapy in conjunction Ketal Patel graduated Cum Laude from Texas Southern University College of Pharmacy and with diet and exercise as well as combination therapy for the Health Sciences with a Pharm. D. degree in treatment of Type II Diabetes Mellitus. It has also been used May of 2010. Her interests lie in research and off label for the treatment of Polycystic Ovarian Syndrome. Rosiglitazone is associated with adverse effects such as joining the academic team, Dr. Patel hopes to fractures, and cardiovascular effects such as increased HDL, bring the Drug Information Center to new LDL and total cholesterol. Due to the serious nature of the heights! She looks forward to serving her cardiovascular related adverse events, rosiglitazone carries a community and dedicated herself to the ever-growing black box warning for either initiating or exacerbating pharmacy profession. Dr. Patel is available at the TSU DIC on M-F from 8:30-4:30 to answer DI questions from health care congestive heart failure with possible increased risk of myocardial infarction or angina. Symptoms associated with congestive heart failure include weight gain, edema and Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) study results Services Offered by the Drug Information Center
related to increased risk of cardiovascular events to the FDA for review. In 2007, an additional study showed increased risk of heart failure with rosiglitazone. At the same time, the FDA added a black box warning for congestive heart failure to the Joint Commission Accreditation Assistance drug while keeping it on the market. A recent re-analysis of the RECORD study published in January 2010 showed 61 cases of heart failure events in the rosiglitazone treatment group versus 29 cases in the control group, approximately a two-fold increase (P= 0.0010).2 In addition, a final updated meta- analysis published June 2010 showed results strikingly similar to previously published studies forcing the FDA to meet through its advisory committee and decide whether to keep the drug on the market, add restrictions or remove it altogether. INSIDE THIS ISSUE:
The recently published meta-analysis included all randomized clinical trials with a minimum duration of 24 weeks conducted till February 2010 which totaled 56 trials with over 35,531 patients of which 19,509 received rosiglitazone while 16,022 Mycophenolate Mofetil for the Treatment of received control therapy. Data sources included extensive Chronic Dermatitis: An Open-label Study of 16 Patients searches on Medline, FDA and GlaxoSmithKline clinical trial registry sites. Trials fell into 3 categories: Group 1 consisting of 5 studies, four of which were published by GSK initially for drug Chlorhexidine-Alcohol versus Povidone-Iodine approval, Group 2 consisting of 48 trials listed in the GSK registry 35 of which were unpublished, and Group 3 consisting Atorvastatin as a potential anti-malarial drug: of 3 large prospective trials all of which were published. The in vitro synergy in com binational therapy with primary outcomes for myocardial infarction using the Cochrane quinine against Plasmodium falciparum. Q statistic were 30.3 (P=0.87) without inclusion of the RECORD study and 29.7 (P=0.27) with inclusion of the study. The primary outcomes for cardiovascular mortality were 16.2 (P=0.91) with RECORD and 12.8 (P=0.97) without RECORD. Using the Peto Odds Ratio (95% CI) the risk for MI including associated with the procedure. Various reports on the RECORD was 1.28 compared to 1.39 without. In addition, the incidence of cyst formation state occurrences of 8 to 53%. risk for cardiovascular mortality including RECORD was 1.03 Despite the variation in reported incidences of cyst formation, compared to 1.46 without. The meta-analysis showed research has clearly associated the occurrence of this adverse comparative results to those previously found by FDA and effect with the IVF procedure as a result of the gonadotropin those found in the unpublished clinical trials by GSK of agonist employed.2 Gonadotropin agents work by stimulating increased risk of myocardial infarction with the use of the development of multiple follicles in women who are rosiglitazone. Increased cardiovascular mortality with use of ovulating and are used as part of IVF or assisted reproductive rosiglitazone was not shown.1 In July 2010, the FDA advisory technology (ART). In particular these agonists increase the panel consisting of the Endocrinologic and Metabolic Drugs effects of follicle stimulating hormone (FSH) and luteinizing and the Drug Safety and Risk Management advisory hormone (LH) thereby stimulating the development and committees, voted 12:10 to remove rosiglitazone from the maturation of the ovarian follicle and causing ovulation.3 market or keep it with tighter restrictions. The FDA has stated it Monitoring for the effects of these agents include checking would take the recommendations by the panel seriously and serum estradiol concentrations as well as FSH and LH levels would decide on an appropriate course of action. However, a throughout the procedure.4 While the mechanism by which few important key facts to consider are that no large outcomes these cysts are formed is unknown, researchers partly attribute clinical trials have been conducted on rosiglitazone. The only cyst formation to the direct effect of GnRH agonists on ovaries. available studies are those of non-inferiority trials. Strength of Ovarian cysts are fluid-filled sacs which reside on the surface study results should also be taken into consideration. The of ovaries. They are classified as either functional or non- previously published study in 2007 and the meta-analysis functional.5 Functional cysts are those to which increased follow-up were conducted by Dr. Steven E. Nissen from the estradiol levels either in the serum or aspirated cyst fluid is chairman of cardiovascular medicine at the Cleveland Clinic attributed. They are follicular or luteal in nature. These cysts who is a paid consultant for pharmaceutical companies are essentially considered to be normal given that they including Takeda and GSK.5 As of now the road for normally self- resolve after a few menstrual cycles. However rosiglitazone and its impact on pharmacy remains uncertain they can pose barriers to conception in reproductively challenged females. Non-functional cysts such as dermoid or endometrial cysts can become abnormal and require close Nissen SE, Wolski K. Rosiglitazone Revisited: An Updated Meta- monitoring. Physicians often perform CT scans or MRIs to Analysis of Risk for Myocardial Infarction and Cardiovascular detect the presence of ovarian type (or any) cysts.5 Mortality. Arch. Intern. Med. June 2010. E1-E11 Conservative management of functional cysts include the use Komajda M, McMurray J, Beck-Nielson H, et al. Heart Failure events with rosiglitazone in type 2 diabetes: data from the of pain medications in complicated cases in which cysts RECORD clinical trial. Eur Heath J.2010; 31:824-831. rupture and exhibit profuse and prolonged bleeding. Also Lexi-Comp Online Web site. http://www.crlonline.com. Accessed included in this treatment method is laparoscopic surgery to remove the cysts or the entire ovary in severe instances. FDA Web site. http://www.fda.gov. Accessed July 12, 2010 Contraceptives have also been employed to prevent the formation of ovarian cysts though this practice is not fully http://www.abcnews.go.com. Accessed July 12, 2010. New approaches to the management of IVF induced ovarian cysts such as aspiration are currently being explored. In one Treatment of IVF induced
study conducted by Firouzabadi et al, 90 cyst aspirations were performed on infertile women who were under a GnRH-a/HMG Ovarian Cysts
protocol and experienced formation of functional ovarian cysts measured at ≥25 mm. Patients were stimulated with GnRH -a and then with HMG on the 21st day of their menstrual cycles. In vitro fertilization (IVF) is a protocol used to stimulate and Transvaginal ultrasonography was conducted every 3 to four enhance reproduction in women of childbearing age that are days to detect and diagnose newly formed cysts. This infertile or experience difficulty conceiving. Agents typically procedure was then followed by the administration of 10,000 used to enhance ovulation and pregnancy include units of HCG to promote ovulation. The overall incidence of gonadotropin releasing hormone agonists (GnRH-a) and cyst formation in the study was reported to be 20%. From the human menopausal gonadotropin (HMG). Use of these agents data obtained it was determined that women undergoing cyst over a long period of time has been associated with the aspiration required a significantly higher number of formation of ovarian cysts which may have negative impacts gonadotropin injections. While it was determined that there on the desired outcome of pregnancy. Studies have been was no significant difference in the number of viable oocytes conducted to determine treatments for these cysts in order to selected from the aspiration group (5.6 ± 2.1) compared to the prevent any mal-effects and ensure positive outcomes. In the group who received conservative treatment (5.2 ± 1.8), there United States, the utilization of IVF has increased with the were more cycle cancellations reported in the aspiration group. availability of physicians that perform the procedure as well as The pregnancy rate (although not statistically significant) with extended insurance policies that provide coverage.1 Along reported for the aspiration group was 10.3% in comparison to with the increase in utilization is the consequent increased 14.9% for the conservative treatment group. Consistently, observation of adverse effects, namely cyst formation, similar studies in this field such as that conducted by Segal et al indicate a 24% pregnancy rate in aspiration groups the prevention of surgical site infection. Recently, a study was compared to 41% in non-aspiration groups.6 Furthermore, it published in the New England Journal of Medicine (NEJM) that was reported that the rate of implantation and the incidence of compared the efficacy of chlorhexidine-alcohol with povidone- pregnancy were lower for patients with cyst aspiration. iodine for prevention of surgical site infections. This was a Additionally, in a study conducted by Qublan et al, a 9.7% prospective, randomized clinical trial that was done between pregnancy rate was reported for patients undergoing cyst the time period of April 2004 and May 2008 at six university- aspiration in comparison to 29.7% in patients receiving no affiliated hospitals in the US. The inclusion criteria for the study intervention.7 In accordance with the aforementioned studies, included patients who were 18 years of age or older and is the reporting of factors that attribute to the formation of undergoing clean-contaminated surgery (procedures that are functional ovarian cysts. These include patient age, agonist done under controlled conditions without significant spillage or used for stimulation, stimulation protocol administered and the unusual contamination). Patients were assigned in a 1:1 ratio presence of residual ovarian tissues from previous surgeries. to have the skin at surgical site be preoperatively scrubbed Furthermore these studies agree that elevated serum estradiol with 2% chlorhexidine gluconate and 70% isopropyl alcohol or levels in aspirated fluids are linked to a higher rate of ovarian an aqueous solution of 10% povidone-iodine. There were a cysts. Overall, the results from the more recent study total of 849 patients, who qualified for the intention-to-treat conducted by Firouzabadi et al indicate that cyst aspiration analysis. Out of these patients, 409 patients were given offers no significant therapeutic advantage over conservative chlorhexidine alcohol and 440 received povidone-iodine. The treatment methods. Moreover, the aspiration technique may primary outcome for the study was the occurrence of any negatively impact the desired outcome and further complicate surgical site infection within 30 days after surgery. Secondary the reproductive ability of fertility challenged women. outcomes assessed individual types of surgical site infections. The results showed that the rate of surgical site infection was Hammond AO, Gibson M, Stanford J, White G, Carrell DT, lower with chlorhexidine-alcohol compared to povidone- iodine Peterson M. In vitro fertilization availability and utilization in the (9.5% vs. 16.1%; p=0.004). Chlorhexidine alcohol patients had United States: a study of demographic, social, and economic lesser superficial incisional infections (4.2% vs. 8.6%; p=0.008) factors. Fertil and Steril. 2009; 91 (5): 1630–1635. Firouzabadi RD, Sekhavat L, Javedanii M. The effect of ovarian and deep incisional infections (1% vs. 3%; p=0.05). There were cyst aspiration on IVF treatment with GnRH. Arch Gynecol no major differences between chlorhexidine alcohol and povidone iodine group for the risk of organ space infection or Lexi-Comp [computer program]. Lexi-Comp; July 14, 2010. sepsis from surgical site infection. Three of the patients from Advanced Fertility; http://www.advancedfertility.com/ivf; July 14, each study group had an adverse event such as pruritus, erythema or both around the surgical wound.3Some other studies that support the NEJM study included an earlier study. http://www.nlm.nih.gov/medlineplus/ency/article/007279.htm. It was done to compare chlorhexidine based solution with Segal S, Shifren JL, Isaacson KB et al. Effect of a baseline alcohol based povidone iodine to find out the rate of catheter ovarian cyst on the outcome of in vitro fertilization-embryo colonization and blood stream infection. This study confirmed transfer. Fertil Steril. 2009; 71(2): 274-277. that alcohol based povidone iodine must be replaced with Qublan HS, Amarin Z, Tahat YA et al. Ovarian cyst formation chlorhexidine based solution to stop catheter related following GnRH agonist administration in IVF cycles: incidence infections.4Another study confirmed that washing patients with and impact. Hum Reprod. 2006; 21(3): 640-644. chlorhexidine-cloths is an effective way to reduce VRE from spreading to patient’s skin, environment and employee.5 Aqueous povidone-iodine is the most commonly used skin Chlorhexidine-Alcohol
antisepsis in the US. The study that was published in NEJM proved that the chlorhexidine alcohol lessened the risk of versus Povidone-Iodine for
surgical site infection by 41% compared to povidone iodine. Both of the drugs have broad-spectrum antimicrobial activity Surgical-Site Antisepsis
but chlorhexidine alcohol has more protection against infections. Potential reasons for this superiority include a rapid onset of action and continual activity even after being exposed to bodily fluids and lasting effect. Two thirds of surgical site According to Centers for Disease Control and Prevention infections are limited to the incision so optimizing skin (CDC), an average of 27 million surgeries are done every year antisepsis before surgery will be very beneficial to patients.3 in the United States (US). Surgical site infections (SSIs) usually happen within 30 days at the site of surgery. Infection Center for Disease Control Website: CDC. can also occur within a year if a foreign body is inserted during http://www.cdc.gov/ncidod/dhqp/FAQ_SSI.html. Accessed on July 12, 2010 the surgery. Seventy percent of SSIs are superficial infections, Digison MB. A review of antiseptic agents for pre-operative skin which mean it involves skin only. Other infections are more preparation. Plastic Surgical Nursing. 2007;27:185-189 serious and involve tissues under the skin, organs or implanted Darouiche RO, Wall MJ, Itani KMF, et al. Chlorhexidine-Alcohol material. Many SSIs do not become fatal.1 Some of the versus Povidone-Iodine for Surgical Site Antisepsis. NEJM. examples of antiseptic pre-operative skin products include povidone iodine, iodophor, chlorhexidine gluconate with Mimoz O, Villeminey S, Ragot S, et al. Chlorhexidine-based alcohol etc.2 There have been studies done before to compare antiseptic solution vs. alcohol based povidone iodine for central efficacy of different types or doses of systemic antibiotics for venous catheter care. Arch Intern Med. 2007;167(19):2066-2072 Vernon MO, Hayden MK, Trick WE, et al. Chlorhexidine gluconate AVA 80 mg daily, the differences in QN IC50 were found to be to cleanse patients in a medical intensive care unit. Arch Intern very significant (p < 0.009). The QN IC50 reductions in the presence of AVA did not significantly correlate with the QN IC50 alone (r= 0.22, P=0.3288) or the AVA IC50 alone (r=0.03, P=0.8946). The QN IC50 response in the presence of AVA Atorvastatin as a potential
0.1µM was reduced by 5% (0% to 15%; 95%CI: 1%-8%). In the presence of AVA 0.5 µM, there was a 10% (3% to 23%; anti-malarial drug
95%CI: 7%-14%) reduction. There was a 22% (14% to 40%; 95%CI: 19%-25%) reduction in the QN IC50 response with AVA 1.0µM group. Of the P. falciparum parasites analyzed, 86% showed potentiation activity of AVA with QN. Nearly 500 million people are afflicted with malaria annually, Furthermore, it was shown that a maximum dose of AVA 120 with roughly 2 million succumbing to this tropical disease.1 Risk mg daily could be administered with limited side effects estimates for contracting malaria have been placed at reported. Adverse events such rhabdomyolysis were not approximately 40% of the world’s population, giving malaria the induced in patients who were administered 120 mg daily. This dubious distinction of being the world’s most destructive study showed promising results of the synergistic effects of parasitic infection.2 Pregnant women, children younger than 5 AVA with QN. The results of in vitro responses (IC50) and years of age, and immunocompromised individuals are polymorphisms in the pfcrt and pfmrp genes showed results especially susceptible to this parasitic infection.1 A major health that were highly significant. Polymorphism in the pfcrt gene risk still exists in the aforementioned sections of the population (codons 75, 76 and 220) were significant (P<0.0022) as well as in highly endemic areas.2 Malaria is transmitted through with the pfmrp gene (codons 191 and 437, P= 0.0008). An various avenues, including blood transfusions, sharing of additional study was conducted to determine the potential for needles, and congenitally, but the primary means of HMG-CoA reductase inhibitors as adjuvant anti-malarial transmission is from person to person through the bite of therapy.4 Results from this study showed that although infected Anopheline mosquitoes.1 Four species of intracellular atorvastatin exhibited more potency than rosuvastatin, it protozoa of the genus Plasmodium are responsible for causing demonstrated weak synergistic activity with chloroquine and human malaria: P. falciparum, P. vivax, P. ovale, and P. dihydroartemisinin. Atorvastatin showed inhibition of growth of malariae. P. falciparum is responsible for causing the most P.falciparum in vitro, but studies need to be conducted to serious infections. Sporozites, injected into the human host by further evaluate the synergistic effects of statins and the mosquitoes, invade hepatocytes and develop into conventional antimalarial agents. Urban developments, proper schizonts. Following the rupture of the hepatocytes, merozoites water management, novel agricultural and animal husbandry are released into circulation. The parasites develop in the red practices have all led to a steady decline in the incidences of blood cells and this cycle is repeated every 48 (P. falciparum, malaria after the mid-19th century. By the mid-20th century, P. vivax, P. ovale) or 72 (P. malariae) hours ultimately resulting transmission was drastically reduced. In malaria-endemic in fevers, sweats, chills, and myriad symptoms of the disease. areas, however, resistance to anti-malarial agents continues to An emerging resistance of some strains of P. falciparum to be an emerging concern. Studies are ongoing to assess the some anti-malarial agents has warranted studies that hope to use of these cholesterol-lowering drugs as potential additions identify and isolate ways to combat the emergence of to a growing arsenal of anti-malarial agents. treatment failure. One such study investigated atorvastatin (AVA) for potential inclusion in a malarial treatment protocol in Shapiro Theresa A, Goldberg Daniel E, "Chapter 39. Chemotherapy of Protozoal Infections: Malaria" (Chapter). response to quinine (QN) resistance.3 HMG-CoA reductase Brunton LL, Lazo JS, Parker KL: Goodman & Gilman's The inhibitors, specifically AVA, have demonstrated ten-fold more Pharmacological Basis of Therapeutics, 11e: activity against P. falciparum strains. A potential link between http://www.accessmedicine.com/content.aspx?aID=946964. the presence of reductase enzymes in the protozoa may Fairhurst RM, Wellems TE. Plasmodium Species (Malaria). Mandell: Mandell, Douglas, and Bennett’s Principles and Practice explain why AVA demonstrates some activity against these of Infectious Diseases. 7th ed. Accessed July 13, 2010. organisms. The objectives of the study were to analyze in vitro Parquet V, Henry M, Wurtz N, et al. Atorvastatin as a potential synergism with AVA in combination with QN and to investigate anti-malarial drug: in vitro synergy in combinational therapy with polymorphisms in the P. falciparum sodium/hydrogen quinine against Plasmodium falciparum. Malar J. 2010;9:139. Wong RP, Timothy ME. Statins as Potential Antimalarial Drugs: exchanger (pfnhe), P. falciparum chloroquine resistance Low Relative Potency and Lack of Synergy with Conventional transporter (pfcrt), and P. falciparum MDR-like protein (pfmrp, Antimalarial Drugs. Antimicrob. Agents Chemother. May 2009; pfmdr) genes. Twenty-one strains of P. falciparum were isolated from several countries and an in vitro study was conducted assessing the potentiation effects of AVA with QN against these strains.3 Twenty-five microliters of AVA and 200 Mycophenolate Mofetil for
µL of a parasitized red blood cell suspension were placed in each of 96-well plates containing concentrations of QN. the Treatment of Chronic
Following three independent experiments assessing evidence Dermatitis
of potentiation for each of the 21 strains, findings showed a 50% inhibition of parasitic growth (IC50). Variations in QN IC50 between AVA groups were accounted for with ANOVA statistical analysis. At plasma concentrations correlating to Denisha Thomas Pharm. D. Candidate Chronic dermatitis is a critical, relapsing inflammatory condition Jackson J, Fowler J, Callen J, et al. Mycophenolate mofetil for in which genetics, environmental stimuli, epidermal the treatment of chronic dermatitis: an open-label study of 16 abnormalities, and immune dysregulation leads to pruitis, patients. Journal of Drugs in Dermatology. 2010; 9(4): 356-362. lichenification, and severe eczema.1 In immunity, T cells van Velsen S, Haeck I, Bruijnzeel-Koomen C, et al. First function to eradicate body cells that are infected from viral experience with enteric-coated mycophenolate sodium (Myfortic®) pathogens. In response to foreign invasion, B cells produce in severe recalcitrant adult atopic dermatitis: an open label study. antibodies that attach to antigens on the surface of pathogens to aid in destruction.2 Collectively, these along with a host of other bodily defenses work simultaneously to aid the body in fighting infection. Mycophenolate Mofetil, commonly referred to Editor: Ketal Patel PharmD
as MMF, is an immunosuppressive agent. It is primarily used Reviewer: Uche Anadu Ndefo, PharmD, BCPS
for the prevention of organ transplant rejections. MMF works by inhibition of de novo synthesis of purines for the production of precursors for RNA and DNA. Ultimately, MMF impedes the proliferation of T cells and B cells; delaying the process of immunity. An open-label study evaluated the use of If you have any comments, questions or
mycophenolate mofetil in sixteen patients with recalcitrant suggestions please feel to call or email us today!
eczema. The investigator-initiated study took place over 34 weeks; 28 weeks of therapy and a follow-up assessment six weeks after completion. The sixteen subjects were divided into three cohorts. In cohort one, once patients received 1g/day safely without therapeutic benefits, enrollment into cohort two took place with an upward dose of 1.5 g/day. Similarly, once patients in cohort two achieved a dosage of 1.5 g/day safely without any therapeutic benefit, enrollment into cohort three took place with a maximum dose of 2 g/day. Upon termination of the study, results were reviewed from both the investigators and the enrolled subjects. The grading rubric for improvement was as follows: worse, no change, mild improvement, marked improvement, or completely clear. By investigator assessment, out of the 14 patients who displayed improvement; three patients were completely cleared, six showed marked improvement, one showed moderate improvement, and four displayed mild improvement. In the patient assessment, within the 12 patients who demonstrated improvement; three were completely cleared, six had marked improvement, two showed moderate improvement, and one had mild improvement. In both analysis among investigators and patients, therapeutic benefits were significantly greater in cohort three in which patients received 2 g/day in comparison to only 1 gram daily in cohort one (P<0.0001.) 3 There was one unfavorable adverse event in which a patient developed pancreatic cancer at week 12. However, prior to entrance into the study, the patient noted Texas Southern University
epigastric pain which was previously diagnosed as chronic reflux. With such, this episode is not considered as an adverse College of Pharmacy and Health Sciences
event from MMF therapy. Other reported adverse events DRUG INFORMATION CENTER
included insomnia and transient nausea. Previous studies have Texas Medical Center
been carried out for assessment of the usage of MMF in the John P. McGovern Campus
management of chronic dermatitis. In a 12 week pilot study 2450 Holcombe Blvd, Houston, TX 77021
involving ten patients from ages 29-47; there was a 68% 713-313-1242
decrease in disease severity. A subsequent study including 713-313-1243
ten patients with severe atopic dermatitis exhibited a median improvement of more than 55%. Altogether, based on the M-F 8:30 AM – 4:30 PM
referenced studies, one could conclude that mycophenolate mofetil is indeed effective in the treatment of chronic dermatitis. Because MMF has the capability to increase a patient’s overall risk of infection as well as gastrointestinal discomfort, further research is warranted for the management of such adverse events. MMF is positioned as a viable option for enhancement of the quality of life in patients suffering from chronic dermatitis.

1.
Akhavan A, Rudikoff D. Atopic dermatitis: systemic immunosuppressive therapy. Semin Cutan Med Surg. 2008; 27:151-155. The Immune System – In More Detail; Nobelprize.org; http://nobelprize.org/educational/medicine/immunity/immune-detail.html; 2010; Accessed July 14, 2010.

Source: http://archive.tsu.edu/PDFFiles/academics/pharmacy/News%20Letter/NLQ1.pdf

barntowire.com

603.60 Amendment 603.90 Amendment 603.200 A Complete Description of the Subjects and Issues Involved: At its March 13, 2007 meeting, the Board approved the establishment of a threshold level for the drug Pyrilamine, based on a report submitted to the Board by the Medication Task Force. The Task Force recommended to the Board that threshold levels should be established for Isoxsuprine (rulemaking

swissgamingmagazine.ch

Reinhold Schmitt, Gründer von «www.isa-casinos.de» Wie kommt man dazu ein Internet- Por tal für das Geldspiel zu eröffnen? Millionenfach wurde die isa-Casinos bereits angeklickt. Kostenlos. Ha ben leer ist. ISA gibt die Realität weiter und Sie als Spieler genug Geld verdient um sich ein solch aufwendiges Hob- by leisten zu können? Also ehrlich, haben Sie einen

Copyright © 2010-2014 Medical Articles