Olaparib in an ovarian cancer patient with end-stage renal disease and hemodialysis.

PURPOSE: For patients with severe renal impairment (CrCl ≤ 30 ml/min) or end-stage renal disease (ESRD), olaparib intake is not recommended as the pharmacokinetics and safety of olaparib have not been evaluated in this patient group. Therefore, this valuable patient group is generally excluded from poly(ADP-ribose) polymerase inhibitor (PARPi) therapy. Here we report the pharmacokinetics (PK), efficacy, safety and tolerability of olaparib capsules 200 mg BID in a patient with recurrent epithelial ovarian cancer (EOC) and ESRD requiring hemodialysis. METHODS: Blood and dialysate samples of the patient were collected on a dialysis and non-dialysis day. Olaparib total plasma concentrations were determined through high-performance liquid chromatography with tandem mass spectrometric detection. Actual scheduled sample times were used in the PK analysis to determine multiple dose PK parameters at steady state. RESULTS: Maximum concentration was achieved 1.5 h after drug administration on non- dialysis and after 1 h on dialysis day. The steady-state trough concentration and the maximal plasma concentration were similar on dialysis and non- dialysis day. On non-dialysis day, the AUCss was 30% higher (24.0 µg.h/mL vs. 16.9 µg.h/ml) than on dialysis day. The plasma clearance CLss/F was lower on non-dialysis day. Olaparib was not detectable in the dialysate samples. CONCLUSION: A total dose of olaparib 200 mg BID capsule formulation was well tolerated by our patient with ESRD and hemodialysis. Moreover, this maintenance therapy led to 16 months of progression free survival. Further trials on PARPi therapy in patients with hemodialysis are warranted.

Sex Differences in Characteristics Associated with Potentially Inappropriate Medication Use and Associations with Functional Capacity in Older Participants of the Berlin Aging Study II.

INTRODUCTION: Medication safety is a vital aim in older adults' pharmacotherapy. Increased morbidity and vulnerability require particularly careful prescribing. Beneath avoiding unnecessary polypharmacy and prescribing omissions, physicians have to be aware of potentially inappropriate medications (PIMs) and related outcomes to optimize older adults' drug therapy, and to reduce adverse drug events. OBJECTIVE: The aim of this study was to identify participants characteristics associated with PIM use and associations of PIM use with functional capacity with a focus on sex differences. METHODS: Multivariable logistic regression analyses of cross-sectional Berlin Aging Study II (BASE-II) data (N = 1,382, median age 69 years, interquartile range 67-71, 51.3% women) were performed with PIM classification according to the EU(7)-PIM list. RESULTS: In the overall study population, higher education was associated with lower odds of PIM use (odds ratio [OR] 0.93, confidence interval [CI] 95% 0.87-0.99, p = 0.017). Falls (OR 1.53, CI 95% 1.08-2.17, p = 0.016), frailty/prefrailty (OR 1.68, 1.17-2.41, p = 0.005), and depression (OR 2.12, CI 95% 1.32-3.41, p = 0.002) were associated with increased odds of PIM use. A better nutritional status was associated with lower odds of PIM use (OR 0.88, CI 95% 0.81-0.97, p = 0.008). In the sex-stratified analysis, higher education was associated with lower odds of PIM use in men (OR 0.90, CI 95% 0.82-0.99, p = 0.032). Frailty/prefrailty was associated with increased odds of PIM use in men (OR 2.04, CI 95% 1.18-3.54, p = 0.011) and a better nutritional status was associated with lower odds of PIM use in men (OR 0.83, CI 95% 0.72-0.96, p = 0.011). Falls in the past 12 months were related to an increased prevalence of PIM use in women (OR 1.74, CI 95% 1.10-2.75, p = 0.019). Depression was associated with a higher prevalence of PIM use in both men (OR 2.74, CI 95% 1.20-6.24, p = 0.016) and women (OR 2.06, CI 95% 1.14-3.71, p = 0.017). We did not detect sex differences regarding the overall use of drugs with anticholinergic effects, but more men than women used PIMs referring to the cardiovascular system (p = 0.036), while more women than men used PIMs referring to the genitourinary system and sex hormones (p < 0.001). CONCLUSION: We found similarities, but also differences between men and women as to the associations between PIM use and participants' characteristics and functional capacity assessments. The association of lower education with PIM use may suggest that physicians' prescribing behavior is modified by patient education, a relationship that could evolve from more critical attitudes of educated patients towards medication use. We conclude that sex differences in associations of PIM use with functional capacities might be partly attributable to sex differences in drug classes used, but not with regard to anticholinergics, as these are used to a similar extent in men and women in the cohort studied here.

Concerted EP2 and EP4 Receptor Signaling Stimulates Autocrine Prostaglandin E2 Activation in Human Podocytes.

Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman's space. Elevated Prostaglandin E2 (PGE2) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE2 autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE2, 15-keto-PGE2, and 13,14-dihydro-15-keto-PGE2 levels. hPC were treated with PGE2 with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE2 led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE2. PTGER4 was downregulated after PGE2 stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE2 and 15-keto-PGE2 levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE2 pathway in hPC linked to concerted EP2 and EP4 signaling.

Potentially inappropriate medication in older participants of the Berlin Aging Study II (BASE-II) - Sex differences and associations with morbidity and medication use.

INTRODUCTION: Multimorbidity in advanced age and the need for drug treatment may lead to polypharmacy, while pharmacokinetic and pharmacodynamic changes may increase the risk of adverse drug events (ADEs). OBJECTIVE: The aim of this study was to determine the proportion of subjects using potentially inappropriate medication (PIM) in a cohort of older and predominantly healthy adults in relation to polypharmacy and morbidity. METHODS: Cross-sectional data were available from 1,382 study participants (median age 69 years, IQR 67-71, 51.3% females) of the Berlin Aging Study II (BASE-II). PIM was classified according to the EU(7)-PIM and German PRISCUS (representing a subset of the former) list. Polypharmacy was defined as the concomitant use of at least five drugs. A morbidity index (MI) largely based on the Charlson Index was applied to evaluate the morbidity burden. RESULTS: Overall, 24.1% of the participants were affected by polypharmacy. On average, men used 2 (IQR 1-4) and women 3 drugs (IQR 1-5). According to PRISCUS and EU(7)-PIM, 5.9% and 22.6% of participants received at least one PIM, while use was significantly more prevalent in females (25.5%) compared to males (19.6%) considering EU(7)-PIM (p = 0.01). In addition, morbidity in males receiving PIM according to EU(7)-PIM was higher (median MI 1, IQR 1-3) compared to males without PIM use (median MI 1, IQR 0-2, p<0.001). CONCLUSION: PIM use occurred more frequently in women than in men, while it was associated with higher morbidity in males. As expected, EU(7)-PIM identifies more subjects as PIM users than the PRISCUS list but further studies are needed to investigate the differential impact of both lists on ADEs and outcome. KEY POINTS: We found PIM use to be associated with a higher number of regular medications and with increased morbidity. Additionally, we detected a higher prevalence of PIM use in females compared to males, suggesting that women and people needing intensive drug treatment are patient groups, who are particularly affected by PIM use.

Moderation of alcohol consumption as a recommendation in European hypertension management guidelines: a survey on awareness, screening and implementation among European physicians.

OBJECTIVES: Moderation of alcohol consumption is included as a class I, level of evidence A recommendation in the current European guidelines for the management of hypertension. We investigated its awareness and self-reported implementation among European physicians across different specialties and workplaces. DESIGN AND SETTING: A cross-sectional survey study conducted in two annual German meetings (German Society of Cardiology and the German Society of Internal Medicine) and two annual European meetings (European Society of Hypertension and European Society Cardiology) in 2015. PARTICIPANTS: 1064 physicians attending the European meetings were interviewed including 52.1% cardiologists, 29.2% internists and 8.8% general practitioners. MAIN OUTCOME MEASURES: Physician screening of alcohol consumption, awareness and self-implementation of the recommendation of the current European guidelines about moderation of alcohol consumption for the management of hypertension. RESULTS: Overall, 81.9% of physicians reported to generally quantify alcohol consumption in patients with hypertension. However, only 28.6% and 14.5% of participants reported screening alcohol consumption in their patients with newly detected or treatment-resistant hypertension. Physicians recommended a maximum alcohol intake of 13.1±11.7 g/day for women (95% CI 12.3 to 13.8) and 19.9±15.6 g/day for men (95% CI 18.8 to 20.9). In case of moderate to high alcohol consumption, 10.3% would manage only hypertension without addressing alcohol consumption, while 3.7% of the physicians would do so in case of alcohol dependence (p<0.001). CONCLUSIONS: The average amount of alcohol intake per day recommended by European physicians in this survey was in agreement with the guidelines. The low number of physicians that screen for alcohol consumption in patients with newly detected and with treatment-resistant hypertension indicates an important deficit in the management of hypertension.

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia.

PURPOSE: Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. METHODS: Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design. We applied univariable and multivariable logistic regression analysis to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for potential risk factors of thromboembolic complications. RESULTS: Our cohort comprised 209 HIT patients. Of those, 53 developed thromboembolic complications. Most HIT patients received heparin for medical indications (42.1%) or in the context of cardiovascular surgery (40.2%). Of the 78 thromboembolic complications, 49 (63%) and 29 (37%) were observed in the venous and arterial vascular bed, respectively. The main locations were deep vein thrombosis (39.7%), pulmonary embolism (16.7%), and limb artery thrombosis (16.7%). In multivariable analysis, immobilization prior to HIT (OR 4.6, 95% CI 1.2-18.0; P = .026) and higher platelet counts before initiation of heparin therapy (OR 1.004, 95% CI 1.000-1.008; P = .046) were independently associated with the occurrence of thromboembolic events. CONCLUSIONS: Immobilization and a high platelet count (with a low effect size) are additional risk factors of thromboembolic complications in the course of HIT.

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy.

BACKGROUND: Tissue factor (TF) is an evolutionary conserved glycoprotein that plays an important role in the pathogenesis of cancer. TF is expressed in 2 naturally occurring protein isoforms, membrane-bound full-length (fl)TF and soluble alternatively spliced (as)TF. Both isoforms have been shown to affect a variety of pathophysiologically relevant functions, such as tumor-associated angiogenesis, thrombogenicity, tumor growth, and metastasis. Therefore, targeting TF either by direct inhibition or indirectly, i.e., on a posttranscriptional level, offers a novel therapeutic option for cancer treatment. CONTENT: In this review we summarize the latest findings regarding the role of TF and its isoforms in cancer biology. Moreover, we briefly depict and discuss the therapeutic potential of direct and/or indirect inhibition of TF activity and expression for the treatment of cancer. SUMMARY: asTF and flTF play important and often distinct roles in cancer biology, i.e., in thrombogenicity and angiogenesis, which is mediated by isoform-specific signal transduction pathways. Therefore, both TF isoforms and downstream signaling are promising novel therapeutic targets in malignant diseases.

Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer.

The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.

Ophthalmic drugs as part of polypharmacy in nursing home residents with glaucoma.

BACKGROUND: Glaucoma comprises age-related neurodegenerative diseases of retinal ganglion cells, the worldwide prevalence of which is increasing. Local pharmacotherapy is the primary treatment option, especially in the elderly. But this therapeutic approach may include risks for adverse drug effects and drug-drug interactions, of particular importance in frail nursing home resident populations. OBJECTIVE: The aim of the present study was to investigate anti-glaucoma pharmacotherapy in nursing home residents in the context of multi-morbidity and related systemic co-medication. METHODS: Data for 8,685 nursing home residents with 88,695 drug prescriptions were analysed according to diagnosis and local or systemic pharmacotherapy. Data were provided in anonymous form by a German public health insurance company. RESULTS: The study cohort was characterized by a mean age of 83.6 ± 7.3 years (range: 65-106 years), 21 % of nursing home residents were at least 90 years old and 83.7 % were women. For each nursing home resident, an average of 6.0 ± 3.3 different drugs were registered. A diagnosis of glaucoma was recorded in 520 (6.0 %) nursing home residents; all subjects had co-existing medical conditions. Dementia was a frequent co-morbidity, diagnosed in 51.7 % of nursing home residents with glaucoma. Anti-glaucoma drugs contributed to 0.5 % of all prescriptions and were prescribed to 341 nursing home residents. The most frequently used anti-glaucoma ophthalmics were ß-blockers (n = 219), followed by prostaglandin analogues (n = 101) and carbonic anhydrase inhibitors (n = 86). Local anti-glaucoma therapy was co-prescribed with a systemic pharmacotherapy in 338 nursing home residents. An ophthalmic agent was, on average, combined with 6.5 ± 3.2 prescriptions for systemic agents. Thus, 71.9 % of nursing home residents were prescribed ophthalmic ß-blockers and a concomitant antihypertensive medication; local and systemic ß-blockers were combined in 20.2 % of these patients. Co-treatment with cardiac glycosides or calcium antagonists was found in 13 % of nursing home residents prescribed ophthalmic parasympathomimetics, and in 14 % of those prescribed ophthalmic ß-blockers, with the potential for drug-drug interactions to influence cardiac function. CONCLUSIONS: Anti-glaucoma pharmacotherapy in nursing home residents is frequently prescribed in the context of polypharmacy. This may modify the efficacy and safety of local and systemic therapies. Therefore, individualized pharmacotherapy that integrates anti-glaucoma drug therapy into the overall treatment rationale in nursing home residents is necessary. However, to realize this concept, further clinical research in nursing home residents is warranted.

The therapeutic management of a twin pregnancy complicated by the presence of cervical cancer, following laparoscopic staging and chemotherapy, with an emphasis on cisplatin concentrations in the fetomaternal compartments amnion fluid, umbilical cord, and maternal serum.

OBJECTIVE: To evaluate the feasibility, toxicity, and pharmacokinetics in the maternal and fetal compartments during chemotherapy in a pregnant patient with cervical cancer. DESIGN: Case report. SETTING: University Hospital. PATIENT: A 35-year-old woman was diagnosed with an adenocarcinoma FIGO stage IB1 of the cervix uteri at 14 weeks' gestation with twin pregnancy. INTERVENTION(S): A laparoscopic transperitoneal pelvic lymphadenectomy was performed at 15 weeks' gestation There was no evidence of lymph node metastases (0/19). The patient decided to continue her pregnancy. Three cycles of neoadjuvant chemotherapy consisting of cisplatin during the second and third trimester were given and well tolerated. Amniocentesis was performed at the time of the second cisplatin cycle. MAIN OUTCOME MEASURE(S) AND RESULT(S): The concentration in the amniotic fluid samples reached 10% of the maternal blood levels at this time. At 32 weeks' gestation, a Caesarean section followed by radical hysterectomy was performed. The twins developed normally and displayed no chemotherapically related side effects. At the time of delivery, the corresponding concentration in the amniotic fluid was approximately one-third of the umbilical cord levels. CONCLUSION(S): To our knowledge, this is the first report quantifying the amount of transplacental transport of cisplatin during pregnancy in vivo. One-tenth of the maternal serum concentration was detected in the amniotic fluid; the concentration of cisplatin in the umbilical cord was three times higher than in the amniotic fluid.

Profiling of the renal kinome: a novel tool to identify protein kinases involved in angiotensin II-dependent hypertensive renal damage.

Regulation of protein kinase activities is crucial in both physiology and disease, but analysis is hampered by the multitude and complexity of kinase networks. We used novel peptide array chips containing 1,152 known kinase substrate sequences to profile different kinase activities in renal lysates from homozygous Ren2 rats, a model characterized by hypertension and angiotensin II (ANG II)-mediated renal fibrosis, compared with Sprague-Dawley (SD) control rats and Ren2 rats treated with an angiotensin-converting enzyme inhibitor (ACEi). Five-wk-old homozygous Ren2 rats were left untreated or treated with the ACEi ramipril (1 mg.kg(-1).day(-1)) for 4 wk; age-matched SD rats served as controls (n = 5 each). Peptide array chips were incubated with renal cortical lysates in the presence of radioactively labeled ATP. Radioactivity incorporated into the substrate motifs was measured to quantify kinase activity. A number of kinases with modulated activities, which might contribute to renal damage, were validated by Western blotting, immunoprecipitation, and immunohistochemistry. Relevant kinases identified by the peptide array and confirmed using conventional techniques included p38 MAP kinase and PDGF receptor-beta, which were increased in Ren2 and reversed by ACEi. Furthermore, insulin receptor signaling was reduced in Ren2 compared with control rats, and G protein-coupled receptor kinase (GRK) activity decreased in Ren2 + ACEi compared with untreated Ren2 rats. Array-based profiling of tissue kinase activities in ANG II-mediated renal damage provides a powerful tool for identification of relevant kinase pathways in vivo and may lead to novel strategies for therapy.