Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

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BACKGROUND Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study investigated the pharmacokinetics of aliskiren and digoxin alone or in combination. METHODS Open‐label, two‐period, multiple‐dose study in 22 healthy individuals aged 18–45 years. Subjects received aliskiren 300 mg once daily on days 1–7, followed by a 10‐day wash out period. Digoxin 0.25 mg was then administered daily on days 18–33, with aliskiren 300 mg once daily added on days 27–33. Blood samples were taken for pharmacokinetic profiling on days 7, 26 and 33. RESULTS Steady‐state pharmacokinetics of aliskiren (mean±SD unless otherwise stated) were not significantly modified by digoxin (aliskiren Cmax 261±95 alone vs 260±123 ng/mL with digoxin, ratio of geometric means 0.98[90% CI 0.80–1.19]; tmax[median] 1.0 vs 2.0h; AUC0‐τ 1671±491 vs 1664±517 ng.h/mL, mean ratio 1.02[0.92–1.13]). Similarly, there was no clinically meaningful difference in Cmax, tmax and AUC0‐τ for digoxin when given alone or in combination with aliskiren (digoxin Cmax 1.5±0.5 vs 1.4±0.5 ng/mL, mean ratio 0.91[0.84–0.99]; tmax 1.0 vs 1.0h; AUC0‐τ 11.6±3.3 vs 13.4±4.4 ng.h/mL, mean ratio 1.15[1.01–1.31]). Aliskiren was well tolerated alone or in combination with digoxin; all adverse events were mild to moderate in intensity. CONCLUSIONS Aliskiren has no clinically significant drug interaction with digoxin and is well tolerated in combination with digoxin in healthy volunteers. Clinical Pharmacology & Therapeutics (2005) 79, P64–P64; doi:

Radiologic breast density is one of the predictive factors for breast cancer and the extent of the density is directly related to postmenopause. However, some patients have dense breasts even during postmenopause. This condition may be explained by the genes that codify for the proteins involved in the biosynthesis, as well as the activity and metabolism of steroid hormones. They are polymorphic, which could explain the variations of individual hormones and, consequently, breast density. The constant need to find markers that may assist in the primary prevention of breast cancer as well as in selecting high risk patients motived this study. We determined the influence of genetic polymorphism of CYP17 (cytochrome P450c17, the gene involved in steroid hormone biosynthesis), GSTM1 (glutathione S-transferase M1, an enzyme involved in estrogen metabolism) and PROGINS (progesterone receptor), for association with high breast density. One hundred and twenty-three postmenopausal patients who were not on hormone therapy and had no clinical or mammographic breast alterations were included in the present study. The results of this study reveal that there was no association between dense breasts and CYP17 or GSTM1. There was a trend, which was not statistically significant (P = 0.084), towards the association between PROGINS polymorphism and dense breasts. However, multivariate logistic regression showed that wild-type PROGINS and mutated CYP17, taken together, resulted in a 4.87 times higher chance of having dense breasts (P = 0.030). In conclusion, in the present study, we were able to identify an association among polymorphisms, involved in estradiol biosyntheses as well as progesterone response, and radiological mammary density.

Objetivos: analisar os custos de um ciclo de rastreamento mamográfico do câncer de mama em população de 1014 mulheres no climatério e comparar com os custos do tratamento do câncer da mama em estádios mais avançados. Métodos: realizouse rastreamento em 1014 mulheres atendidas em ambulatório de Climatério. Todas as mamografias foram classificadas de acordo com as categorias do BI-RADS (Breast Imaging Reporting and Data System-American College of Radiology) e as lesões detectadas foram submetidas a estudo citológico ou histológico. A estimativa dos custos dos exames e procedimentos realizados foram obtidos da Tabela AMB 92. Resultados: a impressão diagnóstica final dos 1014 exames, de acordo com a classificação em categorias do BI-RADS, foi: 1=261; 2=671; 3=59; 4=22; 5=1. Os procedimentos invasivos realizados totalizaram 33 punções com agulha fina dirigida por USG, 6 biópsias com agulha grossa orientada por USG e 20 biópsias orientadas por mamografia (estereotaxia). Com base nos valores da tabela AMB 92, foram necessários para rastrear e diagnosticar essa população cerca de R$ 76.000,00. Detectaram-se 5 cânceres de mama, ao custo aproximado de R$ 15.318,75 por diagnóstico e média de custo por paciente de R$ 75,53. Conclusões: considerando que o custo total do tratamento de um único caso de câncer de mama em estádio II ou mais pode atingir R$ 75.000,00, concluímos que os programas de rastreamento mamográfico podem ser incluídos entre as políticas de saúde.

n Abstract: The purpose of this study is to determine how often breast magnetic resonance imaging (MRI) brings additional information that influences management of patients with breast cancer concerning surgical treatment, axillary lymph node approach, and systemic therapy. From July 2004 to July 2005, 99 patients recently diagnosed with breast cancer in clinical stages 0, I, and II were prospectively evaluated about their therapeutic plans, at first based on usual protocol (physical examination, mammography and ultrasound) and next going through bilateral breast MR. Examinations were carried out at 1.5 T on five sequences of FSPGR 3D for 90 seconds (four post-gadolinium diethylenetriaminepenta acetic acid 0.16 mM ⁄ Kg). Parameters analyzed on MRI were extension of primary lesion; detection of multifocality, multicentricity, or contra lateral lesion; muscular or skin involvement; and presence of lymph node involvement. Pathologic confirmation of additional lesions was achieved by core or excisional biopsy. MRI made 69 additional findings in 53 patients. Fifty-one findings were true-positives (51 ⁄ 69 = 73.9%) including 16 larger single lesions; 18 cases of multifocality; 7 cases of multicentricity; 3 cases of contra lateral lesion; 5 cases of lymph node involvement (one of them involved medial thoracic chain); 1 with muscular involvement; 1 with skin involvement. MRI has changed previous management plans in 44.4% of 99 patients. We observed increase in mastectomies (26.8%) on axillary lymph node dissection (25%) and changes on systemic therapy (20.2%), all because of additional MRI true-positive findings. Breast MRI alters significantly the rate of mastectomy, the approach of axillary chain for staging, and the use of systemic therapy because of its accuracy in evaluating breast cancer local extent. n

Higher nuclear (NG3) and histological (HGIII) grading, associated with a high PCNA index (> 50), distinguish high-risk patients, and it is more appropriate considering all the stained cells as representative of PCNA indices, thus reflecting tumor aggressiveness.