Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer.

PURPOSE: Raloxifene is a second-generation selective estrogen receptor modulator that reduces the incidence of breast cancer in postmenopausal women. Exemestane, a steroidal aromatase inhibitor, decreases contralateral new breast cancers in postmenopausal women when taken in the adjuvant setting. Preclinical evidence suggests a rationale for coadministration of these agents to achieve complete estrogen blockade. EXPERIMENTAL DESIGN: We tested the safety and tolerability of combination exemestane and raloxifene in 11 postmenopausal women with a history of hormone receptor-negative breast cancer. Patients were randomized to either raloxifene (60 mg PO daily) or exemestane (25 mg PO daily) for 2 weeks. Patients then initiated combination therapy at the same dose levels for a minimum of 1 year. Pharmacokinetic and pharmacodynamic data for plasma estrogens, raloxifene, exemestane, and their metabolites were collected at the end of single-agent therapy and during combination therapy. RESULTS: Plasma concentration-time profiles for each drug were unchanged with monotherapy versus combination therapy. Raloxifene did not affect plasma estrogen levels. Plasma estrogen concentrations were suppressed below the lower limit of detection by exemestane as monotherapy and when administered in combination with raloxifene. The most common adverse events of any grade included arthralgias, hot flashes, vaginal dryness and myalgias. CONCLUSIONS: In this small study, coadministration of raloxifene and exemestane did not affect the pharmacokinetics or pharmacodynamics of either agent to a significant degree in postmenopausal women. The combination of estrogen receptor blockade and suppression of estrogen synthesis is well tolerated and warrants further investigation.

Male genital hygiene beliefs and practices in Nairobi, Kenya.

OBJECTIVES: Attitudes and practices concerning genital hygiene may influence topical microbicide use by men. This study examines knowledge and behaviours related to hygiene, genital hygiene, circumcision and hygiene, and to genital hygiene before and after sex among men in Nairobi, Kenya. METHODS: We conducted 463 interviews of men recruited by respondent driven sampling techniques and 10 focus group discussions with a subsample of 100 volunteers from this group. Men were asked individual quantitative survey and qualitative group discussion questions about general hygiene behaviours, genital hygiene, and the temporal relation of genital hygiene behaviours to sexual encounters. RESULTS: Bathing once daily was associated with education, income, and inside tap water. Genital washing aside from regular bathing and washing before sex ever were negatively associated with bathroom crowding. Genital hygiene before the most recent sexual encounter was uncommon and negatively associated with HIV risk perception, bathroom crowding, and ethnicity. Men believed genital hygiene before sex would arouse suspicions of infidelity or cool sexual ardour. Genital hygiene after sex was associated with education, religion, and having inside tap water. Genital hygiene after the most recent sexual encounter was associated with age, income, and with men having at least one child. CONCLUSIONS: Genital hygiene behaviours were associated with resource access factors and group discussions suggest that they are modulated by interactions in sexual partnerships. Topical microbicides may improve hygiene before and after sex.

Early diagnosis and management of Alzheimer's disease.

It is only recently that Alzheimer's disease has become recognized as a major public health concern. Not only those diagnosed with Alzheimer's disease are impacted by the disease; the emotional toll exacted on caregivers is enormous, and the financial costs incurred by the United States are staggering. Early diagnosis of Alzheimer's disease can prevent costly and inappropriate treatment and permits earlier treatment of symptoms. There have been several recent pharmacologic advances in the treatment of Alzheimer's disease, including the development of acetylcholinesterase inhibitors. For any intervention to prove successful, however, early and accurate diagnosis and effective disease management are crucial.

A sequential, test-control methodology for conducting functional analyses of self-injurious behavior.

Multielement and reversal designs used to identify maintaining variables for behavior disorders such as self-injury have several potential limitations, including interaction effects (multielement), inefficiency (reversal), and lack of a continuous control (reversal). This article describes a methodology that minimizes these problems yet captures the best features of both designs. This design consists of several phases implemented in a sequential (A-B-C) fashion, as in the reversal design. However, each phase consists of two conditions, a test and a control, presented concurrently in a multielement format. Five subjects' self-injury was assessed using both the multielement design and the sequential, test-control (or pairwise) design. Results for two subjects indicated that the multielement design produced clear assessment outcomes, and similar findings were obtained using the pairwise design. For two other subjects, the multielement assessments were somewhat undifferentiated, and clearer results were obtained using the pairwise design. The fifth subject's self-injury showed cyclical patterns using both assessment techniques. Benefits and limitations of the sequential assessment methodology are discussed.

Lacidipine metabolism in rat and dog: identification and synthesis of main metabolites.

1. The main metabolites of lacidipine were isolated from bile and plasma of rats and dogs following an oral dose of the 14C-labelled drug (10 mg/kg for rats: 2 and 1 mg/kg for dogs). They were identified by comparison of chromatographic and spectral data with authentic reference compounds synthesized ad hoc. 2. Five metabolites (I-V) were isolated and identified in dog bile by gradient h.p.l.c. with u.v. detection and h.p.l.c.-thermospray mass spectrometry. In all metabolites the heterocyclic ring has been oxidized to pyridine. Further biotransformation reactions involved hydroxylation of the methyl substituents and hydrolysis of the ethyl and t-butyl ester groups to produce carboxylic acids and a lactone. Some of these metabolites also occurred as glucuronide conjugates. 3. A metabolite retaining the intact dihydropyridine ring, the des-ethyl analogue of lacidipine (VI), was isolated from rat plasma where it accounted for 60% of the total circulating radioactivity up to 24 h after administration. To characterize this metabolite, h.p.l.c. with photodiode array u.v. detection also was employed. This compound was detected in dog plasma, but there was no evidence of its presence in dog bile samples. 4. Profiles of circulating metabolites were qualitatively similar in rats and dogs. Identified metabolites accounted for the large majority of total radioactivity in all the analysed samples.