Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers

Objective

Two open‐label, randomized, cross‐over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate.

Methods

Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co‐administration of etravirine with tenofovir disoproxil fumarate on either days 1–8 or days 9–16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h.

Results

The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration–time curve from 0 to 12 h (AUC_{12 h}) for etravirine co‐administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61–0.79) and 0.81 (0.75–0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC_{24 h} was 1.16 (1.09–1.23) in Study 1 and 1.15 (1.09–1.21) in Study 2.

Conclusions

These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co‐administered.     

Sleep-disordered breathing as a mechanism for nocturia: preliminary findings

Nocturia is commonly associated with prostate or bladder problems but is also an important symptom of obstructive sleep apnea, a potentially lethal condition. The primary purpose of this study was to test the relationship between symptoms of sleep-disordered breathing and increased nocturnal urine production as described by the Sleep-Disordered Breathing--Nocturia Model. The purpose of the first phase of this three-phase study was to survey community-dwelling older adults (> 55 years) about nocturia and sleep-disturbance symptoms. A random sample of 1,000 older adults, balanced by ethnicity and gender, were surveyed via a mailed questionnaire. The brief questionnaire included characterizing poor sleep quality, obstructive sleep apnea symptoms, nocturia, lower urinary tract symptoms, naps, and self-rated health. The return rate was low (18%, n = 176), but respondents were equally represented by gender and ethnicity across the targeted age groups. Half of the respondents (n = 87) reported > or = 2 voids per night, two-thirds of whom reported nocturia as bothersome. The data showed that African-American women had significant associations between episodes of nocturia and symptoms of obstructive sleep apnea, poor sleep quality, naps, and lower urinary tract symptoms, thus failing to support the notion that nocturia or sleep-disordered breathing are prostate or gender related. As expected, subjects (n = 80) who volunteered for the later phases of the study, had significantly more problems. These preliminary data suggest that the relationship between obstructive sleep apnea and nocturia is important because older adults are at higher risk of injury due to falls that may occur while attempting to toilet in the dark. Also, older adults may also be at higher risk of receiving inappropriate urologic treatment if they are not screened for sleep disorders when reporting nocturia along with symptoms of excessive daytime sleepiness and sleep-disordered breathing. Phases II and III of the parent study will include a detailed examination of hormonal, biochemical, and physical variables to further test the proposed Sleep-Disordered Breathing--Nocturia Model.     

Psoriasis under the microscope

Histopathology is a major diagnostic tool in dermatology, particularly in psoriasiform diseases. Morphological studies showed that the initial event in psoriatic lesions is perivascular infiltrate, followed by dilatation of superficial papillary vessels. Proliferation of keratinocytes and neutrophil exocytosis are secondary events. Fully developed psoriasis has a very characteristic pattern, which includes elongation of rete ridges leading to regular acanthosis, oedema of the papillary dermis associated with tortuous dilated vessels, thinning of suprapapillar area, decreased thickness of granular layer, and exocytosis of neutrophils in the spinous layer (Kogoj's pustule) or in the cornified parakeratotic layer (Munro microabscesses). Pustular psoriasis is characterized by large or confluent intra‐epidermal multilocular pustules. Whatever the clinical variant of psoriasis, common morphological signs suggest that it is basically a unique pathological process, with many possible presentations according to various factors such as age, size and localization of lesions, or therapy. Similar microscopic elementary lesions indicate that Hallopeau's acrodermatitis continua, Reiter's disease and geographical tongue are variants of psoriasis. Because of the many faces of the disease, psoriasis can resemble many other squamous or pustular disorders. Differential diagnosis by microscopic analysis is based on pattern analysis, PAS (Periodic Acid Schiff) staining to rule out fungal infection, and immunohistochemistry to characterize lymphocytic infiltrate. Psoriasis is one of the most common inflammatory skin diseases. In its characteristic presentation, psoriasis comprises well‐circumscribed red scaly papules and plaques. In this form, the disease is generally easy to identify, especially when the elbows, knees and scalp are affected. Nevertheless, the term ‘psoriasis’ includes more clinical variants than any other inflammatory dermatosis: psoriasis vulgaris vs. pustular, localized vs. generalized, topographic variants, mucous membranes involvement, hair and nail lesions. Although some of these conditions might be extremely different from psoriasis vulgaris, common pathological findings can be identified in all of them. Microscopic analysis of psoriatic lesions may therefore help clinicians to make the diagnosis and to understand that, whatever the clinical presentation, signs and symptoms are mainly due to a unique pathological process.     

Interactions in the aetiology,presentation and management of synchronous and metachronous adenocarcinoma of the prostate and rectum

Adenocarcinoma of the prostate and rectum are common male pelvic cancers and may present synchronously or metachronously and, due to their anatomic proximity. The treatment of rectal or prostate cancer (in particular surgery and/or radiotherapy) may alter the presentation, incidence and management should a metachronous tumour develop. This review focuses on the interaction between prostatic and rectal cancer diagnosis and management. We have restricted the scope of this large topic to general considerations, management of rectal cancer after prostate cancer treatment and vice versa, management of synchronous disease and cancer follow-up issues.     

Analgesic nephropathy

Many questions about analgesic nephropathy (AN) lack clear-cut answers. We present available evidence for and against proposed answers to many of these questions. These include: (1) Is acetaminophen (AC) nephrotoxic when taken as the sole analgesic? (2) Is the combination of acetylsalicylic acid (ASA) and AC more nephrotoxic than AC taken alone, and if so, why? (3) What are the minimum doses and durations of ingestion required to produce analgesic nephrotoxicity? (4) Is the combination of ASA and AC (a major metabolite of phenacetin) less nephrotoxic than that of phenacetin and ASA combined? (5) Does caffeine in combination with analgesics contribute to nephrotoxicity? (6) What is the incidence of end-stage renal disease (ESRD) due to AN? (7) What uniform diagnostic criteria should be established for AN? (8) What are the earliest anatomic and biochemical abnormalities? (9) What are the mechanisms of renal injury? (10) Does AC cause uroepithelial neoplasia? (11) What research might be most beneficial? Based mainly on associations, some strong, we suggest that AN still exists as a cause of ESRD in the United States, where AC/ASA combinations are available over the counter, and in Canada, where they are not. We also suggest that the evidence needed to recommend that the AC/ASA combination be excluded from over-the-counter analgesic preparations still has limitations. A prospective multicenter study comparing incidence related to AC/ASA in the United States and to AC in Canada and the United States may be needed to answer this question. For such a study to be worthwhile, an adequate incidence in both countries is required.     

Radiologic diagnosis of oat cell cancer in a high-risk screened population

A screening program of 10,040 cigarette-smoking men over 45 years of age was undertaken in an attempt to achieve earlier diagnosis, thereby increasing the cure rate, of oat cell lung cancer. Of the 155 men who were found to have lung cancer, 27 (17%) had confirmed oat cell cancer. Only one case was diagnosed at the first examination. The other 26 cases (called incidence cancer) were diagnosed by subsequent examinations. In 24 of the 26 patients, the tumor was not found until it was advanced (Stage III), and of these patients, only one is alive at 21 months follow-up. Two tumors were diagnosed as oat cell carcinoma at an early stage (Stage I), and both patients are alive with no evidence of disease at seven and 24 months. The screening program used in this study did not succeed in detecting oat cell cancer at an early stage.