Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site- -a clinical research center study.

As part of a phase III multicenter study, the pharmacokinetics and metabolism of a permeation-enhanced testosterone (T) transdermal (TTD) system and the influence of application site were investigated in 34 hypogonadal men (21-65 yr of age). After an 8-week androgen washout period, two TTD systems were applied to the back for 24 h. Serum concentrations of total T, bioavailable testosterone (BT), dihydrotestosterone (DHT), and estradiol (E2) increased from hypogonadal levels into the respective normal physiological ranges and declined to baseline levels within 24 h after system removal. Peak concentrations occurred approximately 8 h after application for T and BT and at 13 h for DHT and E2. The baseline-subtracted time-average steady state concentrations (C'ss) for T and BT were 18.1 +/- 7.49 (+/- SD) and 9.08 +/- 3.99 nmol/L, respectively. DHT/T and E2/T ratios, derived from the C'ss values, were 0.063 +/- 0.018 and 0.0033 +/- 0.0018, comparable to the precursor-product conversion ratios reported in healthy men. The estimated half-lives of each hormone were: T, 1.29 +/- 0.71 h; BT, 1.21 +/- 0.75 h; DHT, 2.83 +/- 0.97 h; and E2, 3.53 +/- 1.93 h. The influence of application site was then evaluated by applying two TTD systems for 24 h to the abdomen, back, chest, shin, thigh, or upper arm, according to a sequential cross-over design. Hormone profiles were qualitatively similar at each site, but C'ss values showed significant differences (by ANOVA, P < 0.0001). Based on the BT levels, the rank ordering of the sites were: back > thigh > upper arm > abdomen > chest > shin. DHT/T and E2/T ratios showed negligible site to site variation and were comparable to the results from the initial study. Estimates of T input, based on hormone levels and analysis of the systems used, averaged 4-5 mg/day for the abdomen, back, thigh, and upper arm and were lower and more variable for the chest and shin. Individual C'ss values for T and BT increased linearly with the T input rates (derived from used system analysis) across all studies (n = 235; r = 0.564 for T and r = 0.754 for BT). From these data, T and BT clearance rates were estimated for each patient, averaging 1248 +/- 518 and 2435 +/- 778 L/day, respectively. T clearance rates were proportional to the BT/T ratio (nonsex hormone-binding globulin-bound fraction). On the basis of these studies, the optimal sites of TTD system application were identified as the back, thigh, upper arm, and abdomen

Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status.

OBJECTIVE: To determine whether olfactory status predicts cognitive decline (CD) over a 2-year follow-up period. METHODS: The authors enrolled individuals in a community-based longitudinal study of memory and aging in the Japanese-American community in King County, WA, between 1992 and 1994. At baseline they screened 1,985 persons using the Cognitive Abilities Screening Instrument (CASI) and the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Of these 1,985 people, 1,836 were found not to be demented. Two years later the authors rescreened 1,604 participants with the CASI. They defined CD as a 2-year loss of > or =5.15 points/100 on the CASI. They genotyped 69% of the 1,604 people completing both examinations for apolipoprotein E (apoE). RESULTS: After adjusting for age, CASI score at baseline, education, smoking, sex, and follow-up time, the authors determined an odds ratio (OR) for CD of 0.90 (95% CI, 0.84 to 0.97) for an increase in each correct point on the CC-SIT (range, 0 to 12). Compared with normosmics, the OR for persons with impaired olfaction (microsmics) was 1.25 (95% CI, 0.83 to 1.89) and for anosmics the OR was 1.92 (95% CI, 1.06 to 3.47). Persons who were anosmic at baseline and who had at least one APOE-epsilon4 allele had 4.9 times the risk of CD (95% CI, 1.6 to 14.9) compared with normosmics without the epsilon4 allele. The estimated relative risk among women was 9.7 (95% CI, 1.3 to 70.4), and for men the risk was 3.2 (95% CI, 0.8 to 12.6). Receiver operating characteristic (ROC) curves showed that although the area under the curve (AUC) for baseline CASI was only 0.51, the AUC for CC-SIT alone was 0.62. Adding CC-SIT to the ROC model with CASI improved the AUC curve from 0.51 to 0.62. CONCLUSIONS: Unexplained olfactory dysfunction in the presence of one or more APOE-epsilon4 alleles is associated with a high risk of cognitive decline. Cross-Cultural Smell Identification Test classifies people with cognitive decline correctly to a greater degree than a global cognitive test.

Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system.

OBJECTIVES: This study examined the effects of testosterone replacement using a nonscrotal testosterone transdermal (TTD) system on prostate size and prostate-specific antigen (PSA) levels in hypogonadal men. METHODS: As part of an open-label, multicenter study, prostate volume as measured by transrectal ultrasound and PSA were assessed in 29 hypogonadal men during treatment with intramuscular testosterone enanthate (+TE), followed by 8 weeks of androgen withdrawal (-T), and then during 1 year of therapy with Androderm Testosterone Transdermal System, a nonscrotal permeation-enhanced TTD system (+TTD). RESULTS: Mean prostate volume decreased significantly from the +TE period (17 g) compared with the -T period (14 g) (P < 0.001). Prostate volume increased significantly from the -T period compared with the +TTD period (18 g) (P < 0.001). Maximum prostate size, comparable to that measured during +TE (P = 0.125), was reached by month 3 of +TTD therapy; prostate volume did not increase further during the remaining 9 months of +TTD therapy. Prostate volume correlated with age (P < 0.01) during all three periods of observation (+TE: r = 0.69; -T: r = 0.64; and +TTD: r = 0.55). No patient developed symptomatic benign prostatic hyperplasia during the treatment period. PSA levels decreased during androgen withdrawal compared with levels measured during +TE treatment (P < 0.001) and rose with resumption of androgen therapy with TTD (P < 0.006). However, PSA levels during +TTD replacement remained significantly lower (P < 0.001) than during +TE replacement. CONCLUSIONS: Physiologic testosterone replacement in hypogonadal men was achieved using the TTD system. Prostate size during therapy with TTD was comparable to that reported for normal men. In these men treated with TTD, PSA levels were also within the normal range.

A comparison of education methods and their impact on behavioral change in patients with hyperlipidemia.

We sought to determine the efficacy of a hospital-based, professionally-taught program emphasizing cardiovascular health. Similar programs are in existence throughout the country without documentation of their long-term benefits. Thirty-six hyperlipidemic individuals were treated as a control group or participated in one of two intensive educational interventions. The educational program was based on information obtained from focus group methodology to elicit attitudes about dietary change and learning style preferences. Behavioral changes in smoking, dietary salt and saturated fat intake, stress and tension, physical activity, and departure from ideal body weight were documented using health questionnaires and Lifestyle Risk Indices. At three months of follow-up, there was no change in serum lipids, total fat intake, or cardiovascular risk behavior in either the control or intervention group. We conclude that a one-day program, whether designed by the target population or experts, did not improve cardiovascular risk behaviors, suggesting that more innovative methods are required to address health behaviors in this high risk group.

Cognitive decline and Japanese culture in a cohort of older Japanese Americans in King County, WA: the Kame Project.

OBJECTIVES: The prevalence of Alzheimer's disease in studies of Japanese show generally lower rates when compared with those of Caucasians. We hypothesized that among a cohort of Japanese Americans lifestyle differences would act to modify progression of the Alzheimer pathologic process over many years, resulting in a slower cognitive decline among persons whose lifestyle is more characteristically Japanese. METHODS: One thousand, eight hundred and thirty-six nondemented persons were screened with the Cognitive Abilities Screening Instrument (CASI) at baseline, and 1,604 were rescreened 2 years later. Baseline questions included migration status, exposure to Japanese culture in early life and maintenance of such culture in adulthood, and other risk factors. Cognitive decline was defined as a 2-year loss of > or = 5.15 points/100 on CASI. RESULTS: In multivariable logistic regression, variables relating to reading, writing, and speaking Japanese, being born or having lived in Japan in early life, and having friends who are only/mostly Japanese were inversely associated with cognitive decline (odds ratios ranged between 0.28 and 0.64, with p < .05). Two factors emerged in a factor analysis of these variables. The strongest explained 49% of the variance for acculturation and loaded heavily on knowledge of the Japanese language and having spent one's early years in Japan. When this factor was dichotomized into the top 20th percentile, it predicted cognitive decline with an odds ratio of 0.12 (95% CI 0.03-0.49). DISCUSSION: These results show that a Japanese lifestyle may decrease the risk of expressing cognitive decline over a 2-year follow-up period. Lower cardiovascular disease rates among Japanese may also predispose them to lower rates of cognitive decline. The greater social support characteristic of Japanese culture as well as the role that Japanese language and culture may play in neural connectivity during brain development and/or in mental stimulation in adult life may also explain our findings.

Defining practice patterns in gynecologic oncology to prevent pulmonary embolism and deep venous thrombosis.

OBJECTIVE: The goal of venous thromboembolism (VTE) prophylaxis is to reduce the morbidity and mortality associated with the development of a deep venous thrombosis (DVT) or pulmonary embolism (PE). Because women with gynecologic cancers are at high risk to develop VTE, we sought to determine the present practice patterns of gynecologic oncologists regarding their use of VTE prophylaxis. METHODS: 1073 members of the Society of Gynecologic Oncologists (SGO) were mailed surveys that asked about preferred methods to prevent the development of VTE after gynecologic oncology surgery. Data were collected by online member entry and return mail. Frequency distributions were calculated and nonparametric test used for comparisons. RESULTS: 343/1073 (34%) of SGO members and fellows responded. 142/343 (42%) preferred double prophylaxis consisting of external pneumatic compression (EPC) and an anticoagulant while 41% (n=141) preferred EPC with no additional anticoagulation. Of respondents choosing any anticoagulant, 40% preferred Enoxaparin pre- and/or postoperatively. Ovarian cancer patients were perceived by respondents to have the highest risk of developing a postoperative PE. CONCLUSIONS: Most respondents agree that women with gynecologic cancers undergoing major surgery should receive VTE prophylaxis, though there is not agreement as to which method is optimal. While 42% of members preferred double prophylaxis, 41% chose no additional measures other than EPC. Randomized studies in gynecologic oncology should be initiated in the United States to determine the optimal practice pattern.

Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men.

OBJECTIVE: An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a permeation-enhanced testosterone transdermal system (TTD) in the treatment of hypogonadal men for a 12-month period. DESIGN: Open-label, multicentre study with four consecutive periods: Period I (3 weeks)--evaluation of patients' current androgen therapy, which consisted primarily of testosterone enanthate injections (mean dose 229 mg; mean interval 26d); Period II (8 weeks)--androgen washout; Period III (3-4 weeks)--single-dose pharmacokinetic studies of TTD systems; Period IV (12 months)--efficacy, safety, and steady-state pharmacokinetic evaluation of TTD systems (5 mg/day nominal delivery rate of testosterone). Results from Periods I, II, and IV were compared. PATIENTS: Thirty-seven hypogonadal men 21-65 years old enrolled; 34 entered Periods III and IV; 29 (9 primary, 20 secondary hypogonadism) completed the study. Four patients withdrew because of adverse events (Period II, one; Period IV, three). MEASUREMENTS: Morning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), and oestradiol (E2) levels. Circadian pattern of T profiles and 24-hour time-average T level. LH levels in patients with primary hypogonadism. Reduction of hypogonadal symptoms. Safety assessments including skin tolerability, prostate parameters, lipid profile, and systemic parameters. RESULTS: Twelve months of TTD therapy normalized morning serum T levels in 93% of patients, and produced greater than 80% normalization of BT, DHT and E2 levels. The TTD system mimicked the circadian variation in T levels seen in healthy young men and normalized 24-hour time-average T levels in 86% of patients. Luteinizing hormone was suppressed in 8 of 9 men with primary hypogonadism, and normalized in 5 of these. Subjective symptoms of hypogonadism, including decreased libido and fatigue, showed improvement after 2-4 weeks of TTD treatment in most patients. The majority of adverse events were local skin reactions, and 3 patients (9%) discontinued the study for this reason. Prostate assessments showed a lower prostate-specific antigen level during TTD therapy compared to IM injections (0.66 vs 1.00 microgram/l P < 0.001), while prostate size did not differ significantly between the two treatment regimens. CONCLUSIONS: The permeation-enhanced testosterone transdermal system produces physiological levels and circadian patterns of testosterone, and its metabolites, in hypogonadal men. Although transient erythema and itching is commonly reported, the TTD is generally well tolerated by most patients. This system offers a new treatment option for testosterone replacement therapy that results in physiological serum levels of sex hormones in hypogonadal men.