Linda E. Atkinson

Effect of pentosan polysulfate therapy on intravesical potassium sensitivity

OBJECTIVES To evaluate further the intravesical potassium sensitivity test (PST) as an indicator of the epithelial leak of interstitial cystitis (IC) and determine whether successful pentosan polysulfate (PPS; Elmiron) treatment is associated with a change in PST results. Most individuals with IC appear to have an abnormally permeable epithelium that allows urinary solutes such as potassium to penetrate to the bladder interstitium, provoking symptoms. METHODS Data were from an optimal dose trial of PPS in IC. Patients underwent a PST before and after a 32-week trial of 300, 600, or 900 mg PPS/day. The response to PPS treatment was measured using the Patient Overall Rating of Improvement in Symptoms scale. The before and after treatment PSTs and Patient Overall Rating of Improvement of Symptoms scores were compared. RESULTS Of 377 patients with IC at 28 centers, 302 (80%) had a positive PST at entry. Of the 198 patients who completed the study, 153 were PST positive at entry and 92 (60%) showed clinical improvement at exit. Clinically improved patients had significant improvement on the PST analog pain and urgency scales (3.2 to 1.3 and 3.6 to 1.9, respectively; P <0.0001). In contrast, patients with no clinical improvement had no significant change in pain (3.1 to 2.7) or urgency (3.6 to 3.2). CONCLUSIONS PST shows abnormal epithelial permeability in most patients with IC and a significant reduction in this permeability after successful PPS therapy. PST appears to be a valid indicator of epithelial abnormality and a reliable test in the diagnosis of IC.

Serum LH concentrations in hypogonadal men during transdermal testosterone replacement through scrotal skin: further evidence that ageing enhances testosterone negative feedback

The present study was designed to explore further the mechanism for the decline in androgen production as men age by studying the influence of ageing on testosterone negative feedback control of gonadotrophin secretion.

Comparison of the skin irritation potential of two testosterone transdermal systems: an investigational system and a marketed product

Effective transdermal therapy provides controlled release of the appropriate amount of a therapeutic agent while minimizing local irritation. Transdermal administration of testosterone has the potential to produce skin irritation. This open-label, randomized, 14-day, outpatient study compared the skin irritation of an investigational testosterone transdermal system (System I) with that of a marketed testosterone transdermal system (System II) in healthy men. In Part 1 of the study. System I was applied 10 times over 14 days to the same skin site on the backs of 26 healthy men. In Part 2, the skin irritation resulting from daily application of Systems I and II was assessed over 14 days in 17 men less than 65 years of age and 16 men 65 years of age or older. At the end of Part I of the study, 65.4% of the subjects experienced no erythema, 15.4% of subjects had faint erythema, and 19.2% had moderately intense erythema immediately after System I removal. At the completion of Part 2, none of the System I application sites were assessed as having moderately intense erythema, whereas one third (33.3%) of System II application sites demonstrated moderately intense erythema. There were no differences in erythema rates between younger and older subjects with either transdermal system. During this study, repeated application of System I to the same skin site resulted in acceptable noncumulative irritation, suggesting that application-site rotation may not be necessary. A comparison of the two systems demonstrates that System I results in significantly less application-site irritation than does System II and that older men do not have a higher rate of skin reactions.

Long-term safety of extended-release oxybutynin chloride in a community-dwelling population of participants with overactive bladder: a one-year study.

In this multicenter, open-label study of extended- and immediate-release oxybutynin chloride, community-dwelling participants were studied for up to 12 months to evaluate the long-term safety profile of extended-release oxybutynin. Quality-of-life assessments designed to measure the impact of incontinence and evaluate treatment outcome were used to study subjective improvement.A total of 904 women and 163 men (mean age 64 years, range 29–91 years) were enrolled. The majority of discontinuations were in the first 3 months (25.5%); of those who continued after 3 months, 62% remained on extended-release oxybutynin chloride for one year. The majority of discontinuations were for adverse events; dry mouth was the most frequently cited event leading to discontinuation (8.4%). Significant improvements were seen in QOL measures. Long-term therapy with extended-release oxybutynin chloride was generally well tolerated and effective, improving quality of life significantly in participants with overactive bladder over 3–12 months of therapy.

The Effect of Food, Time of Dosing, and Body Position on the Pharmacokinetics and Pharmacodynamics of Verapamil and Norverapamil

To evaluate the influence of food, time of dosing, and body position on the steady‐state pharmacokinetics of an osmotically controlled formulation of verapamil (COER‐verapamil), each of 29 healthy men received one tablet a day at specified times in an open‐label, multiple‐dose, four‐period, crossover study. The verapamil tablets were administered in a randomized, balanced, crossover design: 240 mg at 8:00 AM on an empty stomach, subjects remaining ambulatory;240 mg at 8:00 AM on an empty stomach, subjects remaining supine for 8 hours; 240 mg at 10:00 PM with a standardized meal, subjects remaining supine for 8 hours; and 240 mg at 10:00 PM on an empty stomach, subjects remaining supine for 8 hours. Plasma verapamil concentrations were measured at steady state over the dosing interval. Steady‐state plasma concentrations were achieved by the fourth administration of the drug. Neither food nor posture had any effect on the pharmacokinetics of verapamil or norverapamil, or on hemodynamic measurements. Time of dosing did affect the rate of appearance and elimination of verapamil, but had no effect on the extent of verapamil absorption, norverapamil appearance, or hemodynamic measurements.

Testosterone Pharmacokinetics after Application of an Investigational Transdermal System in Hypogonadal Men

This open‐label, randomized, placebo lead‐in, three‐treatment crossover study in 19 hypogonadal men (27–82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.

Transdermal Testosterone Administration in Hypogonadal Men: Comparison of Pharmacokinetics at Different Sites of Application and at the First and Fifth Days of Application

In this study of 13 hypogonadal men (25–69 years of age), three open‐label, randomized treatments were administered to determine the pharmacokinetics of serum testosterone after application of an investigational testosterone transdermal system to the upper buttocks, upper arm, and back. Testosterone in vivo input kinetics profiles were estimated by DeMonS, a recently developed numerical deconvolution method for estimating drug absorption at different time intervals and/or drug disposition model parameters, and compared on the first and fifth days of system application. Area under the concentration‐time curve from 0 to 27 hours (AUC0–27) values for testosterone after one‐day applications to the upper buttocks, upper arm, and back were 9,560 ng · hr/dL, 8,651 ng · hr/dL, and 8,988 ng · hr/dL, respectively. Maximum observed concentration (Cmax) values were 482 ng/dL, 462 ng/dL, and 499 ng/dL, respectively. Serum testosterone concentrations were equivalent to each other, and Cmax values fell within the normal range. No drug accumulation was seen with repeated dosing over 5 days.

Long-term experience with testosterone replacement through scrotal skin

Testosterone is the primary endogenous androgenic hormone. Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for the maintenance of secondary sex characteristics. The goals of treating male hypogonadism are the development or restoration of secondary sex characteristics, sexual function, and normal metabolic processes, and prevention of chronic bone loss (Bhasin 1992; Bhasin and Bremner 1997; Ghusn and Cunningham 1991). This chapter will summarize the clinical experience with Testoderm, a transdermal delivery system for testosterone, and the evidence of meeting treatment goals while providing a therapy for chronic use that is generally safe and does not produce untoward side effects with chronic treatment.

Simultaneous First‐Order and Capacity‐Limited Elimination Kinetics After Oral Administration of Verapamil

In this study of the relationship between dose and plasma concentration of verapamil, controlled‐release verapamil in doses of 120 mg, 180 mg, 360 mg, and 540 mg were examined. The 48 study subjects received verapamil daily during each of the 4 sequential 5‐day dosing segments. Blood samples were collected frequently to obtain first‐dose and steady‐state (fifth dose) concentration profiles of verapamil. Plasma concentrations of R‐and S‐verapamil and R‐ and S‐norverapamil were measured by stereospecific assay. Statistical comparisons of pharmacokinetic parameters and mean differences between doses were performed with analysis of variance models. At steady state, area under the concentration—time curve (AUC) values for R‐ and S‐verapamil at both the 120‐mg and 180‐mg doses were about 1.5 times higher than the corresponding first‐dose values. After both first and fifth doses, pharmacokinetic parameters for all four analytes were dose proportional between the 120‐mg and 180‐mg doses. A dose‐proportional relationship also was found between the 360‐mg and 540‐mg dose levels. However, nonlinearity was found between the 180‐mg dose and higher doses, suggesting saturable metabolic pathways. The dose‐proportional relationship between the 360‐mg and 540‐mg doses suggests that other first‐order metabolic pathways become dominant. Although results from this study are partially consistent with previously reported nonlinear verapamil kinetics, this is the first clinical study to demonstrate a dose‐proportional relationship for verapamil at both low and high input rates (mg/hr). In addition, first‐order disposition pathways of verapamil are probably nonexistent at medium input rates and become dominant at higher input rates.