Pharmacokinetics and Safety of a Selegiline Transdermal System Relative to Single-Dose Oral Administration in the Elderly

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.     

Ultrasound Densitometric Analysis: Comparison Between an Online Digital Acquisition Acoustic Program and an Offline Analog Program

Videodensitometric analysis of myocardial contrast echocardiography is traditionally performed off line. Recently, an online contrast ultrasound analysis system, Acoustic Densitometry (Hewlett-Packard), was introduced. We compared pixel intensities acquired with Acoustic Densitometry to pixel intensities derived from videodensitometry. A tissue phantom was imaged in phase I using three transducer frequencies (2.5, 3.5, and 5.0 MHz). In phase II, an in vitro flowing tube model with various concentrations of Albunex® was imaged at two flow rates, 0.6 and 1.2 m/sec, and at two transducer frequencies, 2.5 and 3.5 MHz. The relationship between pixel intensities yielded by the two systems for identical ultrasound signals was determined with linear regression. Intensities derived with Acoustic Densitometry strongly correlated with those derived from the offline videodensitometry system. The intensities were related by a predictive multiplicative factor based on display characteristics of the two systems. These results suggest that semiquantitative, online perfusion analysis with Acoustic Densitometry is as sensitive as analysis offline with videodensitometry.     

Excisional Plication of the Ileocecal Valve: A Useful Adjunct for the Construction of Continent Urinary Diversions

Purpose

A variety of techniques exist to reinforce the ileocecal valve for use as a nonrefluxing mechanism in continent urinary diversion. We report short-term and long-term followup for a new technique of excisional plication of the valve.

Materials and Methods

Since 1988 we performed 16 procedures in 15 patients. The technique was used for repair of an incompetent ileocecal valve to restore continence in 2 patients in whom continent cutaneous diversion failed, and to correct a massively refluxing ileocecal valve following previous augmentation with an ileocecal segment in 1. The remaining patients underwent the procedure in conjunction with continent cutaneous ileocecal diversion with a modified Indiana pouch.

Results

To date no patient undergoing continent cutaneous diversion required reoperation to correct incontinence. Two patients wear a protective pad during the day, while the remainder have been completely dry during followup.

Conclusions

Excisional plication is a versatile and simple procedure that may be used to assist construction and repair of ileocecal valves in conjunction with continent urinary diversion.     

Immunohistochemical analysis of 61 pituitary adenomas with a monoclonal antibody to the neuron-specific β-tubulin isotype

Pituitary adenomas surgically resected from 61 consecutive patients and 9 normal pituitary glands were studied by immunohistochemistry to determine the localization of the class III-tubulin isotype (neuron-specific) which is recognized by the monoclonal antibody TUJ1. In normal pituitary glands only a few cells were weakly immunopositive for TUJ1, whereas, in 43(73%) of 61 adenomas, more than 5% of tumor cells were immunopositive. The result may indicate that this neuron-specific -tubulin isotype may be either expressed de novo or enhanced under the transformation of pituitary acinar cells to tumors.Research fellow of the Department of Pathology, Kitasato University School of Medicine where the work was conducted     

Behavioral and Neurological Characteristics of a Hydranencephalic Infant

A modified Prechtl neurological examination and the Brazelton Neonatal Assessment Scale were serially administered to a hydranencephalic infant over the first eight weeks of life. Clinical, roentgenographic, neurological and behavioral findings are reported. In contrast to earlier reports, visual tracking of a moving field and auditory and visual habituation were observed. Further, in addition to previously reported reflex automatisms, the infant also possessed what are termed "socially relevant behavioral automatisms". The implications of these findings are discussed.     

A stratified randomized study of intradermal BCG in patients with carcinoma of the bronchus: prolongation of quality but not length of life in inoperable patients.

This paper reports the results of a stratified, randomized trial of monthly intradermal injections of Glaxo BCG in addition to conventional therapy (surgery, radiotherapy or no treatment) in a consecutive series of 75 men with confirmed bronchial carcinoma. BCG treatment did not significantly prolong survival but had consistenly more effect in prolonging the period in good general condition and in "acceptable" clinical condition. These were significantly prolonged among the BCG patients (all histopathologies) treated with a full course of radiotherapy (p = 0.01, p = 0.005) and among the 43 patients with squamous carcinoma after adjustment for treatment and general prognostic factors (ratio of observed to expected deaths (O/E) for BCG 0.65, P = 0.025). There was a tendency for BCG patients with oat cell carcinoma to survive less well than controls (O/E for BCG 1.40 not significant). Within comparable groups of patients with squamous carcinoma the delay in decline of general condition was accompanied by reduced weight loss.     

SOME ISSUES IN THE USE,PERCEPTION, AND CONSTRAINTS OF CHOICE OF ACCOMMODATION OPTIONS FOR THE ELDERLY

Choice with respect to relocation for the elderly is rarely simple. Individuals need to be able to make informed choices about relocation whenever they are mentally capable of doing so. When this is not possible it is equally important that the relatives and professionals who decide for them are in a position to make informed decisions. Choice is concerned with ‘notions’ as well as with ‘knowledge’. Successful relocation requires successful adaptation, and the older a person is the longer the process of adaptation and the less the likelihood of it being successful. This paper explores three areas:

• 1 The accommodation situation in South Australia today.
• 2 The thoughts of the elderly regarding their future accommodation.
• 3 Possible directions for future policy.

     

A phase I trial of continuous-infusion cyclophosphamide in refractory cancer patients

Summary Cyclophosphamide demonstrates enhanced tumoricidal activity with decreased bone marrow toxicity when given on a divided-dose schedule in certain animal models. A total of 22 patients presenting with refractory metastatic cancer were treated in a phase I trial of continuous infusion of cyclophosphamide over 96 h. Granulocytopenia of <500/l that lasted for > 14 days or thrombocytopenia of <25,000/l that lasted for > 14 days was the target dose-limiting toxicity in the absence of nonhematologic grade 4 toxicity. The maximal tolerated dose was 7 g/m². Three patients died. Of 21 evaluable patients, 9 responded, including 8/9 who had experienced disease progression during prior oxazaphosphorine-containing combination chemotherapy. Clinically meaningful responses were observed in patients who had demonstrated clinical resistance to an oxazaphosphorine drug given at lower doses.Supported in part by U.S. Public Health Service grant P01CA-38493 and by a grant from the Mather's Foundation. Two of the authors (J. P. E. and A. D. E.) are recipients of Career Development awards from the American Cancer Society, and one (T. C. S.) is a recipient of a Faculty Development Award from the Pharmaceutical Manufacturer's Association Foundation