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.     

Epidemic outbreak of interstitial lung disease in aerographics textile workers--the "Ardystil syndrome": a first year follow up.

BACKGROUND: The longer term respiratory effects of massive inhalational exposure of textile printing sprayers to Acramin (the "Ardystil syndrome") are not well established. METHODS: A 12 month follow up of 27 heavily exposed textile sprayers was performed. RESULTS: Twenty one patients experienced cough, 18 dyspnoea, and 17 nose bleeding at initial exposure, with histological evidence of organising pneumonia in 13 cases, radiological abnormalities detected by computed tomographic scanning in 20 cases, and diminution of diffusion capacity to below 80% of predicted in seven cases. At one year after exposure symptoms persisted in 15 cases, radiological alterations in six, and diffusion capacity was reduced in nine. CONCLUSIONS: Whilst most of our patients showed improvement at one year, evidence of persistent lung involvement was present in an appreciable minority of exposed cases.     

Type I familial amyloid polyneuropathy and pontine haemorrhage

A Portuguese female, aged 47 years, who had emigrated to Spain, was admitted to the hospital in 1991 for pontine haematoma. The patient, four siblings and her father were affected by a peripheral neuropathy, indicating autosomal dominant inheritance. The patient presented in the 2nd decade with sensory and motor neuropathy beginning in the lower extremities. Alternating constipation and diarrhoea, and urinary incontinence became uncontrollable. She had to be colostomised, and, eventually, confined to a wheelchair from the age of 43. Neurological examination showed bilateral facial involvement, and severe signs of sensory and motor peripheral neuropathy, and later right hemiplegia. There were abnormalities of atrial rhythm and left bundle branch block. Computerised axial tomography and magnetic resonance images demonstrated left-sided pontine haemorrhage. Nerve conduction studies revealed severe diminution of motor conduction velocity and absence or reduction of amplitude of sensory and motor action potentials. Inanition and a respiratory infection led to her death. Clinical diagnosis was type I familial amyloid polyneuropathy (FAP). Postmortem examination demonstrated amyloid deposits in peripheral nerves, including spinal roots and cranial nerves, leptomeninges, thyroid, breasts, heart, adrenal glands, kidneys, intestines, pancreas, and meningeal and some pontine vascular structures. Advanced pontine haematoma was verified. Cerebral haemorrhage usually occurs with cerebrovascular amyloidosis, but exceptionally with FAP. A minority of patients presenting with CNS haemorrhage showed arteriovenous malformation or embolism [Da Silva Horta and Dias Coelho (1960) Arch de Vecchi Anal Patol Med Clin 31=163–172]. However, amyloid deposition in some small pontine vessels could have played a role in the pathogenesis of haemorrhage in the present case.     

Congenital pulmonary atresia with ventricular septal defect: angiographic and surgical correlates

Of 181 patients with severe congenital pulmonary atresia and ventricular septal defect or "type IV truncus" (an obsolete term), all but 11% had true central pulmonary arteries. These arteries were demonstrable by large serial biplane angiograms using multiple selective injections into collateral vessels, frequent photographic subtraction, and occasional pulmonary vein-wedge angiograms. These techniques are extremely important for accurate diagnosis and in planning corrective or palliative surgery, which was done in 77% of patients with pulmonary arteries.     

Spatiotemporal profile of synaptic activation produced by the electrical and visual stimulation of retinal inputs to the optic tectum: a current source density analysis in the pigeon (Columba livia)

The optic tectum of the pigeon is a highly organized, multilayered structure that receives a massive polystratified afference of at least five different populations of retinal ganglion cells and gives rise to various anatomically segregated efferent systems. The synaptic organization of retino-tectal circuitry is, at present, mostly unknown. To investigate the spatiotemporal profile of synaptic activation produced by differential (electrical and visual) stimulation of the retinal inputs, we performed a high-spatial-resolution current source density analysis in the optic tectum of the anaesthetized pigeon. Electrical stimuli consisted of brief pulses of different durations applied to the optic nerve head, while visual stimuli consisted of light flashes of different intensities. Electrical stimulation generated sinks confined to retinorecipient layers. The temporal structure, spatial location and thresholds of these sinks indicated that they are all due to primary tectal synapses of retinal fibers with different conduction velocities. Sinks evoked by the fastest retinal axons were more superficially located than sinks produced by slower retinal fibers. Visual stimulation, on the other hand, resulted in a more complex pattern of current sinks, with various sinks located in the retinorecipient layers and also well below. Visual stimulation induced action potentials at superficial as well as deep tectal levels. We conclude that electrical stimulation activates most of the populations of ganglion cells as well as their primary tectal synapses, but is unable to elicit a significant activation of secondary tectal synapses. Visual stimulation, on the contrary, activates just some of the incoming retinal populations, but in a way that produces noticeable secondary activation of intratectal circuits. Laminar segregation of retinally evoked tectal activity, as reported here, has also been found in other vertebrates. Similarities and differences with previous studies are discussed.     

Role of prosaposin in the male reproductive system: effect of prosaposin inactivation on the testis, epididymis, prostate, and seminal vesicles

SGP-1/prosaposin can be secreted or targeted to the lysosomes where it is processed into smaller saposins (A, B, C, and D) required for the hydrolysis of glycosphingolipids. The deficiency of saposins B and C results in variant forms of metachromatic leukodystrophy and Gaucher's disease, respectively, which are characterized by lysosomal storage of undegraded glycosphingolipids. In the nervous system, prosaposin presents trophic activity. A mouse model was recently developed by creating a null allele in embryonic stem cells through gene targeting to investigate the phenotypic diversity of prosaposin mutations and the involvement of this protein in lysosomal storage diseases, and for the development of therapeutic approaches. Mice homozygous mutants die at the age of 35-40 days and neurological disorders contribute to the early demise of the mutant mice. The male reproductive organs in homozygous mutants show several abnormalities, such as a decrease in testis size with reduced spermiogenesis and an involution of the prostate, seminal vesicles, and epididymis. In these animals, the blood levels of testosterone remain normal. In the prostate of homozygous mutants, only the basal epithelial cells appear to be present, while the secretory cells are absent. These findings suggest that prosaposin may be involved in the development and maintenance of the male reproductive organs, as well as, in cellular differentiation.     

Prognostic significance of clinical and angiogenesis-related factors in low-grade oligodendrogliomas

BACKGROUND: Keeping in mind that oligodendrogliomas have unpredictable biological behavior, the aim of this study is to investigate the prognostic significance of VEGF expression and microvessel density in a homogeneous series of low-grade oligodendrogliomas. METHODS: For this study 36 patients with a low-grade oligodendroglioma treated by surgical resection and radiotherapy were selected. At the time of surgery, in all cases the Karnofsky Performance Scale (KPS) score was more than 70, and the study of the resected tumor disclosed a Ki-67/MIB-1 labeling index (MBI-1 LI) less than 1%. In this homogeneous series, immunohistochemical studies were performed using monoclonal antibodies against VEGF in order to study the expression of this cytokine, and against vascular endothelial CD-34 antigen, in order to identify microvessels. RESULTS: Our results show that in contrast to low-grade astrocytomas, low-grade oligodendrogliomas lacked immunoreactive VEGF. Oligodendrogliomas with low vascular density (less than 20 microvessels per microscopical field, at 200 x) or high vascular density (more than 100 microvessels per field, at 200 x) were identified, but this factor had no influence on the survival rate of patients. On the other hand, analysis of the present series showed that clinical factors, such as age or extent of surgical resection, were not significantly associated with survival. CONCLUSIONS: In contrast to low-grade astrocytomas, the angiogenesis score of low-grade oligodendrogliomas (counting the number of microvessels in tumor tissue) adds little information to help predict tumor behavior.