Yasumasa Ishibashi

Clinical Pharmacokinetics of Sparfloxacin

SummarySparfloxacin is a recently developed fluoroquinolone. The drug has shown potent antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, glucose nonfermenters, anaerobes, Legionella spp., Mycoplasma spp., Chlamydia spp. and Mycobacterium spp. Methicillin-resistant Staphylococcus aureus is also susceptible to sparfloxacin.Plasma sparfloxacin concentrations reach a peak (Cmax) of approximately 0.7 mg/L at 3 to 5 hours after a 200mg oral dose. This is followed by a monophasic slow decrease, with an elimination half-life (t½) of 15 to 20 hours. The Cmax and area under the plasma concentration-time curve show dose-related increases. Food intake does not affect the absorption and pharmacokinetics of sparfloxacin.Sparfloxacin binds weakly to plasma protein (37%), and exhibits excellent tissue distribution and effective penetration into extracellular fluids. Concentrations of the drug in most tissues are similar to, or higher than, concomitant plasma concentrations. Sparfloxacin distributes slightly into cerebrospinal fluid. The drug is metabolised to a glucuronide. The urinary excretion of the unchanged drug accounts for 10 to 14% of the given dose. The ratio of Cmax values after multiple and single oral doses is 1.3 to 1.4, but other pharmacokinetic parameters of sparfloxacin are not influenced by multiple doses.Even in patients with severe renal failure, no significant prolongation of the half-life is observed after oral administration. Sparfloxacin appears unlikely to affect the pharmacokinetics of theophylline. Antacids containing aluminium hydroxide reduce the oral bioavailability of sparfloxacin by 25 to 35%. Probenecid does not affect sparfloxacin pharmacokinetics. The pharmacokinetic properties of sparfloxacin allow once-daily administration in the treatment of various infections.

Porokeratosis as a premalignant condition of the skin: cytologic demonstration of abnormal DNA ploidy in cells of the epidermis

Clinical evidence has accumulated of malignant epithelial tumors developing on the lesions of porokeratosis. To determine the cytologic basis for the malignant change of porokeratosis, the nuclear DNA content of epidermal cells from porokeratotic lesions was measured using microfluorometry. A total of 42% of 33 porokeratotic skin lesions in eight of the 16 patients showed DNA polyploidization in the epidermis. Most of the porokeratotic skin lesions, with or without DNA polyploidization, increase cell proportions in the S and G2/M phase range. DNA indices of cells from these porokeratotic lesions distributed widely from the level of normal control epidermis to that of malignant epidermal conditions. These findings suggest that porokeratosis is undergoing the neoplastic process, and is a precursor of malignant tumors.

Neutrophilic dermatosis with myelodysplastic syndrome: Nuclear segmentation anomalies of neutrophils in the skin lesion and in peripheral blood

Neutrophilic dermatosis developed in two patients with myelodysplastic syndrome. Biopsy specimens of their skin lesions showed marked infiltration by neutrophils with nuclear anomalies, that is, hyposegmentation (pseudo-Pelger-Huët anomaly) or hypersegmentation. Peripheral blood and bone marrow neutrophils had similar anomalies. To our knowledge, this is the first report of nuclear segmentation anomalies of neutrophils in neutrophilic dermatosis skin lesions of patients with myelodysplastic syndrome.

Study of HLA class I, class II and complement genes (C2, C4A, C4B and BF) in Japanese psoriatics and analysis of a newly-found high-risk haplotype by pulsed field gel electrophoresis

SummaryGenetic polymorphisms of HLA antigens and HLA-linked serum complement components (C2, C4A, C4B and BF) were investigated in 79 Japanese patients suffering from psoriasis. HLA typing revealed increased frequencies of HLA-A1, A2, B39, Bw46, Cw6, Cw7 and Cw11. Among complement components, positive associations were obtained with C4A4 and C4B2 and a negative association with BFF. The major histocompatibility complex haplotype (supratype), HLA-A2-Cw11-Bw46-C2C-BFS-C4A4-C4B2-DRw8 is purported to be a new high-risk haplotype in Japanese patients with psoriasis. Analysis of patients with this supratype via pulsed field gel electrophoresis showed the existence of specific, extensive DNA deletions near HLA-DR genes, but no disease-specific patterns could be observed by means of this technique. The newly-found high-risk haplotype indicates racial and ethnic differences among psoriatic patients.

Amyotrophic lateral sclerosis Histologic, histochemical, and ultrastructural abnormalities of skin

We studied the reticular dermis in patients with amyotrophic lateral sclerosis (ALS) and controls with or without neurologic diseases. By light microscopy, collagen bundles in ALS dermis were reduced in amount and more loosely woven than in controls. Electronmicroscopy revealed a significant negative correlation between duration of illness and the diameter of collagen fibrils in patients with ALS. There was also a marked increase of amorphous material positive for ruthenium red in the ground substance. These findings were not observed in controls.

Porokeratosis and malignant skin tumors

SummaryA survey of the past 20 years of Japanese literature revealed 198 porokeratosis patients, 23 of whom developed squamous cell carcinomas, Bowens disease (squamous cell carcinoma in situ), and/or basal cell carcinomas on the porokeratosis skin lesions (11.6%). Malignant transformation was not found in the 55 patients of actinic-type porokeratosis. Fifty-six malignant-skin-tumor-associated porokeratosis patients, including the above 23 and those reported in other literature, were further analyzed. Thirty-nine percent of the patients developed multiple tumors. Malignant transformation often occurred after skin lesions were treated with ionizing radiation therapy. Large or coalescing skin lesions were frequently a source of malignancy development. The average age of patients when malignant skin tumors developed was 60 years; the average latency period was 36.7 years. Linear-type porokeratosis, where porokeratosis skin lesions develop at an early age, had a much longer latency period of 48.9 years, while the localized type, which develops skin lesions later and has a higher malignant transformation rate, had a shorter latency period of 22.2 years. Our results have confirmed the cancer-prone nature of porokeratosis and clarified that actinic damage does not accelerate the malignant transformation of porokeratosis skin lesions while ionizing radiation probably does. The clinical characteristics of malignant-skintumor-associated porokeratosis may provide us with useful information to help our understanding of this cancer-prone genodermatosis.

Clinical evaluation of scleroderma spectrum disorders using a points system

We have established a new diagnostic method using a points system to evaluate patients with early scleroderma and those with scleroderma spectrum disorders (SSD). To examine the clinical usefulness of this method, it was applied to a total of 215 cases including 97 patients with scleroderma, 32 with SSD, 28 with presumed primary Raynauds phenomenon (RP) and 58 with other connective tissue disorders (CTD). A total score was obtained for each patient as the sum of the following five factors: (1) extent of skin sclerosis (maximum, 10 points); (2) pulmonary changes (maximum, 4 points); (3) antinuclear antibodies (maximum, 5 points); (4) pattern of Raynauds phenomenon (maximum, 3 points); and (5) nailfold bleeding (maximum, 2 points). Of the 97 scleroderma patients, 86 (89%) had 9 or more points, and of the 32 SSD patients, 28 (88%) had 5 to 8 points. In contrast, all patients with presumed primary RP and 54 of 58 (93%) patients with other CTD had 0 to 4 points. These data suggest that this diagnostic method is very useful not only for clinical evaluation of SSD, but also for the differentiation of scleroderma and SSD from other CTD and primary RP.

Osteosarcomatous changes in malignant melanoma. Immunohistochemical and ultrastructural studies of a case.

Immunohistochemical and ultrastructural studies were conducted to elucidate the nature and origin of osteosarcomatous changes in malignant melanoma in a 43-year-old Japanese man. Immunohistochemical studies with the use of antisera against human S-100 protein and neuron-specific enolase demonstrated positive reactions in the tumor cells within the osteosarcomatous area. Ultrastructurally, the neoplastic cells showed marked similarities to those from osteosarcomas. Additionally, occasional neoplastic cells contained round or ellipsoidal osmiophilic organelles, presumably melanosomes. These findings indicate that osteosarcomatous changes in malignant melanoma are produced by the dedifferentiated melanoma cells.

A comparative study of cytokeratin expression in paget cells located at various sites

Background. Extramammary Paget disease appears in anogenital, axillary, or other areas. In this study, the authors addressed the question of whether the histogenesis of 35 cases of Paget disease arising at different sites was the same.

Abnormal fibrous protein isolated from the stratum corneum of a patient with bullous congenital ichthyosiform erythroderma (BCIE).

SummaryThe fibrous protein of stratum corneum was isolated from a patient with bullous congenital ichthyosiform erythroderma (BCIE), and its properties characterized using electron microscopy, amino acid analysis and SDS gel electophoresis. Results were compared with the characteristics of the fibrous protein isolated from stratum corneum of normal controls.From 900 mg (dry weight) of stratum corneum, 68 mg of fibrous protein was obtained from the patient, while 178 mg was obtained from the normal control. Structural differences were observed with electron microscopy and chemical differences were shown in the ratio of several amino acids. On SDS electrophoresis, the 55,000 dalton constituent of normal fibrous protein could not be identified in the fibrous protein from this patient. These results suggest that an alteration of the polypeptide composition of fibrous protein from this patient with BCIE occurred, and this alteration induced the morphological and clinical features of this dominant genetic keratinization disorder.ZusammenfassungFibrilläres Protein der Hornschicht wurde von einem Patienten mit bullöser congenitaler ichthyosiformen Erythrodermie isoliert.Dessen Eigenschaften wurden mittels Elektronenmikroskopie, Aminosäurenanalyse und SDS Gel-Elektrophorese bestimmt. Die Ergebnisse wurden mit den Charakteristika fibrillärer Proteine der Hornschicht normaler Kontrollen verglichen. 900 mg Trockengewicht des Stratum corneum ergaben eine Ausbeute von 68 mg fibrillärem Protein von den o.g. Patienten, während 178 mg von normalen Kontrollen gewonnen wurden. Strukturelle Unterschiede wurden mit der Elektronenmikroskopie beobachtet und chemische Differenzen wurden im Hinblick auf verschiedene Aminosäuren aufgefunden. Bei der SDS-Elektrophorese konnte ein Fehlen der 55000 Dalton-Verbindung normaler fibrillärer Proteine bei dem genannten Patienten mit BCIE nicht nachgewiesen werden. Die Ergebnisse weisen darauf hin, daß eine Veränderung der Polypeptidzusammensetzung fibrillärer Proteine bei diesen Patienten mit BCIE sich entwickelt, und daß diese Veränderung morphologische und klinische Charakteristika dieses dominant vererblichen Leidens verursacht.