Pharmacokinetic and Pharmacological Profiles of Free and Liposomal Recombinant Human Erythropoietin After Intravenous and Subcutaneous Administrations in Rats

Purpose. Recombinant human erythropoietin (Epo) is used frequently through intravenous (i.v.) and subcutaneous (s.c.) administration for the clinical treatment of the last stage of renal anemia. We encapsulated Epo in liposomes to develop an alternative administration route. The purpose of our study was to evaluate the pharmacokinetics and the pharmacological effects of liposomal Epo in comparison with the Epo after i.v. and s.c. administration to rats. Methods. Epo was encapsulated in liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and soybean-derived sterol mixture (SS) prepared by the reversed-phase evaporation vesicle method. After filtration through a 0.1 m polycarbonate membrane, liposomes were gel filtered (Epo/liposomes). Results. Epo/liposomes showed higher pharmacological activity than Epo/liposomes before gel filtration after i.v. administration to rats. Non-encapsulated Epo lost its activity, whereas encapsulated Epo in liposomes retained it. The pharmacological effects of Epo/liposomes were greater than those of Epo after i.v. administration. Epo/liposomes afforded 3–9 times higher AUC, lower clearance and lower steady-state volume of distribution than Epo after both i.v. and s.c. administrations. Epo/liposomes had an improved pharmacokinetic profile compared with Epo. S.c. administration of Epo/liposomes at 7 h may penetrate primarily (40% of dose) through the blood as a liposome and partly (7% of dose) in lymph. Conclusions. Epo/liposomes may reduce the frequency of injections required for a certain reticulocyte effect in comparison to Epo. The lower clearance of Epo/liposomes may increase the plasma concentrations of Epo, which increases the efficacy.     

Admission,recruitment, and retention

As the country strives to produce larger numbers of generalist physicians, considerable controversy has arisen over whether or not generalist applicants can be identified, recruited, and influenced to keep a generalist-oriented commitment throughout medical training. The authors present new and existing data to show that: 1) preadmission (BA/MD or post-baccalaureate) programs can help to identify generalist-oriented students; 2) characteristics determinedat admission to medical school are predictive of future generalist career choice; 3) current inpatient-oriented training programs strongly push students away from a primary care career; 4) women are more likely than men to choose generalist careers, primarily because of those careers’ interpersonal orientation; and 5) residency training programs are able to select applicants likely to become generalists. Therefore, to produce more generalists, attempts should be made to encourage generalist-oriented students to enter medical schools and to revise curricula to focus on outpatient settings in which students can establish effective and satisfying relationships with patients. These strategies are most likely to be successful if enacted within the context of governmental and medical school-based changes that allow for more reimbursement and respect for the generalist disciplines.     

A new technical aspect of ultrasound-guided liver surgery

Nowadays, resective hepatic surgery should be considered an echo-guided surgical procedure to guarantee that effective anatomical resection is accomplished. We describe a simple and original technique guided by intraoperative ultrasonography (IOUS), called the hooking technique, that enables the ligation sites of the intrahepatic vessels during systematic segmentectomy to be chosen precisely. Together with other IOUS-guided techniques described previously, the hooking technique provides a further guarantee for the successful execution of anatomical and radical liver resection.     

Anterior Transhepatic Approach for Isolated Resection of the Caudate Lobe of the Liver

RID=" ID=" <E5>Correspondence to:</E5> J. Yamamoto, M.D.     

Long-term administration of atrial natriuretic peptide in patients with acute heart failure.

A short-term treatment of atrial natriuretic peptide (ANP), a circulating hormone of cardiac origin, is reported to improve cardiac performance in patients with chronic heart failure. However, clinical usefulness of long-term administration of ANP in patients with congestive heart failure has not been reported. We studied 36 patients with severe acute heart failure who resisted various therapy. Hemodynamic parameters were measured before and 48 h after initiating ANP infusion (n = 18) or normal saline (n = 18). Mean pulmonary capillary wedge pressure (23-->13 mm Hg), mean right atrial pressure (10-->5 mm Hg), systemic vascular resistance (2,169-->1,307 dyn x s x cm(-5)) and pulmonary vascular resistance (318-->136 dyn x s x cm(-5)) decreased significantly, whereas cardiac index (1.9-->2.6 L/min/m2) and urine volume (1,692-->2,560 ml/day) increased during long-term ANP infusion (before-->48 h). Moreover, in eight patients with long-term ANP infusion, these hemodynamic effects were maintained at 7 days after initiating ANP infusion. Vasodilating, pulmonary vasorelaxant, and diuretic activities of ANP are maintained without tolerance, and thus long-term ANP infusion is clinically useful in patients with severe acute heart failure.     

Morphologic and biochemical characterization of erythrophoromas in goldfish (Carassius auratus).

The properties of spontaneous cutaneous erythrophoromas that occurred in 17 adult goldfish (Carassius auratus) were described. This study was based on combined histology, cytochemistry, electron microscopy, and biochemical analysis. Tumors that varied from 0.4 to 2.7 cm in maximum diameter were located on various parts of the skin. As shown by light microscopy, tumors were composed of red- to orange-pigmented, dendritic, stellate, or spindle-shaped cells, which coalesced into an excrescence in the dermal layer. No metastasis was observed. Evidence of invasiveness in five examples and local recurrence in three examples indicated that some of these tumors were malignant. Electron microscopy revealed numerous round cytoplasmic organelles (pterinosomes), which measured 0.4--0.7 mu, and well-developed tubular, smooth endoplasmic reticulum in the tumor cells. Biochemical analysis showed that red pigmentation of tumor cells was imparted by pteridines and carotenoids, most of which were detectable in normal adult erythrophores. These data indicate that tumors were comprised of neoplastic erythrophores.     

DNA repair synthesis in rat retinal ganglion cells treated with chemical carcinogens or ultraviolet light in vitro, with special reference to aging and repair level.

A system in which the retinal tissues of noninbred Wistar rats were used in combination with autoradiography was developed for measurement of DNA repair synthesis in ganglion cells of the central nervous system. Retinal tissues in short-term organ culture were treated with various carcinogens plus tritiated thymidine ([methyl-3H]dThd) or were irradiated with UV light and then treated with [methyl-3H]dThd. Preliminary study with retinal tissues from rats at various ages revealed no age-associated changes in the levels of unscheduled DNA synthesis in ganglion cells.