Pharmacokinetics of recombinant murine interferon-gamma and human interferon-alpha A/D(Bgl) administered in concert and their influence on natural killer cell function in mice.

The pharmacokinetics of recombinant murine interferon-gamma (rMuIFN-gamma) administered alone and in combination with recombinant hybrid human interferon-alpha (rHuIFN-alpha A/D-[Bgl]) were studied following intravenous (i.v.) and intramuscular (i.m.) injections into mice. The concomitant influence of these IFNs on splenic natural killer (NK) cell function was also examined. The coinjection of both IFNs did not affect the pharmacokinetics of either after i.v. administration. However, simultaneous injection of both IFNs i.m. does result in statistically significant changes in the serum concentrations of rHuIFN-alpha A/D(Bgl). The clinical benefits of the increased bioavailability of rHuIFN-alpha A/D(Bgl) are not apparent since NK cell enhancement after both IFNs were injected together was the same as that obtained after injection of rHuIFN-alpha A/D(Bgl) alone. NK cell enhancement after both IFNs were injected together was the same as that obtained after injection of rHuIFN-alpha A/D(Bgl) alone. Correspondingly, the coinjection of both IFNs did not affect the pharmacokinetics of either.

Pharmacokinetics and tissue distribution of recombinant human tumor necrosis factor-alpha in mice.

The serum pharmacokinetics and the major organs of accumulation of recombinant human tumor necrosis factor-alpha (rHuTNF) were determined in BDF1 mice after intravenous and intramuscular administration. Serum concentrations of immunoreactive protein were determined by enzyme-linked immunosorbent assay, and radioactivity was quantitated by beta and gamma scintigraphy. The serum pharmacokinetics of labeled and unlabeled rHuTNF were identical when administered by the intravenous route. After intravenous doses of 165 to 320 micrograms/kg, the clearance was 2.9-3.6 ml/hr, the initial volume of distribution was 1.4-1.6 ml (70-80 ml/kg), and the half-life was 18.5-19.2 min. Intramuscular administration of 320 micrograms/kg resulted in a peak serum concentration of 112 ng/ml. The time of the peak concentration was 1 hr, and the bioavailability of the intramuscular dose was 12%. The data suggest that the disposition of this protein may be biexponential. If this is the case, the terminal phase would appear to account for less than 1% of the total AUC. Since serum concentrations in the terminal phase are at the sensitivity limit of the assay, a single half-life is reported. 125I-Labeled and metabolically labeled 3H-rHuTNF were used to examine tissue distribution. After intravenous 125I-rHuTNF administration, the rank order of accumulation of the 125I-radiolabel in the major organs (per cent dose per organ over 1440 min) was: liver greater than kidney greater than lung greater than heart greater than spleen. This rank order of accumulation was confirmed by intravenous 3H-rHuTNF administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor necrosis factor-alpha in rodents.

Treatment of healthy rats and mice with a single intravenous injection of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) caused a dose-dependent gastrointestinal inflammation. Within 30 min gastric emptying was blocked and tissue edema occurred in the small and large intestine. In the cecum hemorrhage occurred after 4 h at doses greater than or equal to 250 micrograms/kg. The cecum exhibited an acute inflammatory response following rHuTNF-alpha treatment similar to that seen in tumor necrosis at the same dose. The vascular endothelium became swollen, increased numbers of neutrophils and other leukocytes attached to and penetrated the endothelium, and finally hemorrhage occurred. Treatment of rats with daily injections of rHuTNF-alpha (250 micrograms/kg per d) for 3 wk failed to produce cachexia. Within 24-48 h rats became resistant to the hemorrhagic effect of rHuTNF-alpha, however, the cytokine still caused a transitory block of gastric emptying after 10 d of treatment. Treatment at 5- or 10-d intervals produced results similar to the initial injection. These results suggest that maximum hemorrhagic response will occur when rHuTNF-alpha is administered at intervals of 5-10 d rather than daily.

Characterization of the antitumor activities of human tumor necrosis factor-alpha and the comparison with other cytokines: induction of tumor-specific immunity.

We have investigated the in vitro and in vivo antitumor activities of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) against Meth A sarcoma. Meth A sarcoma cells were found to a) be relatively insensitive in vitro to rHuTNF-alpha, and b) express low numbers of TNF-alpha receptors. Intraperitoneally implanted Meth A sarcoma was insensitive to the antitumor effects of rHuTNF-alpha. In contrast, rHuTNF-alpha was highly efficacious against subcutaneously implanted Meth A sarcoma. Biodistribution studies with 125I- or 3H-labeled rHuTNF-alpha demonstrated that, after intravenous administration, the majority of the labeled rHuTNF-alpha localized in the kidney, lungs, and liver. Only low levels of radiolabel were found in subcutaneous Meth A implants. These results support the in vitro data on the low number of TNF-alpha receptors on Meth A sarcoma cells. The ability of rHuTNF-alpha to induce regression of established (7 days) subcutaneous Meth A implants, positively correlated with the degree of both macroscopic and microscopic tumor necrosis. In addition, recombinant human tumor necrosis factor-beta (lymphotoxin) and recombinant murine tumor necrosis factor-alpha induced similar levels of necrosis. Other lymphokines with known antitumor activities, recombinant human interferon-gamma, murine interferon-gamma, and human interleukin 1 alpha, failed to induce detectable necrosis of Meth A sarcoma. Mice which had rejected subcutaneous Meth A sarcoma implants after rHuTNF-alpha treatment and which were later challenged subcutaneously with Meth A sarcoma or other noncross-reacting chemically induced sarcomas were found to be specifically immune to Meth A sarcoma. In addition, low levels of cytotoxic antibodies reactive to Meth A sarcoma were detected in the sera of 21 of 30 Meth A immune mice. Histological evaluation of the hemorrhagic tumor necrosis induced by rHuTNF-alpha suggests that the primary lesion is vascular, possibly directly on the endothelial cells. The mechanisms involved in the generation of specific cell-mediated antitumor immunity in this model are at present unknown.

Protection from genital herpes simplex virus type 2 infection by vaccination with cloned type 1 glycoprotein D.

Guinea pigs were vaccinated with truncated herpes simplex virus type-1 (HSV-1) glycoprotein D produced in the genetically engineered mammalian cell line gD10.2. Vaccinated animals formed antibodies that neutralized both HSV-1 and herpes simplex virus type 2 (HSV-2) in an in vitro neutralization assay. Vaccinated animals were challenged with HSV-2 by intravaginal infection. Animals that received the immunogen in Freund's complete adjuvant were completely protected from the clinical manifestations of genital HSV-2 infection. Animals that received the immunogen incorporated in alum adjuvants were partly protected from clinical disease; the infections that did develop were significantly less severe than those that occurred in control animals injected with adjuvant alone. The results demonstrate that immunization with a purified viral protein can provide significant protection against primary genital infection by HSV-2 in guinea pigs.

Minimizing resistance to death education.

Death education is now an accepted phenomenon within institutions of higher education. Death education is also being taught at the elementary and secondary school levels though less is known about its acceptance as a worthwhile pedagogical endeavor by parents of school-age children. This article addresses the potential sensitivity and hesitation parents may demonstrate relative to death education's delicate, multifaceted subject matter and offers some suggestions for minimizing possible resistance to death and dying pedagogy. Any resistance that parents demonstrate is generally due to their own fear of death and dying and their inability to deal realistically with it. Certain antecedents of fear and strategies for coping with fear are offered.

Death education coverage in selected health education books and periodicals.

This article represents an attempt to ascertain the quantity of death and dying literature within selected health education periodicals and introductory health education books during the past 7 years. The study is part of an ongoing effort by the author to determine relationships between health education and death education. Approximately two-thirds of the general health education books reviewed now include chapters or sections on death-related phenomena. Four nationally refereed periodicals, viewed by the author as most useful to the health educator, have also been publishing a considerable number of death education pieces in recent years. Involvement by health educators, via the publication of death and dying information, should be viewed as a positive gesture toward achieving multidisciplinary goals within death education.

Update: mitral valve prolapse syndrome.

A contemporary "in" diagnosis in the field of cardiology is the mitral valve prolapse syndrome. This abnormality is evident in populations ranging from very young children to older adults. It is being recognized with increasing frequency among college and university students. In many cases, the syndrome is of limited consequence, while in others, it may be life threatening. This paper (1) defines what it is, (2) reports on its occurrence, (3) depicts some relationships with related health entities and (4) discusses certain implications for health professionals and heart health education.

Death education within health education: current status, future directions.

A national survey was conducted among 205 university level divisions/departments of health education to determine the current status of death education courses within the health education field. Forty-nine college and university health educators currently teaching the course returned usable instruments. Death education receives the same credit, utilizes similar grading systems and is generally managed much like other academic courses. Since the discipline is in its infancy and many teachers are relatively unprepared, respondents called for greater quality control and improved professional preparation. Several concerns accompanying the growth of death education were identified.