Therapeutic uses of sexually explicit materials in the United States and the Czech and Slovak Republics: a qualitative study.

This study investigates the reflections of 279 U.S. and Czech and Slovak mental health and health professionals about their use of sexually explicit materials. Professionals were 2.6 times as likely to cite specific instances when their use of sexually explicit materials was useful with their clients and students than they were to cite instances when such materials were not useful. In addition, no significant differences were observed between the ways in which U.S. and Czech and Slovak mental health and health professionals evaluated these materials. The article presents several suggestions for the judicious and efficacious use of sexually explicit materials in therapy or in the classroom in either Western or Central European settings.

Attitudes of U.S. and Czech/Slovak mental health and health professionals toward five types of sexually explicit materials.

Mental health and health professionals' attitudes toward sexually explicit materials in the U.S. and Czech/Slovak Republics were investigated. An instrument measuring attitudes toward educational, soft-core, hard-core, violence, and bizarre/paraphiliac sexually explicit materials was administered to sexologists, psychologist/counselors, and medical professionals. These professionals were attending conferences in the U.S. and the Czech/Slovak Republics between November 1992 and September 1993. Mental health and health professionals had the most favorable attitudes toward educational sexually explicit materials followed by soft-core and hard-core materials, respectively. They had unfavorable attitudes toward violent and bizarre/paraphiliac sexually explicit materials, with particularly negative attitudes toward violent materials. Analysis of covariance showed that strength of religious conviction was a significant covariate; thus professionals with stronger religious conviction had more negative attitudes toward all five types of sexually explicit materials. When controlling for strength of religious conviction: (i) sexologists had more positive attitudes toward most types of sexually explicit materials; (ii) Czech professionals generally had more positive attitudes toward such materials than their U.S. counterparts; and (iii) there were few differences between female and male professionals in their reported attitudes. While previous literature has reported gender differences in attitudes toward sexually explicit materials, findings from this study suggest that this effect may be due to differences in religiosity among women and men, namely, that women tend to be more religious.

Macrophage endotoxin tolerance: effect of TNF or endotoxin pretreatment.

Macrophages pretreated with low-dose endotoxin [lipopolysaccharide (LPS1)] have an altered response to subsequent endotoxin (LPS2) stimulation, a process known as endotoxin tolerance. In this study we investigated whether the LPS1 pretreatment effects were mediated primarily via tumor necrosis factor (TNF alpha). Murine peritoneal macrophages were pretreated in vitro with either TNF alpha or LPS1 and the effects on mediator production in response to a second endotoxin exposure, LPS2, were compared. Mediators in macrophage supernatant were measured using specific bioassays [TNF, interleukin-1 (IL-1), and IL-6] or enzymatic immunoassays [prostaglandin E2 (PGE2) and TNF]. Macrophage production of all mediators was stimulated by endotoxin in the absence of LPS1 pretreatment. Pretreatment with LPS1 completely inhibited LPS2-triggered TNF release whereas preexposure to TNF alpha had no effect. In contrast, LPS1 pretreatment significantly augmented IL-1 and PGE2 release in response to LPS2, whereas pretreatment using either high- or low dose TNF alpha did not. TNF, stimulated by an initial exposure to endotoxin, LPS1, is not solely responsible for the observed alterations in macrophage mediator release following a subsequent endotoxin stimulus (LPS2). Thus, the data suggest that endotoxin tolerance is mediated primarily by factors other than TNF.

Autoregulation of hepatic macrophage activation in sepsis.

Endotoxin (LPS)-stimulated macrophages release mediators, such as tumor necrosis factor (TNF) and prostaglandin E2 (PGE2), which modulate the function of many different cells. We hypothesize that macrophage regulation is altered in sepsis and that mediators from LPS-stimulated macrophages "autoregulate" their activation state. Alterations in the LPS dose response relationships for inhibition of hepatocyte protein synthesis by hepatic macrophages (hMøs) were examined to investigate factors that regulate hMø activation. In vitro pretreatment was compared using TNF alpha, PGE2, subactivating concentrations of LPS, or LPS plus indomethacin. Pre-exposure to LPS resulted in a dose-dependent loss of subsequent LPS-triggered activation of hMøs in co-culture. Pretreatment with LPS and 1 mumol/L indomethacin partially restored hMø responsiveness. Pre-exposure to PGE2 significantly decreased LPS responsiveness of co-cultured hMøs, suggesting that PGE2 produced by LPS-stimulated hMøs may mediate this effect. Pretreatment of hMøs with TNF alpha, but not IL-1 beta, significantly lowered the LPS concentration required for maximal hMø activation. We conclude that both macrophage mediators and LPS pretreatment alter macrophage activation state. These data suggest an "autoregulatory" role for mediators of LPS-stimulated macrophages in sepsis.

A hypothesis concerning the relationship of cellular pharmakokinetics to optimal scheduling of anti-cancer agents.

It is well recognized that the degree of toxicity, type of toxicity, and therapeutic to toxic ratio of most anti-cancer agents are dependent upon schedule. It is postulated that an optimal schedule is one that creates the largest possible difference in uptake of drug between neoplastic and normal cells, especially those cells that by their death limit the amount of drug that can be given to the patient. Specific pharmacokinetic parameters can be determined that optimize the relative distribution of drug between neoplastic tissues and dose-limiting normal tissues, and thus may permit optimization of schedule.

Hormonal regulation of serum alpha 1-antitrypsin and hepatic alpha 1-antitrypsin mRNA in rats.

We evaluated the effects of pituitary dependent hormones on alpha 1-antitrypsin in male rats. Hepatic alpha 1-antitrypsin mRNA was measured by in vitro translation and by specific hybridization with a mouse cDNA alpha 1-antitrypsin probe. Hypophysectomy caused a 50-75% decrease in serum elastase inhibitory capacity (measuring functional alpha 1-antitrypsin) and hepatic alpha 1-antitrypsin mRNA content. In hypophysectomized animals, no increase in elastase inhibitory capacity or alpha 1-antitrypsin mRNA levels by translation was found when met-human growth hormone alone or corticosterone, dihydrotestosterone and thyroxine were given together. Growth hormone increased alpha 1-antitrypsin mRNA by hybridization to a small extent. Addition of growth hormone to the combination of corticosterone, dihydrotestosterone, and thyroxine increased serum elastase inhibitory capacity and alpha 1-antitrypsin mRNA. We conclude that growth hormone acts synergistically with the other pituitary dependent hormones to regulate serum and hepatic mRNA levels of alpha 1-antitrypsin.

Hepatic alpha 1-antitrypsin mRNA content in cirrhosis with normal and abnormal protease inhibitor phenotypes.

We quantitated alpha 1-antitrypsin mRNA in normal, alpha 1-antitrypsin-deficient cirrhotic and biliary cirrhotic livers using two-dimensional electrophoretograms of [35S]methionine-labeled translational products of total hepatic RNA and RNA/DNA hybridization. alpha 1-Antitrypsin precursor product was identified by immunoprecipitation. The relative abundance of alpha 1-antitrypsin product from normal (0.989 +/- 0.197), cirrhotic (0.956 +/- 0.062) and alpha 1-antitrypsin deficient (0.818 +/- 0.12) livers was not significantly different. Although (RNA/DNA) was decreased in the PiZZ cirrhotic livers compared to normal (0.56 +/- 0.045 vs. 0.95 +/- 0.225), it equaled that found in the PiM cirrhotic livers (0.56 +/- 0.055). The concentration of alpha 1-antitrypsin mRNA [relative abundance X (RNA/DNA)], while decreased in PiZZ compared to normal liver, is thus no different in PiZZ cirrhotics than in PiM cirrhotics. We confirmed this observation by quantitation of the alpha 1-antitrypsin mRNA using an alpha 1-antitrypsin genomic probe. By RNA/DNA hybridization, alpha 1-antitrypsin mRNA was equal in PiM cirrhotic and PiZZ cirrhotic (38.48 +/- 4.5 vs. 31.93 +/- 2.1), but significantly decreased from noncirrhotic PiM liver (58.36 +/- 12.7). We conclude that alpha 1-antitrypsin mRNA is decreased in cirrhosis of any etiology, and this decrease appears to represent a general response of the liver to injury. Since the decreased alpha 1-antitrypsin mRNA in PiM cirrhotics is associated with normal serum alpha 1-antitrypsin levels, it is unlikely that the decreased alpha 1-antitrypsin mRNA in PiZZ cirrhotics accounts for their decreased serum levels.

Ontogenesis of growth hormone (GH)-responsive hepatic gene products: lack of correlation with hepatic GH receptor content.

The ontogenesis of hepatic GH receptor content is postulated as a major determinant of expression of hepatic GH-responsive gene products, since the ontogeny of the receptors and the responsive gene products, somatomedin-C, somatomedin-binding protein, and GH-responsive acidic protein, have similar qualitatively ontogenetic patterns. Two-dimensional gel electrophoresis of in vitro synthesized [35S]methionine-labeled proteins formed in the cell-free mRNA-dependent rabbit reticulocyte lysate system in response to hepatic RNA was used to quantitate the ontogenetic changes in a family of five GH-responsive gene products (S3, S11, S15, S16, and S20). These gene products were altered 2- to 12-fold by the administration of methionyl-human GH to adult hypophysectomized animals and were not altered by the combined administration of T4, corticosterone, and dihydrotestosterone. The translational activity of three of the five products (S3, S15, and S20) in animals younger than 15 days ranged from 1-12% of the values observed in normal adults and was consistent with diminished GH action. The translational activities of two mRNA sequences (S11 and S16) were not consistent with diminished GH action in the newborn animal. In the newborn animal, S11, induced 3-fold by GH in the adult animal, was 7.4 times the level observed in the adult. During the time of increasing GH receptor content (2-35 days), S16, attenuated by GH 2-fold in the adult, increased 6-fold. Injection of GH from days 2 through 11 augmented S20 and D2 (a hormonally nonresponsive, developmentally dependent product) 2-fold. The combined administration from days 2 through 11 of GH, T4, and corticosterone augmented S16 1.8-fold, a response paradoxical to that in the adult animal, but consistent with advancing maturation of the liver. We conclude that GH receptor content is not the sole determinant for the ontogenetic expression of GH-responsive products and that important alternate mechanisms exist for their regulation. In addition, GH, along with T4 and corticosterone, appear to modulate the rate at which adult levels of some mRNA sequences are achieved.

A hypothesis concerning the effect of changes in scheduling upon the cardiotoxicity of adriamycin.

Evidence is accumulating that the cardiotoxicity of adriamycin is a function of not only total dosage but of scheduling, with those schedules associated with low peak plasma levels of the drug being associated with significant decrease in cardiac toxicity. It is believed that adriamycin enters the cell by passive diffusion, and most cells studied, both normal and neoplastic, have an active excretory mechanism that pumps adriamycin out of the cell. If it is assumed that the myocardium has such a pump then it can be shown pharmacokinetically that those schedules associated with a low peak plasma level can, under certain circumstances, selectively protect the myocardium.

The effect of client choice of therapist on therapy outcome.

This study compared the therapeutic progress of three randomly assigned groups (n = 14 in each group) of community mental health center clients: (a) clients who viewed a slide/sound presentation about all available therapists and chose their own therapist; (b) clients who viewed the presentation and were assigned to a therapist by the center's clinical director; (c) clients who were assigned to a therapist by the clinical director without seeing the presentation. There were no significant differences among the three groups in their initial reaction to the clinic, number of therapy sessions, type of termination, severity of presenting problems, General Well-Being Schedule scores, Current Adjustment Rating Scale scores, or therapist's satisfaction with therapy. Further analysis revealed that three out of four clients had improved significantly as a result of therapy. It was concluded that in the absence of research evidence demonstrating the efficacy of client choice on therapy outcome, support for the notion of client choice must be based solely on social, ethical, and legal considerations.

Analysis of procarbazine and metabolites by gas chromatography-mass spectrometry.

Twelve compounds representing procarbazine, seven metabolites, and an internal standard were analyzed by gas chromatography-mass spectrometry on a 3% OV-1 column. Procarbazine and four metabolites were derivatized with acetic anhydride. A sensitive, specific and quantitative assay was established by selected ion monitoring using a synthetic analogue of the drug as an internal standard. The limits of detection were approximately 1 ng/ml of plasma while the limits of quantitation were 10 ng/ml of plasma. Studies of the degradation of procarbazine . HCl in 0.05 M phosphate buffer (pH 7.4) were compared to in vivo studies. At 1 h after incubation of procarbazine . HCl in buffer, the azo and aldehyde metabolites were detected in the highest concentrations representing 27.2% and 20.3% of total drug and metabolites. In the in vivo studies, analyses of rat plasmas indicated that 1 h after an oral dose of procarbazine . HCl, the aldehyde metabolite represented 72% of the total drug and metabolites, and that relatively little of the azo metabolite was present.

Phase II study of 5-azacytidine in solid tumors.

One hundred and seventy-seven patients were evaluated after therapy with 5-azacytidine using a dose of 1.6 mg/kg/day X 10 days followed by a maintenance regimen. One hundred and forty-eight of the patients received the drug by rapid iv infusion and 29 received the drug daily by and infusion that lasted between 18 and 24 hours. Hematologic toxicity was significant but transient in both groups. Nausea was severe using the rapid iv infusion and minimal with the slow infusion. Antitumor effect was seen in 17% of the evaluable patients with carcinoma of the breast and 21% of the patients with malignant lymphomas. Occasional responses were seen with a variety of other solid tumors. The responses were transient, and clinically, resistance to 5-azacytidine appeared to develop quite rapidly. No clear-cut difference was seen in response rates or duration of response between the two groups of patients. Cross resistance to other anticancer agents was not noted. It is believed that the drug is only of minimal value as a single agent in solid tumors using either of the methods of administration described.

Fate of streptozotocin (NSC-85998)in patients with advanced cancer.

We have investigated the distribution, biotranformation, and excretion of streptozotocin and its 14C- and 3H-labeled metabolities in 15 patients with advanced cancer. Streptozotocin was detected in the plasma during the first 3 hours after administration while radioactive products were present for longer than 24 hours. No unchanged streptozotocin was detected in the cerebrospinal fluid (CSF); however, 14C-labeled metabolites were detected in the 2-hour CSF sample in a concentration equivalent to the 2-hour plasma level. H activity is the CSF was not detected at this time period. Radioactivity measured in biopsied tissues indicated that streptozotocin labeled with 14C and 3H or its metabolites penetrated tumor tissue. 14C tissue levels were found to approximate plasma levels; however, 3H levels were found to be greater than the corresponding plasma levels. Fifteen percent of the total dose of streptozotocin administered was recovered in the urine. 3H-labeled metabolites were recovered in excess of 60% in the urine, and approximately 30% of the 14C-labeled metabolites were recovered in the urine during a similar interval. Less than 1% of the administered 14C and 3H was recovered in the feces. 14C-labeled CO2 was also recovered, although quantitative recovery was not attained. At least three major metabolites of streptozotocin were detected in the urine by radiochromatography. Two metabolites contained only 3H and one metabolite contained both 14C and 3H in the same ratio as administered.

Absorption, distribution, and excretion of 5-azacytidine (NSC-102816) in man.

Patients with advanced cancer were given 5-azacytidine labeled at position 4 with radioactive carbon (14C) by either the intravenous (iv) or subcutaneous (sc) route. Absorption of the drug from the sc injection site was rapid and peak plasma levels were attained within one-half hour. Within 2 hours, the plasma level of radioactivity was approximately equal to that noted in the patients treated iv. The plasma half-life after iv injection was 3.5 hours; after sc administration, the plasma half-life was 4.2 hours. Patients receiving the drug sc excreted less drug in the urine than did those receiving the drug iv. No radioactivity was detected in the expired carbon dioxide when the drug was given by either route. Drug uptake into tumor tissue was always greater than uptake into surrounding normal tissue. The highest concentrations of radioactivity in the tissues were achieved when the drug had been given iv. Traces of radioactivity were still detectable in the tissues for as long as 6 days after administration of the drug. The incorporation of radioactivity into tumor RNA but not into DNA was demonstrated. The maximum level of radioactivity detected in the spinal fluid was equivalent to 0.2 microg of 5-azacytidine per milliliter of fluid.