The association between depressive mood and cigarette smoking among adolescents was examined within a multivariate model. Subjects were 205 eleventh graders (123 boys and 82 girls) enrolled in a Northeast metropolitan public high school for scienceoriented students. Logistic regression analysis showed an indepen- IntroductionA host of factors have been investigated in numerous attempts to determine the antecedents of cigarette smoking among adolescents. Peer and family smoking behavior have been consistently implicated'-3; while less evidence has been demonstrated for the effects of psychological traits, knowledge and attitudes about smoking, school achievement, and demographic characteristics.'A prospective study involving 1,004 subjects found that depressive symptoms reported at ages 15-16 predicted the frequency and duration ofcigarette smoking nine years later.4 This association was not seen for future alcohol or drug use. Another study found higher scores on the Beck Depression Inventory among cigarette smokers than in nonsmokers in males.5 Both studies limited analysis to simple associations; neither controlled for the effect of other known risk factors. We have found no other attempts to examine the relation between depression and smoking among adolescents. In contrast, a recent paper cited seven studies that examined the relation between depressive disorders and drug and alcohol abuse.6The present study reports our investigation into the relation between depressive symptoms and cigarette smoking among adolescents within the context of a multifactorial model.
This article is available online at http://dmd.aspetjournals.org ABSTRACT:Recently, a physiologically-based, segregated flow model that incorporates separate intestinal tissue and flow to both a nonabsorptive and an absorptive outermost layer (enterocytes) was shown to better describe the observations on route-dependent morphine glucuronidation in the rat small intestine than a traditional physiologically-based model. These theoretical models were expanded, as the segmental segregated flow model and the segmental traditional model, to view the intestine as three segments of equal lengths receiving equal flows to accommodate heterogeneities in segmental transporter and metabolic functions. The influence of heterogeneity in absorptive, exsorptive, and metabolic functions on drug clearance, bioavailability (F), and metabolite formation after intravenous and oral dosing was examined for the intestine when the tissue was the only organ of removal. Simulations were performed for first-order conditions, when drug partitioned readily (flow-limited distribution) or less readily (membrane-limited distribution) into intestinal tissue, and for different gastrointestinal transit times. The intestinal clearance was found to be inversely related to the rate constant for absorption of a drug that was subjected to secretion and was positively correlated with the metabolic and secretory intrinsic clearances. F was positively correlated with the absorption rate constant but was inversely related to the metabolic and secretory intrinsic clearances. The gastrointestinal transit time decreased metabolite formation, increased clearance, and decreased F. The simulations further showed that a descending metabolic intrinsic clearance yielded a lower F and an ascending segmental distribution of metabolic intrinsic clearance yielded a higher F.The small intestine is endowed with transporters that effect the penetration of drugs across the luminal (or apical) membrane into the cell against a concentration gradient (for review, see Tsuji and Tamai, 1996;Lin et al., 1999). Permeation via passive diffusion of lipophilic drugs exists and is highly correlated to the surface area of contact and the pKa that influence the degree of ionization and hence lipophilicity. The varying abundance of the villi along the intestinal length constitutes differing surface areas among the intestinal segments, being highest at the duodenum and upper jejunum and lowest toward the ileum (Magee and Dalley, 1986). Net apical to basolateral transport is additionally influenced by the presence of drug binding, metabolizing enzymes, transporters for efflux and basolateral transport, and the gastrointestinal motility that modulates drug transit time.Several models have been developed to describe processes of intestinal absorption, metabolism, and secretion simultaneously (Yu and Amidon, 1998;Ito et al., 1999;Cong et al., 2000). A traditional, physiologically-based model (TM 2 ), which regards the intestine as a single homogeneous compartment with all of the intestinal bl...
This article is available online at http://dmd.aspetjournals.org ABSTRACT:Studies on the Caco-2 cell monolayer system that contained cytochrome P450 and P-glycoprotein activities had advanced the theory that increased intestinal metabolism resulted with increased drug efflux due to an increase in mean residence time (MRT) in the system. To confirm or refute the claim, we developed compartmental models to study the effects of intestinal secretion on the MRT and rates of metabolism under first-order and nonlinear conditions. The theoretical examinations showed that under first-order conditions, intestinal secretion increased the MRT of drug in all compartments but failed to increase the rate of metabolite formation or the total amount of metabolite formed. Instead, reduced metabolic rates arose with increased efflux from cell, either into the apical or the basolateral compartment. By contrast, under saturable metabolic conditions, there were some conditions found whereby rates of metabolism increased with intestinal secretion and rapid reabsorption, albeit the total amount of metabolite formed eventually equaled the administered dose. Intestinal secretion failed to induce higher rates of metabolism for other conditions (saturable cellular binding, cellular efflux, or cell entry). With saturation of metabolic enzymes, drug efflux brought about desaturation, and, upon rapid recovery of drug into the cellular compartment, higher rates of metabolite formation were attained. The simulation study showed that, under first-order conditions, intestinal secretion reduced the rate of metabolism even though the MRT was prolonged within the cell preparation. With nonlinear metabolism, however, instances may exist whereby higher rates of metabolism would result with secretion.The intestine is the first physical barrier to which drug is presented following oral administration. In addition to transporters for uptake (Tsuji and Tamai, 1996), drug-metabolizing enzymes for oxidation and conjugation (Dubey and Singh, 1988;Ilett et al., 1990) and efflux transporters for excretion are present (Lin et al., 1999;Suzuki and Sugiyama, 2000). An important efflux transporter is P-glycoprotein (Pgp 1 ), a multidrug resistance (MDR1) gene product that is present at the villous tips of the enterocytes (Thiebaut et al., 1987). Drugs that are substrates of Pgp include verapamil (Saitoh and Aungst, 1995;Sandström et al., 1998;Johnson et al., 2001); the anticancer drugs vincristine, etoposide, daunorubicin, and paclitaxel (Leu and Huang, 1995;Sonnichsen et al., 1995;Nakayama et al., 2000;Chico et al., 2001;Wacher et al., 2001;Abraham et al., 2002); digoxin (Cavet et al., 1996;Greiner et al., 1999); the human immunodeficiency virus protease inhibitor indinavir (Hochman et al., 2000;Li et al., 2002); and immunosuppressive agents cyclosporin (Gan et al., 1996;, tacrolimus (Lampen et al., 1996;Hashimoto et al., 1998;Hashida et al., 2001), and sirolimus (Paine et al., 2002).Because of the significance of the intestine as an important firstpass organ, in...
ABSTRACT:Digoxin, a substrate of P-glycoprotein (Pgp) and cytochrome P450 3a (Cyp3a), was used to illustrate the inductive effects of pregnenolone-16␣-carbonitrile (PCN), a ligand of the pregnane X receptor, on the absorption and disposition of
Introduction CD47 binds to SIRPα on the surface of macrophages and delivers a “do not eat” signal that suppresses phagocytosis. There is increasing evidence that acute myeloid leukemia (AML) stem cells exploit the CD47-SIRPα pathway to escape macrophage-mediated destruction. Blockade of CD47 using a soluble SIRPα-Fc fusion protein (SIRPαFc) has emerged as a promising strategy to neutralize the suppressive effects of CD47 and promote the eradication of AML cells. However, little information is available regarding the optimal structure of SIRPαFc. In particular, the influence of the Fc region, which can mediate antibody-dependent cellular cytotoxicity and complement activation, on anti-leukemic activity and toxicity has not been explored. Results We have generated three unique human SIRPαFc fusion proteins that vary in their Fc regions: SIRPα-G1, which contains the Fc region from human IgG1 with full effector activity; SIRPα-G4, bearing the Fc region from human IgG4, which has low effector activity; and SIRPα-G4m, which possesses a mutated human IgG4 Fc region that is devoid of any effector activity. These three fusion proteins were tested for their ability to promote macrophage-mediated phagocytosis of patient-derived AML cells in vitro. Although all three proteins were able to stimulate tumor cell destruction, SIRPα-G4m was clearly the least potent, while SIRPα-G1 and SIRPα-G4 showed similar activity. Next, the anti-leukemic activity of the fusion proteins was assessed in an AML xenograft model in NOD.SCID mice. SIRPα-G1 induced a profound anti-leukemic effect and was superior to both SIRPα-G4 and SIRPα-G4m, particularly with respect to eradicating tumor cells within the transplanted femur. Thus, while only a low level of Fc activity was required for maximal pro-phagocytic activity in vitro, full effector activity (human IgG1) provided superior anti-leukemic activity in vivo. The strong anti-tumor activity of this fusion protein presumably results from the simultaneous delivery of a positive macrophage activating signal (through Fc receptors) and blockade of the negative “do not eat” signal from CD47. Increased Fc effector activity could also carry the risk of increased toxicity. Since human SIRPα has no measurable binding to mouse CD47, to assess tolerability in mice we generated a surrogate fusion protein consisting of NOD mouse SIRPα linked to a mouse IgG2a Fc region with full effector function (mSIRPα-G2a). Repeat administration of high dose mSIRPα-G2a to mice (50 mg/kg IP twice per week for 8 weeks) produced no adverse clinical effects. No abnormalities were observed in hematological parameters, (including erythrocyte, platelet and leukocyte counts) or bone marrow CD150+CD48- LSK hematopoietic stem cells, nor were gross or microscopic changes noted in any tissue. Furthermore, taking advantage of a fortuitous cross-reactivity between NOD SIRPα and human CD47, we conducted a xenograft study with patient-derived AML cells using the mSIRPα-G2a fusion protein. Compared to control Fc, mSIRPα-G2a profoundly reduced leukemic burden in both the injected femur and non-injected bone marrow at doses significantly below the 50 mg/kg used in the tolerability studies. Thus, a mouse surrogate fusion that can bind both human CD47 on xenograft AML cells and endogenous CD47 on host tissue is both safe and effective. A pilot repeat-dose toxicity study using various human SIRPαFc proteins is currently underway in non-human primates. Conclusions These results demonstrate that SIRPαFc fusion proteins that combine Fc activity with CD47 blockade lead to effective AML destruction in vitro and in vivo, and are well tolerated in mice. Thus the therapeutic window in a homologous model system appears to be sufficiently wide to proceed with formal IND-enabling studies. On the basis of these findings we are moving forward with the development of a SIRPαFc therapeutic for the treatment of AML. Disclosures: Uger: Trillium Therapeutics/Stem Cell Therapeutics: Employment. Pang:Trillium Therapeutics/Stem Cell Therapeutics: Employment. Wong:Trillium Therapeutics/Stem Cell Therapeutics: Employment. House:Trillium Therapeutics/Stem Cell Therapeutics: Employment. Dodge:Trillium Therapeutics/Stem Cell Therapeutics: Employment. Viau:Trillium Therapeutics/Stem Cell Therapeutics: Employment. Vigo:Trillium Therapeutics/Stem Cell Therapeutics: Employment. Tam:Trillium Therapeutics/Stem Cell Therapeutics: Employment. Truong:Trillium Therapeutics/Stem Cell Therapeutics: Employment. Jin:Trillium Therapeutics/Stem Cell Therapeutics: Research Funding. Malko:Trillium Therapeutics/Stem Cell Therapeutics: Research Funding. Ho:Trillium Therapeutics/Stem Cell Therapeutics: Research Funding. Prasolava:Trillium Therapeutics/Stem Cell Therapeutics: Research Funding. Danska:Trillium Therapeutics/Stem Cell Therapeutics: Research Funding. Wang:Trillium Therapeutics/Stem Cell Therapeutics: Research Funding. Petrova:Trillium Therapeutics/Stem Cell Therapeutics: Employment.
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