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Biomedical subjects

P Sriramarao

Publications and source records attributed to P Sriramarao.

At least 19 recordsLinked to original sources
PubMed2000

VCAM-1 is more effective than MAdCAM-1 in supporting eosinophil rolling under conditions of shear flow.

The ability of the alpha4 integrin counterligands vascular cell adhesion molecule (VCAM)-1 or mucosal addressin (MAd)CAM-1 to support eosinophil rolling or firm adhesion under conditions of physiologic flow has not been delineated. Using a parallel plate flow chamber in vitro and intravital microscopy in vivo, we demonstrate that eosinophil rolling and adhesion on VCAM-1 is mediated by both alpha4beta1 and alpha4beta7 integrins. Eosinophils rolled equally efficiently on both VCAM-1 2 domain and VCAM-1 7 domain, suggesting that the N-terminal 2 domains of VCAM-1 are sufficient to support eosinophil rolling under conditions of flow. Furthermore, activation of the eosinophil beta1 integrin with monoclonal antibody (mAb) 8A2 resulted in both resistance to shear stress-induced detachment from VCAM-1 in vitro and in stable arrest of rolling eosinophils on interleukin (IL)-1beta-stimulated venules in vivo. Eosinophils rolled less efficiently on MAdCAM-1- than on VCAM-1-coated coverslips under conditions of flow. However, eosinophils firmly adhered as efficiently to MAdCAM-1 as to VCAM-1. Overall, these results demonstrate that both VCAM-1 and MAdCAM-1 can support eosinophil firm adhesion under conditions of flow. In contrast, VCAM-1 is significantly more efficient than MAdCAM-1 in supporting eosinophil rolling under conditions of flow. (Blood. 2000;95:592-601)

Antibodies, Monoclonal↗
PubMed2000

Inhibition of eosinophilic inflammation in allergen-challenged, IL-1 receptor type 1-deficient mice is associated with reduced eosinophil rolling and adhesion on vascular endothelium.

To determine the relative in vivo importance of IL-1 release after allergen challenge to the subsequent endothelial adhesion and recruitment of eosinophils, the authors used ovalbumin sensitization and inhalation challenge to induce airway eosinophilia in IL-1 receptor type 1-deficient and control wild-type mice. Bronchoalveolar lavage (BAL) eosinophil recruitment in IL-1 receptor type 1-deficient mice challenged with ovalbumin (24.3% +/- 6.3% BAL eosinophils) was significantly reduced compared with wild-type mice (63.7% +/- 2.5% BAL eosinophils). To determine whether the inhibition of eosinophil adhesion to vascular endothelium contributed to the inhibition of eosinophil recruitment in IL-1 receptor type 1-deficient mice, the authors used intravital microscopy to visualize the rolling and firm adhesion of fluorescence-labeled mouse eosinophils in the microvasculature of the allergen-challenged mouse mesentery. Eosinophil rolling, eosinophil firm adhesion to endothelium, and transmigration across endothelium (peritoneal eosinophils) were significantly inhibited in allergen-challenged IL-1 receptor type 1-deficient mice compared with wild-type mice. Overall, these studies demonstrate that cytokines such as IL-1, released after allergen challenge, are important in the induction of endothelial cell adhesiveness, a prerequisite for the recruitment of circulating eosinophils. (Blood. 2000;95:263-269)

Allergens↗
PubMed1999

Activation of mitogen-activated protein kinase regulates eotaxin-induced eosinophil migration.

Eotaxin is a potent eosinophil chemoattractant that plays an important role in regulating eosinophil tissue levels both in healthy individuals and in diseases associated with significant eosinophil infiltrates, such as the allergic inflammation observed in asthma. Here, we demonstrate that treatment of eosinophils with eotaxin induces the phosphorylation of the mitogen-activated protein kinases (MAPKs) p42 and p44, leading to kinase activation. Blockade of MAPK activation by the MAPK kinase inhibitor PD98059 leads to a dramatic decrease in eotaxin-induced eosinophil rolling in vivo and chemotaxis in vitro. This blockade in the leukocyte migration process is consistent with the observed inhibition of actin polymerization and rearrangement within the eosinophil following treatment with MAPK inhibitor. It is suggested, therefore, that the intrinsic mechanism of eotaxin-induced eosinophil rolling and migration involves activation of the p42/p44 MAPK, possibly through regulation of the cytoskeletal rearrangements necessary for chemotaxis.

Actins↗
PubMed1999

A comparison of C3a and C5a-mediated stable adhesion of rolling eosinophils in postcapillary venules and transendothelial migration in vitro and in vivo.

The comparative ability of the complement anaphylatoxins C3a and C5a to mediate leukocyte adhesion and transendothelial migration in vivo and in vitro was investigated. Superfusion of IL-1beta-stimulated rabbit mesentery with C3a resulted in a rapid and stable adhesion of rolling eosinophils, but not neutrophils, to postcapillary venules. However, C3a failed to evoke subsequent transmigration of the adherent eosinophils. In contrast, C5a induced both the rapid activation-dependent firm adhesion and transmigration of eosinophils and neutrophils through venular endothelium. C3a induced selective shedding of L-selectin and an increase in alphaMbeta2 integrin expression on eosinophils but not neutrophils, while C5a induced shedding of L-selectin and up-regulation of alphaMbeta2 integrin on both eosinophils and neutrophils. Both C3a- and C5a-dependent adhesion to venular endothelium was blocked by ex vivo treatment of eosinophils with anti-alpha4 and anti-beta2 integrin mAbs. In vitro, both C3a (but not C3a(desArg)) and C5a (including C5a(desArg))-dependent transmigration of eosinophils across IL-1beta-stimulated endothelial monolayer was mediated by alpha4beta1 and alphaMbeta2 integrins. Overall these studies suggest that C3a is eosinophil-specific chemotactic mediator that influences selectively eosinophil adhesion but not transmigration in vivo. C5a in contrast is a complete activator of integrin-dependent adhesion as well as transmigration of eosinophils and neutrophils.

Animals↗
PubMed1999

Deposition of complement C3 and factor H in tissue traumatized by burn injury.

Activation of complement is known to accompany burn injury. To study deposition of complement proteins within tissue traumatized by burn we employed the technique of intravital microscopy using a murine dorsal skinfold chamber model. C3, factor H, factor B, HSA, and transferrin were labeled fluorescently and injected into the tail vein of mice which had been subjected to a small third degree burn within the skin fold. Only C3 and factor H deposited within blood vessels of the traumatized tissue. Binding was specific because it occurred only in and proximal to burn sites, and neither C3 nor factor H was observed to accumulate in blood vessels of healthy tissue. Furthermore, fluorescently labelled HSA, factor B, and transferrin all failed to deposit at or around burn loci. The deposition of C3 and factor H occurred within 10 min of injury and was intravascular occurring in major blood vessels, capillaries, and post-capillary venules, with little evidence of accumulation in the interstitium. Since both C3 fragments and factor H are recognized as adhesion molecules by granulocyte receptors, these deposited proteins could promote leukocyte accumulation, thereby contributing to an initiation of an inflammatory cascade at a site of burn injury.

Animals↗
PubMed1998

Inhibition of eosinophil rolling and recruitment in P-selectin- and intracellular adhesion molecule-1-deficient mice.

To determine the relative in vivo importance of endothelial expressed adhesion molecules to eosinophil rolling, adhesion, and transmigration, we have induced eosinophilic peritonitis using ragweed allergen in P-selectin-deficient, intracellular adhesion molecule-1 (ICAM-1)-deficient and control wild-type mice. Circulating leukocytes visualized by intravital microscopy exhibited reduced rolling and firm adhesion in P-selectin-deficient mice and reduced firm adhesion in ICAM-1-deficient mice. Eosinophils exhibited reduced rolling and firm adhesion to endothelium in P-selectin-deficient mice. Eosinophil recruitment in P-selectin-deficient mice ( approximately 75% inhibition of eosinophil recruitment) and ICAM-1-deficient mice ( approximately 67% inhibition of eosinophil recruitment) was significantly reduced compared with wild-type mice. Eosinophil recruitment was not completely inhibited in P-selectin/ICAM-1 double-mutant mice (eosinophil recruitment inhibited approximately 62%). However, pretreatment of P-selectin/ICAM-1-deficient mice with an anti-vascular cell adhesion molecule (VCAM) antibody induced near complete inhibition of eosinophil recruitment. Overall, these studies show that eosinophil rolling and firm adhesion is significantly reduced in P-selectin-deficient mice and that P-selectin, ICAM-1, and VCAM are important to eosinophil peritoneal recruitment after ragweed challenge.

Animals↗
PubMed1998

Human polymorphonuclear leukocytes adhere to complement factor H through an interaction that involves alphaMbeta2 (CD11b/CD18).

The work presented here demonstrates that human complement factor H is an adhesion ligand for human neutrophils but not for eosinophils. The adherence of polymorphonuclear leukocytes (PMNs) to plastic wells coated with factor H depended on divalent metal ions and was augmented by C5a and TNF-alpha. PMN adhesion to factor H in the presence or absence of C5a was blocked specifically by mAbs against CD11b or CD18. Affinity purification using factor H Sepharose followed by immunoprecipitation using mAbs to various integrin chains identified Mac-1 (CD11b/CD18) as a factor H binding receptor. The presence of surface bound factor H enhanced neutrophil activation resulting in a two- to fivefold increase in the generation of hydrogen peroxide by PMNs stimulated by C5a or TNF-alpha. When factor H was mixed with PMNs, 1.4 to 3.8-fold more cells adhered to immobilized heparin or chondroitin A. In addition, augmented adhesion of PMNs was measured when factor H, but not HSA or C9, was absorbed to wells that were first coated with heparin or chondroitin A. The adhesion of PMNs to glycosaminoglycan-factor H was blocked by mAbs to CD11b and CD18. These studies demonstrate that factor H is an adhesion molecule for human neutrophils and suggest that the interaction of factor H with glycosaminoglycans may facilitate the tethering of this protein in tissues allowing factor H to serve as a neutrophil adhesion ligand in vivo.

Antibodies, Monoclonal↗
PubMed1998

Neutralizing anti-vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo.

BACKGROUND: Neovascularization mediated by growth factors produced by tumors is critical for the growth of tumors. Vascular endothelial growth factor (VEGF) is one such growth factor. A neutralizing anti-VEGF antibody (A4.6.1) was recently shown in vivo to inhibit tumor angiogenesis and growth of the human rhabdomyosarcoma cell line A673. The antibody profoundly changed the growth characteristics of the tumor line from a rapidly growing malignancy to a dormant microcolony. METHODS: In the present study, we evaluated the effects of A4.6.1 (100 microg twice weekly, i.p.) on growth and angiogenic activity of spheroids of the human prostatic cell line DU 145 (diameter 700 microm at implantation) implanted in dorsal skinfold chambers in nude mice (n = 11). An antibody of the same isotype (n = 5) or saline (n = 5) was used as control. Tumor cells were prelabeled with a fluorescent vital dye (CMTMR), which allowed measurement of size of the implanted tumor spheroids throughout a two week observation period. FITC-dextran was used for plasma enhancement to visualize angiogenic activity. RESULTS: Tumors of control animals induced a neo-vasculature with high vascular density (350+/-12 cm[-1]). In animals treated with the anti-VEGF antibody, there was complete inhibition of neovascularization of the micro tumors and complete inhibition of tumor growth after the initial prevascular angiogenesis independent growth phase. CONCLUSIONS: These results demonstrate that inhibition of the key regulatory paracrine growth factor for endothelial cells, VEGF, results in complete suppression of prostate cancer induced angiogenesis and prevents tumor growth beyond the initial prevascular growth phase.

Animals↗
PubMed1998

Inhibition of pulmonary eosinophilia in P-selectin- and ICAM-1-deficient mice.

Adhesion molecule expression by pulmonary endothelial cells is considered to play an important role in the recruitment of circulating leukocytes to sites of inflammation in the lung. We have used P-selectin- and intercellular adhesion molecule type 1 (ICAM-1)-deficient mice to determine whether these adhesion molecules are important to pulmonary eosinophil recruitment after allergen challenge. There was a significant inhibition of lung tissue eosinophil recruitment in ICAM-1-deficient mice (approximately 84% inhibition compared to wild-type mice) and P-selectin-deficient mice (approximately 67% inhibition compared to wild-type mice) 3 h after allergen challenge. The number of bronchoalveolar lavage (BAL) eosinophils in P-selectin-deficient and ICAM-1-deficient mice was also significantly reduced compared with wild-type mice. Levels of BAL eosinophil peroxidase (EPO) were significantly lower in ICAM-1-deficient mice (0.21 +/- 0.03 EPO units) compared with wild-type mice (3.34 +/- 0.65 EPO units). There was no significant difference in the degree of inhibition of eosinophil recruitment in ICAM-1-deficient mice at the three time points (3, 12, and 24 h) of study after allergen challenge. However, in P-selectin-deficient mice there was a decline in the degree of inhibition of eosinophil recruitment from 3 h (67% inhibition) and 12 h (72% inhibition) postchallenge, to 24 h postchallenge (38% inhibition), suggesting that other adhesion molecules may be playing a more prominent role than P-selectin at later time points. These studies suggest an important role for ICAM-1 and P-selectin in eosinophil recruitment to the lung after allergen challenge.

Animals↗
PubMed1997

Leukocyte adhesion in angiogenic blood vessels. Role of E-selectin, P-selectin, and beta2 integrin in lymphotoxin-mediated leukocyte recruitment in tumor microvessels.

Interaction of circulating leukocytes with tumor microvasculature is a critical event in the recruitment of effector cells into the tumor stroma. We have examined the ability of lymphotoxin (TNF-beta), to stimulate rolling, adhesion, and transmigration of leukocytes in angiogenic blood vessels induced by tumor spheroids of Lewis lung carcinoma (LLC) implanted in dorsal skinfold chambers of nude mice. In the absence of cytokine stimulation, circulating leukocytes failed to appreciably interact with tumor microvessels (TMV), although significant rolling and adhesion was observed in normal vessels. However, stimulation with lymphotoxin (LT) resulted in a rapid increase in the number of fast and slow rolling leukocytes in TMV. Treatment with anti-P-selectin mAb 5H1 resulted in inhibition of fast rollers alone, while combination treatment with anti-P-selectin and anti-E-selectin (9A9) mAbs effectively blocked slow rolling of leukocytes. Superfusion of the lymphotoxin-stimulated neovasculature with leukotriene B4 (LTB4) resulted in stable cell adhesion followed by emigration of leukocytes into the tumor stroma. LTB4-mediated adhesion and transmigration was significantly inhibited by treatment with anti-beta2 mAb 2E6. These studies delineate a multistep cascade of leukocyte adhesion in TMV and demonstrate that stimulation of the neovasculature with cytokines and chemoattractants can result in P- and E-selectin-dependent rolling and beta2-dependent stable adhesion followed by transmigration into the tumor stroma.

Animals↗
PubMed1997

Granulocyte-macrophage colony-stimulating factor regulates the functional adhesive state of very late antigen-4 expressed by eosinophils.

As very late antigen-4 (VLA-4) can exist in different functional states, we have sought to determine whether a cytokine expressed by inflamed endothelium (i.e., granulocyte-macrophage CSF (GM-CSF)) could regulate the functional state of VLA-4 expressed by eosinophils. Using a micropipette single cell adhesion assay able to measure the strength of adhesion forces, eosinophils exhibited low levels of basal adhesion to unstimulated endothelium (separation force, 0.022 +/- 0.003 mdynes). In contrast, individual eosinophils bound to IL-1beta-stimulated endothelium (0.49 +/- 0.02 mdynes), TNF-stimulated endothelium (0.62 +/- 0.05 mdynes), or IL-4-stimulated endothelium (0.11 +/- 0.01 mdynes) with increased avidity as assessed by separation force. Eosinophil binding to IL-4-stimulated endothelium was significantly inhibited by neutralizing Abs to either vascular cell adhesion molecule (VCAM) or VLA-4. The strength of eosinophil adhesion to VCAM (0.31 +/- 0.02 mdynes) or to connecting segment-1 (CS-1) (0.18 mdynes) was greater than the strength of eosinophil adhesion to unstimulated endothelium (0.02 mdynes), but was less than the strength of eosinophil adhesion to IL-1beta-stimulated endothelium (0.49 +/- 0.02 mdynes). After incubating eosinophils for 30 min with GM-CSF, the mean adhesion strength of eosinophils to CS-1 and VCAM increased significantly by 84 and 54%, respectively, compared with that of controls. This increased binding of eosinophils to VCAM or CS-1 was not due to alterations in VLA-4 receptor number (assessed by FACS analysis) or alterations in VLA-4 receptor distribution (assessed by confocal microscopy). These studies suggest that endothelial-derived cytokines such as GM-CSF have the potential to alter the functional state of eosinophil-expressed VLA-4 from a low affinity state to a high affinity state.

Carrier Proteins↗
PubMed1996

E-selectin preferentially supports neutrophil but not eosinophil rolling under conditions of flow in vitro and in vivo.

The selectin family of adhesion molecules is composed of the L-, E-, and P-selectins, which promote leukocyte rolling during inflammation. Although E-selectin supports neutrophil and lymphocyte rolling, its ability to mediate eosinophil rolling under conditions of flow in vitro and in vivo has not been determined. Using function-blocking mAbs raised against rabbit E-selectin, we have determined whether E-selectin supports human eosinophil rolling in comparison to human neutrophil rolling in IL-1-stimulated rabbit mesenteric venules utilizing intravital microscopy. Anti-rabbit E-selectin mAbs 8B9 and 8G9 were found to inhibit neutrophil rolling but had no significant effect on eosinophil rolling. Likewise, mAb 8B9 F(ab')2 fragments were found to block neutrophil rolling, but did not significantly alter the flux of rolling eosinophils. Isotype-matched Abs and a nonblocking anti-rabbit E-selectin mAb 2A5 failed to inhibit both neutrophil and eosinophil rolling on venular endothelium. In support of these in vivo observations, significant numbers of human neutrophils but not eosinophils were found to avidly roll on monolayers of E-selectin transfectants under physiologic condition of flow in vitro. Under subphysiologic conditions of shear (0.17-0.5 dyn/cm2), eosinophils rolled on E-selectin, albeit in lower numbers (three- to sevenfold) compared with neutrophils. In addition, the rolling velocity of eosinophils was significantly higher compared with neutrophils on E-selectin transfectants. These studies suggest that at physiologic shear rates, E-selectin is likely to function as a major vascular adhesion receptor in mediating neutrophil but not eosinophil rolling in inflamed postcapillary venules.

Animals↗
PubMed1996

Fibrinogen mediates leukocyte-endothelium bridging in vivo at low shear forces.

In addition to preserving hemostasis, fibrinogen assembly on leukocytes mediates inflammatory responses and may aberrantly contribute to vascular injury. In this study, we used real-time intravital video microscopy in exposed rabbit mesentery to investigate the potential role of fibrinogen on leukocyte adherence mechanisms, in vivo. At physiologic concentrations of 0.15 to 0.5 mg/mL, human fibrinogen dose-dependently enhanced by threefold to fivefold the adhesion of chemoattractant-stimulated monocytic HL-60 cells to rabbit mesenteric endothelium, by acting as a bridging molecule between the two types. Fibrinogen-dependent intercellular bridging occurred in venules, but not in arterioles or capillaries (1), was optimal at reduced flow shear forces (range: 0.77 to 2.79 dyne/cm2) (2), and produced a firm attachment of monocytic cells to endothelium, rather than transient rolling (3). Consistent with this model, rabbit fibrinogen failed to support human leukocyte adhesion, while human fibrinogen enhanced monocytic cell attachment to rabbit endothelial cells in vitro, in a reaction indistinguishable from that observed with human endothelium. Antagonists of the recently described association of fibrinogen with intercellular adhesion molecule-1 (ICAM-1), including monoclonal antibodies (MoAbs) LB-2 or 2D5, or the fibrinogen gamma 3 peptide gamma Asn117-Ala133, blocked fibrinogen-dependent leukocyte-endothelium interaction in vitro or in vivo, respectively, while a control nonbinding antibody or the fibrinogen L10 peptide gamma Leu402-Val411 were ineffective. These data suggest that simultaneous assembly of fibrinogen on leukocytes and endothelial ICAM-1 provides a pathway of intercellular adhesion which may act in concert with beta 2 integrins to stabilize firm leukocyte attachment to endothelium, in vivo. Given the recognized role of fibrinogen as a major risk factor for atherosclerosis, this mechanism may directly contribute to thrombus formation and endothelial cell damage in vascular diseases.

Animals↗
PubMed1996

Differential regulation of eosinophil adhesion under conditions of flow in vivo.

The proinflammatory role of eosinophils in patients with allergic inflammation is now well recognized. However, the molecular mechanisms mediating the sequential events of eosinophil recruitment from the blood stream to sites of allergic inflammation under conditions of shear force have not been clearly established. Using the xenogeneic rabbit model system to study human eosinophil adhesion under conditions of flow in vivo, we have demonstrated that eosinophils like neutrophils roll, adhere, and extravasate across cytokine-stimulated endothelial cells at physiological shear rates in vivo. Eosinophils rolling on venular endothelial cells is mediated by L-selectin and VLA-4. Mediators of cellular activation such as GM-CSF, PAF, or PMA had a differential effect on neutrophil and eosinophil receptor expression and their rolling function. It would thus appear that acting sequentially or in concert a variety of cytokines, including GM-CSF, RANTES, IL-5, and specific cell adhesion molecules (VLA-4/VCAM-1) might play a critical role in the selective sequestration of eosinophils and other proinflammatory leukocytes into the inflamed tissues during episodes of allergic inflammation. Further understanding of the function of these mediators as well as other traffic signals that regulate eosinophil adhesion will help in developing better therapeutic strategies to block the emigration of eosinophils from the blood stream, and also to inhibit the activation of eosinophils once they have reached sites of tissue inflammation.

Animals↗
PubMed1996

Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy.

In the present study, we evaluated the effects of a neutralizing antivascular endothelial growth factor (anti-VEGF) antibody on angiogenesis and growth of tumor spheroids using an intravital microscopic technique permitting noninvasive, in vivo and in situ study of tumor angiogenesis and tumor growth in conscious mice. Tumor spheroids of the human rhabdomyosarcoma cell line A673, with a diameter between 600 and 1000 microns, were implanted in dorsal skinfold chambers inserted on Beige nude/xid mice. Tumor cells were prelabeled with a fluorescent vital dye [(5-(and-6)-((4-chloromethyl)benzoyl)amino)tetramethylrhodamine], which allowed estimation of the growth of the implanted tumor spheroids. Treatment (i.p.) with the monoclonal antibody A4.6.1, specific for VEGF, completely inhibited neovascularization of the microtumors and suppressed their growth to the extent that tumors implanted in treated animals leveled off at a volume less than 1 mm3, i.e., the anti-VEGF antibody dramatically changed the growth characteristics of the tumor line from being a rapidly growing malignancy to a dormant microcolony.

Animals↗
PubMed1996

Mouse bone marrow-derived mast cells roll on P-selectin under conditions of flow in vivo.

Increased numbers of mast cells are noted at sites of wound healing and inflammation. These mast cells are either recruited from the bone marrow or proliferate locally under cytokine stimulation. However, the molecular mechanisms mediating initial adhesive interactions between mast cell precursors and vascular endothelial cells are not well understood. We have used a syngeneic dorsal skinfold chamber model of microcirculation to study early events of mast cell-endothelial cell interactions by intravital fluorescence microscopy. Because "rolling" represents the earliest step of granulocyte adhesion under conditions of flow, our objective was to determine whether vascular selectins promote rolling of immature mouse bone marrow-derived mast cells (MBMMC) on endothelial cells lining murine blood vessels in vivo. In this study, titanium window chambers were implanted on the dorsal skinfolds of BALB/c mice. The passage of injected fluorescently labeled MBMMC within blood vessels of the striated skin muscle was observed by stroboscopic epi-illumination. As previously determined for other leukocytes, MBMMC were observed to roll in venules but not in arterioles or capillaries. Mice were also treated with neutralizing anti-E-selectin (mAb 9A9) and anti-P-selectin (mAb 5H1) antibodies and tested for their ability to block MBMMC rolling on venular endothelial cells. Intravenous administration of mAb 5H1 resulted in a marked decrease in MBMMC rolling, whereas mAb 9A9 and isotype matched control antibodies had no effect on the rolling flux of MBMMC. These studies represent the first identification of P-selectin as a rolling receptor for MBMMC, and demonstrate the use of a dorsal skinfold technique to study MBMMC-endothelial cell interactions under conditions of physiologic flow. Further studies will determine whether vascular selectins participate in the rolling and tissue recruitment of true circulating immature mast cell precursors in vivo.

Animals↗
PubMed1995

Structure-antitubercular activity relationship of phenothiazine-type calmodulin antagonists.

Six neuroleptic (antipsychotic) phenothiazine derivatives which are calmodulin antagonists were tested for their activity against Mycobacterium tuberculosis H37Rv in order to understand their structure-antitubercular activity relationship. Out of the six derivatives tested (trifluoperazine, chlorpromazine, triflupromazine, thioridazine, acetopromazine and fluphenazine), trifluoperazine appears to be a more potent antitubercular drug than others with a minimum inhibitory concentration (MIC) of 5 micrograms/ml. Chlorpromazine, triflupromazine and thioridazine are also active but less potent and have a higher MIC of 20 micrograms/ml. Acetopromazine and fluphenazine could not completely inhibit the growth even at a high concentration of 20 micrograms/ml. These results indicate that a methylpiperazinylpropyl group attached to the nitrogen (position 10) atom and trifluoromethyl group at the second carbon confer antitubercular activity to the phenothiazine molecule. It is suggested that trifluoperazine or one of its derivatives could be useful as one of the drugs in the multi-drug regimen for the treatment of tuberculosis with psychotic problems or vice versa.

Antipsychotic Agents↗