Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mesylates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2003

Imatinib mesylate causes hypopigmentation in the skin.

BACKGROUND: Imatinib mesylate is a tyrosine kinase inhibitor that targets the BCR-ABL protein in CML, c-kit (KIT) and platelet-derived growth factor receptors. In clinical trials with imatinib mesylate, common side effects of nausea, emesis, diarrhea, periorbital edema, fluid retention, and myelosuppression have been documented. METHODS: In this case series, the authors describe unique clinical findings of skin hypopigmentation in six patients with CML who were treated with imatinib mesylate. RESULTS: Most patients developed onset of skin hypopigmentation within the first month of treatment and all of the patients experienced additional drug toxicity. Despite patient susceptibility to toxicity, the presence of hypopigmentation did not appear to predict leukemic cell response or clinical outcome. All six patients established a hematologic response but only two patients had a complete cytogenetic response. Imatinib mesylate induced hypopigmentation also appeared to be reversible and potentially dose related. CONCLUSION: Skin hypopigmentation is a benign side effect from imatinib mesylate treatment that appears to be reversible upon discontinuation or dose reduction. Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk-2). Microphthalmia (Mi), a basic helix-loop-helix leucine zipper (bHLHZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73). Once phosphorylated, Mi transactivates the tyrosine pigmentation gene promoter and affects pigment production.

Adult↗
PubMed2003

Anagrelide and imatinib mesylate combination therapy in patients with chronic myeloproliferative disorders.

PURPOSE: The tyrosine kinase inhibitor imatinib mesylate inhibits the function of the Bcr-Abl oncoprotein associated with Philadelphia-positive chronic myelogenous leukemia (CML). Anagrelide suppresses megakaryocyte proliferation and differentiation. The objectives of this study were to investigate the feasibility and safety of imatinib mesylate and anagrelide combination therapy in patients with Ph-positive CML or chronic myeloproliferative disorders (MPD) with persistent thrombocythemia. METHODS: This study was a retrospective review of all available records of patients with chronic MPD presenting to the M.D. Anderson Cancer Center between October 1998 and May 2002, treated with imatinib mesylate combined with anagrelide. RESULTS: Of 22 patients identified, 18 had Ph-positive CML (chronic phase, 16 patients; accelerated phase, 2 patients), 1 had agnogenic myeloid metaplasia (AMM), 2 had essential thrombocythemia (ET) and 1 had MPD transformed into refractory anemia with excess blasts (RAEB). The median age was 57 years (range 26-82 years). The median dose of imatinib mesylate administered was 400 mg (range 300-800 mg) and the median dose of anagrelide was 1.5 mg (range 0.5-4.0 mg). Imatinib mesylate and anagrelide combination therapy was feasible and tolerable. Of the 18 patients with Ph-positive CML, 15 in chronic phase and 1 in accelerated phase achieved a complete hematologic response (CHR), and 9 of the 18 achieved cytogenetic response (complete in 8 patients). No responses were noted in patients with AMM, ET or MPD transformed into RAEB. CONCLUSIONS: The combination of imatinib mesylate and anagrelide was safe and was associated with an 89% CHR rate in patients with CML in chronic phase and persistent thrombocythemia.

Adult↗
PubMed2006

Immunohistochemical analysis of platelet-derived growth factor receptor-alpha, -beta, c-kit, c-abl, and arg proteins in glioblastoma: possible implications for patient selection for imatinib mesylate therapy.

Inhibition of tyrosine kinase (TK) receptors by synthetic small molecules has become a promising new therapy option in oncology. The TK inhibitor imatinib mesylate selectively targets PDGFR-alpha, -beta, c-kit, c-abl and arg and has proven successful in the treatment of chronic myeloid leukaemia. In recurrent glioblastoma, phase II therapy trials using imatinib mesylate have been initiated. As only a fraction of patients seems to benefit from imatinib mesylate therapy and due to potential side effects and high costs of imatinib mesylate therapy, selection of the right patients is important. The goal of our study was to assess systematically immunohistochemical expression of the major TKs targeted by imatinib mesylate in glioblastoma, as expression of these factors could be used to select patients for imatinib mesylate therapy. In a cohort of 101 glioblastoma patients, anti-PDGFR-alpha, -beta, c-kit, c-abl and arg protein immunohistochemistry was performed. Expression of these proteins was assessed semi-quantitatively and correlated with patient survival.PDGFR-alpha and arg expression in tumor cells was widespread in 1/101 cases, respectively. Focal PDGFR-alpha, -beta, c-kit, c-abl and arg immunolabeling was detected in 25/101, 19/101, 4/101, 7/101 and 31/101 cases, respectively. Statistical analysis did not reveal any correlation between expression of the TKs and patient survival. We show here for the first time in a large series of glioblastomas that PDGFR-alpha, -beta, c-kit, c-abl and arg expression is immunohistochemically detectable in a fraction of cases. The value of anti-tyrosine kinase immunolabeling as predictive factor for patient selection remains to be clarified by comparative analysis of tumor tissue of therapy-responders versus non-responders.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Importance of using physiologically relevant volume of dissolution medium to correlate the oral exposure of formulations of BMS-480188 mesylate.

BMS-480188 is a weak base. The aqueous solubility of BMS-480188 is 0.036 mg/ml at pH 6.5 at 37 degrees C. The mesylate salt of BMS-480188 was prepared to improve its solubility. Capsules containing mesylate salt alone (Formulation A) or mesylate salt with excipients, including lactose, croscarmellose sodium, sodium lauryl sulfate, syloid and magnesium stearate (Formulation B), were prepared. Both formulations show similar dissolution profiles in 1l 0.01N HCl at 37 degrees C. However, the bioavailability of Formulations A and B is 5.7 and 24%, respectively, in monkeys. Since very small amount of fluid is available in the stomach of monkeys in fasted state, 30 ml of 0.01N HCl was used as the dissolution medium to simulate the ratio of the drug to dissolution medium in vivo. The dissolution studies in 30 ml of 0.01N HCl show that the amount of drug dissolved from the Formulation B is 80% greater than the Formulation A after 2h. These results are consistent with the higher bioavailability of the formulated capsules. The pK(a) of the free base is 3.0 and the apparent solubility of the mesylate salt (>20mg/ml) is much greater than the equilibrium solubility of BMS-480188 (1.08 mg/ml) in 0.01N HCl at 37 degrees C. Therefore, the mesylate salt of BMS-480188 converts to the free base in 0.01N HCl. The presence of excipients delays the conversion of the mesylate salt to the free base in the dissolution test using 30 ml medium, leading to a greater percentage of the dissolved drugs. This inhibitory effect of excipients is masked during the dissolution using 1l medium because the concentration of the dissolved drug is below the solubility limit of BMS-480188. This study demonstrates the importance of the volume of the dissolution medium for the in vitro dissolution test to qualitatively predict the bioavailability of a salt of weak base with low intrinsic aqueous solubility.

Administration, Oral↗
PubMed2004

A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2.

The relationship between the Src kinase Lyn and Bcl-2 expression was examined in chronic myelogenous leukemia cells (K562 and LAMA84) displaying a Bcr/Abl-independent form of imatinib mesylate resistance. K562-R and LAMA-R cells that were markedly resistant to induction of mitochondrial dysfunction (e.g. loss of mitochondrial membrane potential, Bax translocation, cytochrome c, and apoptosis-inducing factor release) and apoptosis by imatinib mesylate exhibited a pronounced reduction in expression of Bcr/Abl, Bcl-x(L), and STAT5 but a striking increase in levels of activated Lyn. Whereas basal expression of Bcl-2 protein was very low in parental cells, imatinib-resistant cells displayed a marked increase in Bcl-2 mRNA and/or protein levels. Treatment of LAMA-R cells with the Src kinase inhibitor PP2 significantly reduced Lyn activation as well as Bcl-2 mRNA and protein levels. Transient or stable transfection of LAMA84 or K562 cells with a constitutively active Lyn (Y508F), but not with a kinase-dead mutant (K275D), significantly increased Bcl-2 protein expression and protected cells from lethality of imatinib mesylate. Ectopic expression of Bcl-2 protected K562 and LAMA84 cells from imatinib mesylate- and PP2-mediated lethality. Conversely, interference with Bcl-2 function by co-administration of the small molecule Bcl-2 inhibitor HA14-1 or down-regulation of Bcl-2 expression by small interfering RNA or antisense strategies significantly increased mitochondrial dysfunction and apoptosis induced by imatinib mesylate and the topoisomerase inhibitor VP-16 in LAMA-R cells. In marked contrast, these interventions had little effect in parental LAMA84 cells that display low basal levels of Bcl-2. Together, these findings indicate that activation of Lyn in leukemia cells displaying a Bcr/Abl-independent form of imatinib mesylate resistance plays a functional role in Bcl-2 up-regulation and provide a theoretical basis for the development of therapeutic strategies targeting Bcl-2 in such a setting.

Apoptosis↗
PubMed2006

Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment.

Reactivation of chronic hepatitis B virus (HBV) infection in patients undergoing chemotherapy is well-documented, but reactivation during imatinib mesylate treatment has not been reported. This study reports a 54-year-old man, without prior liver dysfunction but with chronic HBV infection, in whom fatal HBV reactivation occurred during treatment of chronic myeloid leukemia (CML) with imatinib mesylate. He developed fulminant hepatitis followed by marked elevation of HBV DNA polymerase, probably from the lymphocytopenic and immunosuppressive status induced by imatinib mesylate. Imatinib mesylate is widely used to treat CML patients. Although therapy with imatinib mesylate is generally well tolerated, the case presented here suggests that viral reactivation should be considered, even when using imatinib mesylate to treat CML.

Antineoplastic Agents↗
PubMed2006

Synergistic interactions between DMAG and mitogen-activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate.

PURPOSE: To characterize interactions between the heat shock protein 90 antagonist 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor PD184352 in Bcr/abl(+) leukemia cells sensitive and resistant to imatinib mesylate. EXPERIMENTAL DESIGN: K562 and LAMA 84 cells were exposed to varying concentrations of DMAG and PD184352 for 48 hours; after which, mitochondrial integrity, caspase activation, and apoptosis were monitored. Parallel studies were done in imatinib mesylate-resistant cells, including BaF3 cells transfected with plasmids encoding clinically relevant Bcr/abl mutations conferring imatinib mesylate resistance (e.g., E255K, M351T, and T315I) and primary CD34(+) bone marrow cells from patients refractory to imatinib mesylate. RESULTS: Cotreatment of Bcr/abl(+) cells with minimally toxic concentrations of DMAG and PD184352 resulted in synergistic induction of mitochondrial injury (cytochrome c release and Bax conformational change), events associated with the pronounced and sustained inactivation of ERK1/2 accompanied by down-regulation of Bcl-x(L). Conversely, cells ectopically expressing Bcl-x(L) displayed significant protection against PD184352/DMAG-mediated lethality. This regimen effectively induced apoptosis in K562 cells overexpressing Bcr/abl, in BaF3 cells expressing various clinically relevant Bcr/abl mutations, and in primary CD34(+) cells from patients resistant to imatinib mesylate, but was relatively sparing of normal CD34(+) bone marrow cells. CONCLUSIONS: A regimen combining the heat shock protein 90 antagonist DMAG and the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor potently induces apoptosis in Bcr/abl(+) cells, including those resistant to imatinib mesylate through various mechanisms including Bcr/abl kinase mutations, through a process that may involve sustained ERK1/2 inactivation and Bcl-x(L) down-regulation. This strategy warrants further attention in Bcr/abl(+) hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.

Antineoplastic Agents↗
PubMed2006

The effects of ergoloid mesylates and ginkgo biloba on the pharmacokinetics of ticlopidine.

Ticlopidine is sometimes coadministered with ergoloid mesylates or ginkgo biloba in clinical situations. Our objective was to examine the effect of ergoloid mesylates and ginkgo biloba on ticlopidine pharmacokinetics. Ticlopidine, ergoloid mesylates, and ginkgo biloba significantly inhibited the organic anion transporting polypeptide (OATP-B)-mediated uptake of [(3)H]-estrone-3-sulfate in a concentration-dependent manner. When ergoloid mesylates was coadministered with ticlopidine, the ticlopidine area under the plasma drug concentration-time profile (AUC) from 0 to 12 hours was decreased 30% and the peak plasma drug concentration (C(max)) was decreased 29%, compared with ticlopidine administration alone. There were no significant changes in the pharmacokinetic parameters of ticlopidine when it was coadministered with ginkgo biloba. In summary, ergoloid mesylates is a more potent inhibitor of OATP-B than is ginkgo biloba, and it can reduce the oral bioavailability of drugs transported by OATP-B. Ergoloid mesylates markedly decreased the AUC and C(max) of ticlopidine, probably by inhibiting the OATP-B-mediated uptake of ticlopidine during the intestinal absorption phase. The results support a new model of intestinal drug-drug interaction.

Adult↗
PubMed2003

Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment.

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) has shown remarkable efficacy in the treatment of chronic myelogenous leukemia (CML), with a high proportion of patients achieving complete cytogenetic responses (CCRs). However, it is not clear whether remissions will be durable and whether imatinib mesylate can eliminate the malignant primitive progenitors in which the disease arises. We investigated whether residual BCR/ABL+ hematopoietic progenitors were present in patients who achieved CCRs with imatinib mesylate treatment. CD34+ progenitor cells were selected from bone marrow mononuclear cells (MNCs) and analyzed for the presence of the BCR/ABL fusion gene by fluorescence in situ hybridization (FISH). CD34+ cells were also plated in committed progenitor (colony-forming cell, or CFC) and primitive progenitor (long-term bone marrow culture-initiating cell, or LTCIC) cultures and resulting colonies analyzed for the presence of BCR/ABL+ cells by FISH. Using these assays, residual BCR/ABL+ progenitors were detected in all patients studied. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated increased levels of BCR/ABL mRNA in CD34+ cells compared with total MNCs. Evaluation of samples collected at different time points demonstrated persistence of BCR/ABL+ progenitors despite continued treatment with imatinib mesylate. Our results indicate that inhibition of BCR/ABL tyrosine kinase activity by imatinib mesylate does not eliminate malignant primitive progenitors in CML patients. Patients in CCR with imatinib mesylate treatment need to be followed carefully to assess for risk of relapse.

Adult↗
PubMed2003

The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia.

The chronic myelogenous leukemia (CML)-like myeloproliferative disorder observed in the BCR/ABL murine bone marrow transduction and transplantation model shares several features with the human disease, including a high response rate to the tyrosine kinase inhibitor imatinib mesylate (STI571). To study the impact of chronic imatinib mesylate treatment on the CML-like illness, mice were maintained on therapeutic doses of this drug and serially monitored. Unexpectedly, despite excellent systemic control of the CML-like illness, many of the mice developed progressive neurologic deficits after 2 to 4 months of imatinib mesylate therapy because of central nervous system (CNS) leukemia. Analysis of imatinib mesylate cerebral spinal fluid concentrations revealed levels 155- fold lower than in plasma. Thus, in the mouse, the limited ability of imatinib mesylate to cross the blood-brain barrier allowed the CNS to become a sanctuary for Bcr/Abl-induced leukemia. This model will be a useful tool for the future study of novel anti-CML drugs and in better defining the mechanisms for limited imatinib mesylate penetration into the CNS.

Animals↗
PubMed2005

Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells.

The precise mechanisms by which imatinib mesylate (STI571) and interferon alpha (IFNalpha) exhibit antileukemic effects are not known. We examined the effects of IFNs or imatinib mesylate on signaling pathways regulating initiation of mRNA translation in BCR-ABL-expressing cells. Treatment of IFN-sensitive KT-1 cells with IFNalpha resulted in phosphorylation/activation of mammalian target of rapamycin (mTOR) and downstream activation of p70 S6 kinase. The IFN-activated p70 S6 kinase was found to regulate phosphorylation of S6 ribosomal protein, which regulates translation of mRNAs with oligopyrimidine tracts in the 5'-untranslated region. In addition, IFNalpha treatment resulted in an mTOR- and/or phosphatidyl-inositol 3'(PI 3') kinase-dependent phosphorylation of 4E-BP1 repressor of mRNA translation on sites that are required for its deactivation and dissociation from the eukaryotic initiation factor-4E (eIF4E) complex. In contrast to the effects of IFNs, imatinib mesylate suppressed p70 S6 kinase activity, consistent with inhibition of BCR-ABL-mediated activation of the mTOR/p70 S6 kinase pathway. Moreover, the mTOR inhibitor rapamycin enhanced the suppressive effects of imatinib mesylate on primary leukemic granulocyte macrophage-colony-forming unit (CFU-GM) progenitors from patients with chronic myelogenous leukemia (CML). Taken altogether, our data demonstrate that IFNs and imatinib mesylate differentially regulate PI 3' kinase/mTOR-dependent signaling cascades in BCR-ABL-transformed cells, consistent with distinct effects of these agents on pathways regulating mRNA translation. They also support the concept that combined use of imatinib mesylate with mTOR inhibitors may be an appropriate future therapeutic strategy for the treatment of CML.

5' Untranslated Regions↗
PubMed2005

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Administration, Oral↗
PubMed2005

Imatinib mesylate in the treatment of gastrointestinal stromal tumour.

Imatinib mesylate is a selective and potent small-molecule inhibitor of tyrosine kinases, including Kit, platelet-derived growth factor receptor, and the BCR-Abl fusion protein. Kit plays an important role in gastrointestinal stromal tumours (GISTs) and is one of the most exciting therapeutic targets discovered so far. Clinical trials have consistently shown the dramatic efficacy of imatinib mesylate in patients with GIST. This article will review the development and pharmacology of this small-molecule inhibitor and summarise the clinical trials of imatinib mesylate for the treatment of GIST. Although imatinib mesylate has significantly improved the outcomes of most patients with advanced GIST, unanswered questions remain: what is the role of imatinib mesylate in the pre- and postoperative settings? What is the mechanism of the antitumour activity of imatinib? How do you manage patients whose tumours are refractory to imatinib mesylate?

Benzamides↗
PubMed2005

Identification of differentially expressed proteins in imatinib mesylate-resistant chronic myelogenous cells.

Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a 1 microM imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.

Antineoplastic Agents↗
PubMed2004

[Efficacy of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, on chronic myeloid leukemia in blast phase].

BACKGROUND & OBJECTIVE: Chronic myeloid leukemia (CML) in blast phase is refractory with a poor prognosis. This study was to evaluate efficacy of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, on CML in blast phase. METHODS: Nineteen patients with CML in blast phase (imatinib treatment group) received induction of cytarabine-based standard chemotherapy for 2 cycles, and 400 mg/d of imatinib mesylate for 4 weeks. Patients with no remission received 600 mg/d of imatinib mesylate for another 8 weeks. Treatment of 600 mg/d of imatinib mesylate was maintained if it showed effects after 8 weeks, otherwise it would be stopped. Twenty-two patients with CML in blast phase (historical control group) received inducement of cytarabine-based chemotherapy for 2 cycles, and other regimens of consolidation or continuous induction. RESULTS: Sixteen patients of imatinib treatment group achieved no hematologic remission after induction. After treated with imatinib mesylate, 6 of 16 (38%) achieved hematologic complete remission (CHR), and major cytogenetic response; 2 of 16(13%) achieved hematologic partial remission (PHR); 1 of 16 (6%) returned to chronic phase with minor cytogenetic response. Total hematologic response rate of imatinib treatment group was 57%; 1-year survival rate was 38% (6/16). Eighteen patients of historical control group achieved no hematologic remission after inducement. After treated with other regimens, 2 (11%) achieved CHR, and 1 (6%) achieved PHR. Total hematologic response rate of historical control group was 17%; 1-year survival rate was 6%(1/18), significantly lower than that of imatinib treatment group (P< 0.05). CONCLUSIONS: Imatinib mesylate may have anti-leukemic activity, and prolong survival time of patients with CML in blast phase. But problems of tumor relapse, and drug resistance are still present.

Adolescent↗
PubMed1993

Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: II. Multiple-dose administration.

The multiple dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 50 healthy male volunteers. Volunteers were randomized to receive intravenous normal saline placebo (n = 10), citrate vehicle placebo (n = 10), or 0.5 mg/kg/day (n = 6), 1.0 mg/kg/day (n = 6), 2.0 mg/kg/day (n = 6), 4.0 mg/kg/day (n = 6), or 6.0 mg/kg/day (n = 6) tirilazad mesylate in divided doses every 6 hours for 5 days, for a total of 21 doses. Drug was infused over 10 or 30 minutes. All tirilazad mesylate treatment groups and the citrate vehicle group had significantly more frequent and more intense pain at the injection site than did the saline group, but the pain intensity did not require interruption of dosing. Three episodes of clinical thrombophlebitis were observed. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, or renal function were apparent. Moderate and transient increases in serum alanine transaminase were observed in several subjects. In the 6.0 mg/kg/day group, 50% of the subjects exhibited increased alanine transaminase. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Tirilazad mesylate pharmacokinetics were linear over the dosage range studied. Steady state appeared to be achieved by the fifth day of dosing. After the last dose, a mean terminal half-life of 35 hours was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Effect of gabexate mesylate (FOY), a drug for serine proteinase-mediated diseases, on the nitric oxide pathway.

Considering the structural similarity between gabexate mesylate (FOY), a drug for serine proteinase-mediated diseases, and L-arginine, the effect of gabexate mesylate on the nitric oxide (NO) pathway has been investigated. Gabexate mesylate inhibits competitively constitutive and inducible NO synthase (cNOS and iNOS, respectively), with Ki values of 1.0 x 10(-4) M and 5.0 x 10(-3) M, respectively, at pH 7.4 and 37.0 degrees C. However, gabexate mesylate is not an NO precursor. Moreover, like other NOS inhibitors, gabexate mesylate increases iNOS mRNA expression in rat C6 glioma cells, as induced by E. coli lipopolysaccharide plus interferon-gamma. Finally, gabexate mesylate inhibits dose-dependently nitrite production (i.e. NO release) in rat C6 glioma cells, as induced by E. coli lipopolysaccharide plus interferon-gamma. Thus, this drug should be administered under careful control, since enzyme inhibition may occur also in vivo.

Animals↗
PubMed1997

Tirilazad mesylate improves survival of rat and human embryonic mesencephalic neurons in vitro.

The survival rate of embryonic dopamine (DA) neurons after transplantation to the striatum is only 5-20%. Therefore, mesencephalic tissue from several donors needs to be implanted in a parkinsonian patient to induce a therapeutic improvement. Lazaroids are a group of neuroprotective compounds which inhibit lipid peroxidation. Previously, two lazaroids (U-74389G and U-83836F) have been found to improve the survival of both cultured and grafted rat DA neurons. The only lazaroid approved for human use is tirilazad mesylate. The objective of the present study was to explore the effects of tirilazad mesylate on DA neuron survival in cultures of rat ventral mesencephalon and its capacity to promote the in vitro cell viability of embryonic rat and human mesencephalic tissue, treated and dissociated in the same way as in clinical trials. After 7 days in vitro, the number of tyrosine hydroxylase-immunopositive, presumed DA neurons was 140% higher in rat cultures treated with 0.3 microM tirilazad mesylate than that in control cultures. Rat and human cell suspensions supplemented with tirilazad mesylate maintained a high degree of viability for several hours longer than control suspensions. These results indicate that tirilazad mesylate promotes the survival of both rat and human embryonic mesencephalic neurons in vitro. Tirilazad mesylate can be administered clinically and may become a useful tool for increasing survival of grafted DA neurons in patients, thereby reducing the needed quantity of human donor tissue.

Animals↗