Showing papers by "Novartis published in 2002"

Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.

Abstract: Background Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors. Methods We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients. Results A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow...

Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia

Abstract: Background Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. Methods A total of 532 patients with late–chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. Results Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment be...

Molecular, pharmacological and functional diversity of 5-HT receptors

Abstract: Serotonin (5-hydroxytryptamine, 5-HT) is probably unique among the monoamines in that its effects are subserved by as many as 13 distinct heptahelical, G-protein-coupled receptors (GPCRs) and one (presumably a family of) ligand-gated ion channel(s). These receptors are divided into seven distinct classes (5-HT(1) to 5-HT(7)) largely on the basis of their structural and operational characteristics. Whilst this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity continues to emerge. The challenge for modern 5-HT research has therefore been to define more precisely the properties of the systems that make this incredible diversity possible. Much progress in this regard has been made during the last decade with the realisation that serotonin is possibly the least conservative monoamine transmitter and the cloning of its many receptors. Coupled with the actions of an extremely avid and efficient reuptake system, this array of receptor subtypes provides almost limitless signalling capabilities to the extent that one might even question the need for other transmitter systems. However, the complexity of the system appears endless, since posttranslational modifications, such as alternate splicing and RNA editing, increase the number of proteins, oligomerisation and heteromerisation increase the number of complexes, and multiple G-protein suggest receptor trafficking, allowing phenotypic switching and crosstalk within and possibly between receptor families. Whether all these possibilities are used in vivo under physiological or pathological conditions remains to be firmly established, but in essence, such variety will keep the 5-HT community busy for quite some time. Those who may have predicted that molecular biology would largely simplify the life of pharmacologists have missed the point for 5-HT research in particular and, most probably, for many other transmitters. This chapter is an attempt to summarise very briefly 5-HT receptor diversity. The reward for unravelling this complex array of serotonin receptor--effector systems may be substantial, the ultimate prize being the development of important new drugs in a range of disease areas.

The Bioperl Toolkit: Perl Modules for the Life Sciences

Abstract: The Bioperl project is an international open-source collaboration of biologists, bioinformaticians, and computer scientists that has evolved over the past 7 yr into the most comprehensive library of Perl modules available for managing and manipulating life-science information. Bioperl provides an easy-to-use, stable, and consistent programming interface for bioinformatics application programmers. The Bioperl modules have been successfully and repeatedly used to reduce otherwise complex tasks to only a few lines of code. The Bioperl object model has been proven to be flexible enough to support enterprise-level applications such as EnsEMBL, while maintaining an easy learning curve for novice Perl programmers. Bioperl is capable of executing analyses and processing results from programs such as BLAST, ClustalW, or the EMBOSS suite. Interoperation with modules written in Python and Java is supported through the evolving BioCORBA bridge. Bioperl provides access to data stores such as GenBank and SwissProt via a flexible series of sequence input/output modules, and to the emerging common sequence data storage format of the Open Bioinformatics Database Access project. This study describes the overall architecture of the toolkit, the problem domains that it addresses, and gives specific examples of how the toolkit can be used to solve common life-sciences problems. We conclude with a discussion of how the open-source nature of the project has contributed to the development effort.

Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs

Abstract: Only a small proportion of the mouse genome is transcribed into mature messenger RNA transcripts There is an international collaborative effort to identify all full-length mRNA transcripts from the mouse, and to ensure that each is represented in a physical collection of clones Here we report the manual annotation of 60,770 full-length mouse complementary DNA sequences These are clustered into 33,409 'transcriptional units', contributing 901% of a newly established mouse transcriptome database Of these transcriptional units, 4,258 are new protein-coding and 11,665 are new non-coding messages, indicating that non-coding RNA is a major component of the transcriptome 41% of all transcriptional units showed evidence of alternative splicing In protein-coding transcripts, 79% of splice variations altered the protein product Whole-transcriptome analyses resulted in the identification of 2,431 sense-antisense pairs The present work, completely supported by physical clones, provides the most comprehensive survey of a mammalian transcriptome so far, and is a valuable resource for functional genomics

Large-scale analysis of the human and mouse transcriptomes

Abstract: High-throughput gene expression profiling has become an important tool for investigating transcriptional activity in a variety of biological samples. To date, the vast majority of these experiments have focused on specific biological processes and perturbations. Here, we have generated and analyzed gene expression from a set of samples spanning a broad range of biological conditions. Specifically, we profiled gene expression from 91 human and mouse samples across a diverse array of tissues, organs, and cell lines. Because these samples predominantly come from the normal physiological state in the human and mouse, this dataset represents a preliminary, but substantial, description of the normal mammalian transcriptome. We have used this dataset to illustrate methods of mining these data, and to reveal insights into molecular and physiological gene function, mechanisms of transcriptional regulation, disease etiology, and comparative genomics. Finally, to allow the scientific community to use this resource, we have built a free and publicly accessible website (http://expression.gnf.org) that integrates data visualization and curation of current gene annotations.

Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug

Abstract: In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.

Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.

Abstract: Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.

A Heat-Sensitive TRP Channel Expressed in Keratinocytes

Abstract: Mechanical and thermal cues stimulate a specialized group of sensory neurons that terminate in the skin. Three members of the transient receptor potential (TRP) family of channels are expressed in subsets of these neurons and are activated at distinct physiological temperatures. Here, we describe the cloning and characterization of a novel thermosensitive TRP channel. TRPV3 has a unique threshold: It is activated at innocuous (warm) temperatures and shows an increased response at noxious temperatures. TRPV3 is specifically expressed in keratinocytes; hence, skin cells are capable of detecting heat via molecules similar to those in heat-sensing neurons.

Intravenous zoledronic acid in postmenopausal women with low bone mineral density.

Abstract: Background Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored. Methods We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point. Results There were similar increases in bone ...

Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence

Abstract: The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity. Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms. Here, we show that SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras (Ha-rasV12). SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation. Moreover, we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation. When overexpressed in primary mouse embryo fibroblasts (MEFs), SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence. Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence.

Novel antiangiogenic effects of the bisphosphonate compound Zoledronic Acid

Abstract: Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC(50) values 4.1, 4.2, and 6.9 microM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED(50), 3 microg/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component.

Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP

Abstract: Dicer is a multi-domain RNase III-related endonuclease responsible for processing double-stranded RNA (dsRNA) to small interfering RNAs (siRNAs) during a process of RNA interference (RNAi). It also catalyses excision of the regulatory microRNAs from their precursors. In this work, we describe the purification and properties of a recombinant human Dicer. The protein cleaves dsRNAs into approximately 22 nucleotide siRNAs. Accumulation of processing intermediates of discrete sizes, and experiments performed with substrates containing modified ends, indicate that Dicer preferentially cleaves dsRNAs at their termini. Binding of the enzyme to the substrate can be uncoupled from the cleavage step by omitting Mg(2+) or performing the reaction at 4 degrees C. Activity of the recombinant Dicer, and of the endogenous protein present in mammalian cell extracts, is stimulated by limited proteolysis, and the proteolysed enzyme becomes active at 4 degrees C. Cleavage of dsRNA by purifed Dicer and the endogenous enzyme is ATP independent. Additional experiments suggest that if ATP participates in the Dicer reaction in mammalian cells, it might be involved in product release needed for the multiple turnover of the enzyme.

Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2 Double-Blind, Randomized, Controlled Clinical Trial

Abstract: Background— Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2). Methods and Results— FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 μg/kg (n=337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall P=0.035) and the physical component summary scale of the Short-Form 36 ...

SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile

Abstract: Objective: The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. Design: A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. Results: SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201 ‐ 995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC50 of 0:4^0:1 nmol=lOna 5U: In vivo, SOM230 also potently suppressed GH secretion in rats. The ED50 values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201 ‐ 995 and SOM230 after subcutaneous application. Whereas SMS 201 ‐ 995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animalsOt1=2a 23 hU: Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulinlike growth factor-I (IGF-I) levels compared with SMS 201 ‐ 995. The infusion of 10mg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201 ‐ 995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201 ‐ 995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. Conclusion: We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.

Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta.

Abstract: Background A small proportion of patients with chronic myeloproliferative diseases have constitutive activation of the gene for platelet-derived growth factor receptor beta (PDGFRB), which encodes a receptor tyrosine kinase. The gene is located on chromosome 5q33, and the activation is usually caused by a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene. The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL–positive chronic myeloid leukemia. Methods We treated four patients who had chronic myeloproliferative diseases and chromosomal translocations involving 5q33 with imatinib mesylate (400 mg daily). Three of the four patients presented with leukocytosis and eosinophilia; their leukemia cells carried the ETV6-PDGFRB fusion gene. The fourth patient had leukocytosis, eosinophilia, and a t(5;12) translocation involving PDGFRB and an unknown partner gene; he also had extensive raised, ulcerated...

Management of malignant gastrointestinal stromal tumours.

Abstract: Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal tumour of the gastrointestinal tract Clinically, they range from small indolent tumours curable with surgery alone to aggressive cancers Making a distinction between an indolent and a malignant GIST is unreliable with conventional histopathological techniques The presence of metastases at the time of diagnosis confirms malignancy, but all GISTs should be regarded as having malignant potential GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor Most GISTs have a mutation in the KIT proto-oncogene that translates into a gain-of-function constitutive activation of the KIT kinase KIT activation seems to be an early tumour-promoting event in pathogenesis Commonly, malignant GISTs show high-level primary resistance to conventional chemotherapy Imatinib mesylate is an orally administered selective inhibitor of certain tyrosine kinases including KIT Most patients with advanced malignant GISTs achieve clinical benefit and significant antitumour responses with imatinib mesylate Responses have been durable, and most patients tolerate the drug well at clinically effective doses Imatinib mesylate is the first effective systemic therapy for advanced GIST

Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells.

Abstract: Allergic asthma is a chronic inflammatory disease and despite the introduction of potent and effective drugs, the prevalence has increased substantially over the past few decades(1). The explanation that has attracted the most attention is the 'hygiene hypothesis', which suggests that the increase in allergic diseases is caused by a cleaner environment and fewer childhood infections(2-4). Indeed, certain mycobacterial strains can cause a shift from T-helper cell 2 (Th2) to Th1 immune responses, which may subsequently prevent the development of allergy in mice(5-7). Although the reconstitution of the balance between Th1 and Th2 is an attractive theory, it is unlikely to explain the whole story, as autoimmune diseases characterized by Th1 responses can also benefit from treatment with mycobacteria and their prevalence has also increased in parallel to allergies(8). Here we show that treatment of mice with SRP299, a killed Mycobacterium vaccae-suspension, gives rise to allergen-specific CD4(+)CD45RB(Lo) regulatory T cells, which confer protection against airway inflammation. This specific inhibition was mediated through interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), as antibodies against IL-10 and TGF-beta completely reversed the inhibitory effect of CD4(+)CD45RB(Lo) T cells. Thus, regulatory T cells generated by mycobacteria treatment may have an essential role in restoring the balance of the immune system to prevent and treat allergic diseases.

Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae

Abstract: The 2,160,267 bp genome sequence of Streptococcus agalactiae, the leading cause of bacterial sepsis, pneumonia, and meningitis in neonates in the U.S. and Europe, is predicted to encode 2,175 genes. Genome comparisons among S. agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, and the other completely sequenced genomes identified genes specific to the streptococci and to S. agalactiae. These in silico analyses, combined with comparative genome hybridization experiments between the sequenced serotype V strain 2603 V/R and 19 S. agalactiae strains from several serotypes using whole-genome microarrays, revealed the genetic heterogeneity among S. agalactiae strains, even of the same serotype, and provided insights into the evolution of virulence mechanisms.

Cerebral Hemorrhage After Passive Anti-Aβ Immunotherapy

Abstract: Immunotherapy for Alzheimer's disease (AD) has been the subject of intense investigation. Both active and passive immunization against β-amyloid peptide (Aβ) in mouse models reduce levels of Aβ, prevent and clear amyloid plaques, and improve cognitive behavior ([1][1]). We studied passive

MAPKK-Independent Activation of p38α Mediated by TAB1-Dependent Autophosphorylation of p38α

Abstract: Phosphorylation of mitogen-activated protein kinases (MAPKs) on specific tyrosine and threonine sites by MAP kinase kinases (MAPKKs) is thought to be the sole activation mechanism. Here, we report an unexpected activation mechanism for p38α MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38α with TAB1 [transforming growth factor-β–activated protein kinase 1 (TAK1)–binding protein 1] leading to autophosphorylation and activation of p38α. We detected formation of a TRAF6-TAB1-p38α complex and showed stimulus-specific TAB1-dependent and TAB1-independent p38α activation. These findings suggest that alternative activation pathways contribute to the biological responses of p38α to various stimuli.

IR Spectroscopy. An introduction

Abstract: Introduction.Absorption and Molecular Design.Spectrometers.Sample Preparation.Special Sample Techniques.Qualitative Spectral Interpretation.Quantitative Spectral Assertions.Spectroscopy in Near and Far Infrared, as well as Related Methods.Reference Spectra and Expert Systems.Appendix.Index.

Structural genomics of the Thermotoga maritima proteome implemented in a high-throughput structure determination pipeline

Abstract: Structural genomics is emerging as a principal approach to define protein structure–function relationships. To apply this approach on a genomic scale, novel methods and technologies must be developed to determine large numbers of structures. We describe the design and implementation of a high-throughput structural genomics pipeline and its application to the proteome of the thermophilic bacterium Thermotoga maritima. By using this pipeline, we successfully cloned and attempted expression of 1,376 of the predicted 1,877 genes (73%) and have identified crystallization conditions for 432 proteins, comprising 23% of the T. maritima proteome. Representative structures from TM0423 glycerol dehydrogenase and TM0449 thymidylate synthase-complementing protein are presented as examples of final outputs from the pipeline.

Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases.

Abstract: The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa), a new-generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5),4 mg/l5 min (n = 7),8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half-lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end-of-infusion C(max) to < 1% of C(max) at 24 hours postdose and half-lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0-24 h and C(max) were dose proportional and showed little accumulation (AUC0-24 h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered C(max) by 34%, with no effect on AUC0-24 h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0-24 h of 38% +/- 13%, 41% +/- 14%, and 37% +/- 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24-hour urines. Renal clearance (Ae0-24 h)/(AUC0-24 h) was on average 69 +/- 28,81 +/- 40, and 54 +/- 34 ml/min after 4,8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 +/- 23, 82 +/- 25, and 80 +/- 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine-corrected urine C-telopeptide (by 74%), N-telopeptide (69%), pyridinium cross-links [19-33%), and calcium (62%), with an increasing trend (by 12%) in bone alkalinephosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0-24 h, AUC0-24 h or C(max). The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.