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1.
Antimicrob Agents Chemother ; 67(2): e0114422, 2023 02 16.
Article in English | MEDLINE | ID: mdl-36648233

ABSTRACT

Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.


Subject(s)
Clofazimine , Mycobacterium Infections, Nontuberculous , Male , Animals , Dogs , Female , Clofazimine/pharmacology , Nontuberculous Mycobacteria , Toxicokinetics , Mycobacterium Infections, Nontuberculous/drug therapy , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Lung
2.
Br J Cancer ; 109(7): 1775-81, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-24045660

ABSTRACT

BACKGROUND: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised. METHODS: The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared. RESULTS: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug. CONCLUSION: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Azacitidine/administration & dosage , Azacitidine/therapeutic use , Benzamides/therapeutic use , Lung Neoplasms/drug therapy , Pyridines/therapeutic use , Administration, Inhalation , Aerosols , Animals , Antimetabolites, Antineoplastic/pharmacokinetics , Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/pharmacokinetics , Cytidine Deaminase/metabolism , DNA Methylation/drug effects , Epigenesis, Genetic/drug effects , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/therapeutic use , Male , Neoplasm Transplantation , Rats , Tumor Burden/drug effects
3.
Int J Pharm ; 409(1-2): 156-63, 2011 May 16.
Article in English | MEDLINE | ID: mdl-21356284

ABSTRACT

Mechanistic models of the spray drying and particle formation processes were used to conduct a formulation study with minimal use of material and time. A model microparticle vehicle suitable for respiratory delivery of biological pharmaceutical actives was designed. L-leucine was chosen as one of the excipients, because of its ability to enhance aerosol dispersibility. Trehalose was the second excipient. The spray drying process parameters used to manufacture the particles were calculated a priori. The kinetics of the particle formation process were assessed using a constant evaporation rate model. The experimental work was focused on the effect of increasing L-leucine mass fraction in the formulation, specifically its effect on leucine crystallinity in the microparticles, on powder density, and on powder dispersibility. Particle, powder and aerosol properties were assessed using analytical methods with minimal sample requirement, namely linear Raman spectroscopy, scanning electron microscopy, time-of-flight aerodynamic diameter measurements, and a new technique to determine compressed bulk density of the powder. The crystallinity of leucine in the microparticles was found to be correlated with a change in particle morphology, reduction in powder density, and improvement in dispersibility. It was demonstrated that the use of mechanistic models in combination with selected analytical techniques allows rapid formulation of microparticles for respiratory drug delivery using batch sizes of less than 80 mg.


Subject(s)
Drug Delivery Systems , Excipients/chemistry , Leucine/chemistry , Models, Theoretical , Aerosols , Crystallization , Lung/metabolism , Microscopy, Electron, Scanning , Microspheres , Spectrum Analysis, Raman , Time Factors , Trehalose/chemistry
4.
Inhal Toxicol ; 20(11): 1029-36, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18720170

ABSTRACT

Nonhuman primates are often the animal models of choice to study the infectivity and therapy of inhaled infectious agents. Most animal models for inhaled infectious diseases use aerosol/droplets generated by an atomization technique such as a Collison nebulizer that produces particles in the size range of 1 to 3 microm in diameter. There are few data in the literature on deposition patterns in monkeys. Our study was designed to measure the deposition pattern in monkeys using droplets having diameters of 2 and 5 microm using an exposure system designed to expose monkeys to aerosols of infectious agents. Six cynomolgus monkeys were exposed to droplets. The aerosol solution was generated from a Vero cell supernate containing DMEM + 10% fetal bovine serum tagged with Tc-99m radiolabel. Collison and Retec nebulizers were used to generate small and large droplets, respectively. The particle size (as determined from a cascade impactor) showed an activity median aerodynamic diameter (AMAD) of 2.3 and 5.1 microm for the Collison and Retec nebulizer, respectively. The animals were anesthetized, placed in a plethysmography box, and exposed to the aerosol. The deposition pattern was determined using a gamma camera. Deposition in the head airways was 39% and 58% for 2.3- and 5.1-microm particle aerosols, respectively, whereas the deposition in the deep lung was 12% and 8%, respectively. This information will be useful in developing animal models for inhaled infectious agents.


Subject(s)
Lung/metabolism , Technetium/metabolism , Administration, Inhalation , Aerosols , Animals , Cell Extracts/administration & dosage , Chlorocebus aethiops , Female , Lung/diagnostic imaging , Macaca fascicularis , Male , Nasal Mucosa/metabolism , Nebulizers and Vaporizers , Nose/diagnostic imaging , Particle Size , Radionuclide Imaging , Technetium/administration & dosage , Vero Cells
5.
Carcinogenesis ; 28(5): 957-61, 2007 May.
Article in English | MEDLINE | ID: mdl-17114645

ABSTRACT

The objective of this study was to determine the effects of 5-lipoxygenase (5-LO) inhibitors on the incidence of benzo(a)pyrene-induced pulmonary adenomas in female A/J mice. Two novel compounds, S-29606 and S-30621, and the Food and Drug Administration-approved Zileuton were investigated. S-29606 and S-30621 were selected from a group of similar active structures on the basis of local versus systemic 5-LO inhibitory activity. Preliminary studies found them to lack oral bioavailability, in direct contrast to Zileuton. Treatment was initiated 1 week following exposure to the carcinogen benzo(a)pyrene. Both S-29606 and S-30621 were dosed via nose-only inhalation 5 days a week, for 16 weeks, whereas Zileuton was administered orally. Dose levels for S-29606 and S-30621 were determined to be 220 and 430 microg/kg for the low- and high-dose groups, respectively, whereas the dose of Zileuton was 245 mg/kg. Both test compounds exhibited a significant reduction of pulmonary adenomas, compared with a positive control for high and low doses, P < 0.05. Additionally, a dose response for both S-29606 and S-30621 was observed when compared with placebo. Despite a dose 575 times greater than that of the novel test compounds, orally administered Zileuton did not produce a reduction in adenoma occurrence. The findings of this study offer compelling preliminary data for the use of S-29606 and S-30621 in further investigations of the treatment of pulmonary adenomas and support the use of inhalation drug delivery as an alternate to oral delivery for these compounds.


Subject(s)
Adenoma/prevention & control , Administration, Inhalation , Hydroxyurea/analogs & derivatives , Lipoxygenase Inhibitors/administration & dosage , Lung Neoplasms/prevention & control , Adenoma/chemically induced , Administration, Oral , Animals , Benzo(a)pyrene , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Hydroxamic Acids/pharmacology , Hydroxyurea/pharmacology , Incidence , Lipoxygenase Inhibitors/pharmacology , Lung Neoplasms/chemically induced , Mice , Mice, Inbred Strains , Phenylurea Compounds/pharmacology
6.
Drug Dev Ind Pharm ; 32(6): 687-97, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16885124

ABSTRACT

Imexon is an aziridine containing iminopyrrolidone that, through aziridine ring opening, is able to induce oxidative stress resulting in apoptosis. The main objective of this research was to conduct extensive preformulation studies on Imexon in order to understand the factors that affect its stability. The results obtained indicate that the stability of Imexon is dependent on pH, ionic strength, temperature, buffer species, and initial concentration. Degradation of Imexon follows apparent first-order degradation kinetics with the primary degradation product resulting from opening of the aziridine ring. In order to maximize stability, ionic strength, temperature, and initial concentration should be minimized, with an optimal range pH between 7.2 and 9.0. Experimentation with other aqueous solutions indicates that Imexon has increased stability in D5W as opposed to normal saline, while it undergoes rapid degradation in 6% H(2)O(2). Imexon is not ionizable between pH 5.0 to 8.5 and has an aqueous solubility of approximately 25 mg/mL over this range. Solid-state characterization has concluded that Imexon is a crystalline solid that begins decomposition at 165 degrees C, prior to melting.


Subject(s)
Antineoplastic Agents/chemistry , Hexanones/chemistry , Buffers , Chromatography, High Pressure Liquid , Crystallization , Deuterium Oxide/chemistry , Drug Stability , Hydrogen Peroxide/chemistry , Hydrogen-Ion Concentration , Kinetics , Magnetic Resonance Spectroscopy , Mass Spectrometry , Osmolar Concentration , Sodium Chloride/chemistry , Solubility , Solvents/chemistry , Temperature
8.
Pharmacogenetics ; 11(7): 555-72, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11668216

ABSTRACT

The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets.


Subject(s)
Alleles , Aryl Hydrocarbon Hydroxylases , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Steroid/chemistry , Receptors, Steroid/genetics , Xenobiotics/metabolism , Amino Acid Sequence , Animals , Chromosome Mapping/methods , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Humans , Models, Molecular , Molecular Sequence Data , Oxidoreductases, N-Demethylating/genetics , Oxidoreductases, N-Demethylating/metabolism , Polymorphism, Single Nucleotide/genetics , Pregnane X Receptor , Receptors, Cytoplasmic and Nuclear/physiology , Receptors, Steroid/physiology , Sequence Homology, Amino Acid , Transcriptional Activation/physiology
9.
Cancer Res ; 61(16): 6046-9, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11507051

ABSTRACT

Coding region frameshift mutation caused by microsatellite instability (MSI) is one mechanism contributing to tumorigenesis in cancers with MSI in high frequency. Mutation of TGFBR2 is one example of this process. To identify additional examples, a large-scale genomic screen of coding region microsatellites was conducted. 1115 coding homopolymeric loci with six or more nucleotides were identified in an online genetic database. Mutational screening was performed at 152 of these loci in 46 colorectal tumors with MSI in high frequency. Nine loci were mutated in > or =20% of tumors, 10 loci in 10-20%, 24 loci in 5-10%, 43 loci in <5%, and 66 loci were not mutated in any tumors. The most frequently mutated novel loci were the activin type II receptor gene (58.1%), SEC63 (48.8%), AIM 2 (47.6%), a gene encoding a subunit of the NADH-ubiquinone oxidoreductase complex (27.9%), a homologue of mouse cordon-bleu (23.8%), and EBP1/PA2G4 (20.9%). This genome-wide approach identifies coding region MSI in genes or pathways not implicated previously in colorectal tumorigenesis, which may merit functional study or other additional analysis.


Subject(s)
Colorectal Neoplasms/genetics , Frameshift Mutation/genetics , Microsatellite Repeats/genetics , Multidrug Resistance-Associated Proteins , Proto-Oncogene Proteins c-bcl-2 , 3' Untranslated Regions/genetics , Activin Receptors, Type II , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Electron Transport Complex I , Humans , MutS Homolog 3 Protein , NADH, NADPH Oxidoreductases/genetics , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/genetics , Receptor, Transforming Growth Factor-beta Type II , Receptors, Growth Factor/genetics , Receptors, Transforming Growth Factor beta/genetics , bcl-2-Associated X Protein
10.
Nat Genet ; 27(4): 383-91, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11279519

ABSTRACT

Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.


Subject(s)
Cytochrome P-450 Enzyme System/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Alleles , Alternative Splicing , Cytochrome P-450 CYP3A , Humans , Molecular Sequence Data , Racial Groups
11.
Nature ; 409(6821): 685-90, 2001 Feb 08.
Article in English | MEDLINE | ID: mdl-11217851

ABSTRACT

The RIKEN Mouse Gene Encyclopaedia Project, a systematic approach to determining the full coding potential of the mouse genome, involves collection and sequencing of full-length complementary DNAs and physical mapping of the corresponding genes to the mouse genome. We organized an international functional annotation meeting (FANTOM) to annotate the first 21,076 cDNAs to be analysed in this project. Here we describe the first RIKEN clone collection, which is one of the largest described for any organism. Analysis of these cDNAs extends known gene families and identifies new ones.


Subject(s)
Computational Biology , DNA, Complementary , Mice/genetics , Animals , Chromosome Mapping , Enzymes/genetics , Gene Library , Genome , Humans , Mice, Inbred C57BL , Protein Biosynthesis , Protein Structure, Tertiary , RNA, Messenger , Sequence Analysis, DNA
12.
Science ; 287(5461): 2204-15, 2000 Mar 24.
Article in English | MEDLINE | ID: mdl-10731134

ABSTRACT

A comparative analysis of the genomes of Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae-and the proteins they are predicted to encode-was undertaken in the context of cellular, developmental, and evolutionary processes. The nonredundant protein sets of flies and worms are similar in size and are only twice that of yeast, but different gene families are expanded in each genome, and the multidomain proteins and signaling pathways of the fly and worm are far more complex than those of yeast. The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.


Subject(s)
Caenorhabditis elegans/genetics , Drosophila melanogaster/genetics , Genome , Proteome , Saccharomyces cerevisiae/genetics , Animals , Apoptosis/genetics , Biological Evolution , Caenorhabditis elegans/chemistry , Caenorhabditis elegans/physiology , Cell Adhesion/genetics , Cell Cycle/genetics , Drosophila melanogaster/chemistry , Drosophila melanogaster/physiology , Fungal Proteins/chemistry , Fungal Proteins/genetics , Genes, Duplicate , Genetic Diseases, Inborn/genetics , Genetics, Medical , Helminth Proteins/chemistry , Helminth Proteins/genetics , Humans , Immunity/genetics , Insect Proteins/chemistry , Insect Proteins/genetics , Multigene Family , Neoplasms/genetics , Protein Structure, Tertiary , Saccharomyces cerevisiae/chemistry , Saccharomyces cerevisiae/physiology , Signal Transduction/genetics
13.
Hum Mol Genet ; 8(12): 2325-33, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10545614

ABSTRACT

Cerebral cavernous malformations (CCM) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. One locus for autosomal dominant CCM ( CCM1 ) maps to chromosome 7q21-q22. Recombination events in linked family members define a critical region of approximately 2 Mb and a shared disease haplotype associated with a presumed founder effect in families of Mexican-American descent points to a potentially smaller region of interest. Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene. Seven different KRIT1 mutations have been identified in 23 distinct CCM1 families. The identical mutation is present in 16 of 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 kindreds harbor other KRIT1 mutations. Identification of a common Mexican-American mutation has potential clinical significance for presymptomatic diagnosis of CCM in this population. In addition, these data point to a key role for the Krev-1/rap1a signaling pathway in angiogenesis and cerebrovascular disease.


Subject(s)
Blood Vessels/abnormalities , Brain/blood supply , Microtubule-Associated Proteins , Mutation , Proto-Oncogene Proteins/genetics , Ethnicity , Genetic Linkage , Humans , KRIT1 Protein , Molecular Sequence Data , Physical Chromosome Mapping
14.
Genome Res ; 9(2): 189-94, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10022984

ABSTRACT

Ongoing efforts to sequence the human genome are already generating large amounts of data, with substantial increases anticipated over the next few years. In most cases, a shotgun sequencing strategy is being used, which rapidly yields most of the primary sequence in incompletely assembled sequence contigs ("prefinished" sequence) and more slowly produces the final, completely assembled sequence ("finished" sequence). Thus, in general, prefinished sequence is produced in excess of finished sequence, and this trend is certain to continue and even accelerate over the next few years. Even at a prefinished stage, genomic sequence represents a rich source of important biological information that is of great interest to many investigators. However, analyzing such data is a challenging and daunting task, both because of its sheer volume and because it can change on a day-by-day basis. To facilitate the discovery and characterization of genes and other important elements within prefinished sequence, we have developed an analytical strategy and system that uses readily available software tools in new combinations. Implementation of this strategy for the analysis of prefinished sequence data from human chromosome 7 has demonstrated that this is a convenient, inexpensive, and extensible solution to the problem of analyzing the large amounts of preliminary data being produced by large-scale sequencing efforts. Our approach is accessible to any investigator who wishes to assimilate additional information about particular sequence data en route to developing richer annotations of a finished sequence.


Subject(s)
Base Sequence , DNA/analysis , Sequence Analysis, DNA/methods , Software , Algorithms , Databases, Factual , Genome, Human , Humans , Internet
15.
J Invest Dermatol ; 108(3): 275-80, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9036924

ABSTRACT

Among the symptoms that characterize neurofibromatosis type 1 (NF1) are pigmentation anomalies such as cafe au lait spots. It has been suggested that the reduction of the neurofibromin level in the epidermis of NF1 patients is responsible for the observed signs such as altered melanogenesis and altered density of melanocytes. Our studies show that in cultured normal human melanocytes, the neurofibromin level can be varied in vitro over a wide range by using different culture conditions. The influence of factors that control differentiation and proliferation of melanocytes on neurofibromin levels was studied. Immunoprecipitation followed by western blotting showed a 3- to 4-fold increase of neurofibromin after stimulation by PMA or bFGF, respectively, and a 1.5-fold increase in cells stimulated with steel factor. The increase of neurofibromin was not paralleled by a higher NF1 mRNA level as proved by northern blotting. Pulse-chase experiments with 35S-labeled melanocytes revealed an approximately 3-fold increase in the half-life of neurofibromin in bFGF- or PMA-stimulated cells compared to controls. These results indicate that the neurofibromin level of cultured melanocytes can be regulated by a mechanism independent of NF1 gene transcription and translation, which might influence the degradation rate of the protein.


Subject(s)
Growth Substances/pharmacology , Melanocytes/metabolism , Protein Biosynthesis , Cells, Cultured , Culture Media, Conditioned/pharmacology , Fibroblast Growth Factor 2/pharmacology , Half-Life , Humans , Neurofibromin 1 , Proteins/genetics , RNA Processing, Post-Transcriptional , RNA, Messenger/metabolism , Tetradecanoylphorbol Acetate/pharmacology
16.
Crit Care Med ; 24(11): 1913-9, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8917045

ABSTRACT

OBJECTIVE: Inhaled nitric oxide is a potent and selective pulmonary artery vasodilator. We studied the effects of nitric oxide inhalation in neonatal and pediatric acute respiratory distress syndrome (ARDS) patients with respect to dosage, prolonged inhalation, and weaning. DESIGN: Prospective, open-label study. SETTING: Neonatal and pediatric intensive care units of a level three university hospital. PATIENTS: Seventeen patients with severe ARDS (1 day to 6 yrs of age [mean 1.75]; oxygenation index of > 20 cm H2O/torr) were enrolled. INTERVENTIONS: To identify the optimal dosage for continuous nitric oxide inhalation, doses between 1 and 80 parts per million (ppm) of nitric oxide were tested after the patients had stabilized. Daily withdrawals of nitric oxide were made, according to predetermined criteria. MEASUREMENTS AND MAIN RESULTS: Nine neonatal and eight pediatric ARDS patients (mean Pediatric Risk of Mortality score 28.4 +/- 6.1; mortality risk 54 +/- 15%) were studied. The following variables changed within 24 hrs of nitric oxide inhalation: mean oxygenation index decreased by 56% (from 34 +/- 12 to 15 +/- 7 cm H2O/torr, p = .0004); alveolar-arterial O2 gradient decreased by 31% (from 579 +/- 71 to 399 +/- 102 torr (77.2 +/- 9.5 to 53.2 +/- 13.6 kPa), p = .0004); and mean systemic arterial pressure increased by 15% (from 49 +/- 10 to 57 +/- 12 mm Hg, p = .0029). The optimal dose of nitric oxide was 20 ppm in neonates (with additional persistent pulmonary hypertension of the newborn) and 10 ppm in pediatric patients. Prolonged inhalation (4 to 21 days) was associated with continuous improvement of oxygenation. An oxygenation index of < 5 cm H2O/torr predicted successful withdrawal, with a sensitivity of 75% and a specificity of 89%. None of the patients had to be rescued with extracorporeal membrane oxygenation and 16 of the 17 patients survived. CONCLUSIONS: Inhaled nitric oxide enhances pulmonary gas exchange, with concomitant hemodynamic stabilization, in neonatal and pediatric ARDS. Best effective doses were 10 ppm of nitric oxide in pediatric ARDS and 20 ppm in neonates. Treatment should be continued until an oxygenation index of < or = 5 cm H2O/torr is achieved. Effects on outcome need verification in larger controlled trials.


Subject(s)
Nitric Oxide/administration & dosage , Pulmonary Gas Exchange/drug effects , Respiratory Distress Syndrome, Newborn/drug therapy , Respiratory Distress Syndrome/drug therapy , Administration, Inhalation , Child , Child, Preschool , Dose-Response Relationship, Drug , Female , Hemodynamics/drug effects , Humans , Infant , Infant, Newborn , Intensive Care Units, Neonatal , Prospective Studies , Respiration, Artificial , Ventilator Weaning
18.
Clin Pharmacokinet ; 18(5): 409-18, 1990 May.
Article in English | MEDLINE | ID: mdl-2335046

ABSTRACT

This study retrospectively evaluated the predictive performance of a 1-compartment Bayesian forecasting program in adult intensive care unit (ICU) patients with stable renal function. A comparison was made of the reliability of 3 sets of population-based parameter estimates and 2 serum concentration monitoring strategies. A larger mean error for prediction of peak gentamicin concentrations was seen with literature-derived parameters than when ICU population-based parameter estimates were used. Bias and precision improved when non-steady-state peak and trough concentrations were used to predict those at steady-state; the addition of steady-state values did not provide additional information for predictions once non-steady-state feedback concentrations were incorporated. The addition of 4 serial gentamicin concentrations obtained at both non-steady-state and steady-state did not noticeably improve the predictive performance. The results demonstrate that initial ICU pharmacokinetic parameter estimates for a 1-compartment Bayesian model provide accurate prediction of steady-state gentamicin concentrations. Prediction bias and precision showed the greatest improvement when non-steady-state gentamicin concentrations were used to determine individualised pharmacokinetic parameters.


Subject(s)
Gentamicins/blood , Adult , Aged , Aged, 80 and over , Bayes Theorem , Creatinine/blood , Female , Gentamicins/administration & dosage , Gentamicins/pharmacokinetics , Humans , Illinois , Intensive Care Units , Male , Middle Aged , Retrospective Studies
19.
J Pediatr ; 108(6): 977-82, 1986 Jun.
Article in English | MEDLINE | ID: mdl-3519915

ABSTRACT

Urinary excretion of prostacyclin and thromboxane metabolites (2,3-dinor-6-ketoprostaglandin F1 alpha, thromboxane B2, and 2,3-dinor-thromboxane B2) as indices of systemic biosynthesis was prospectively determined in nine premature infants during the first 10 days of life, by gas chromatography-mass spectrometry. The patients ranged in gestational age from 27 to 29 weeks and in birth weight from 720 to 980 gm. Four infants developed symptomatic patent ductus arteriosus (PDA). Excretion of all metabolites exceeded adult values on the basis of body surface area at birth, reached a maximum on the fourth day of life, was related to urine output, and did not distinguish patients with and without symptomatic PDA. We conclude that neither circulating prostacyclin nor thromboxane A2 contribute significantly to the pathophysiology of symptomatic PDA in very low birth weight infants.


Subject(s)
Ductus Arteriosus, Patent/metabolism , Epoprostenol/biosynthesis , Infant, Low Birth Weight , Infant, Premature, Diseases/metabolism , 6-Ketoprostaglandin F1 alpha/analogs & derivatives , 6-Ketoprostaglandin F1 alpha/urine , Gas Chromatography-Mass Spectrometry , Gestational Age , Humans , Infant, Newborn , Prospective Studies , Thromboxane B2/analogs & derivatives , Thromboxane B2/urine
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