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1.
Expert Rev Clin Pharmacol ; : 1-10, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32730191

RESUMO

INTRODUCTION: Three major classes of natural products (NPs) for medicinal purposes or improving wellbeing are generally available in the US: conventional drugs of herbal origin, botanical drugs, and dietary supplements (DSs). Consumer consumption of DSs is growing annually. The U.S. FDA regulates conventional and botanical drugs for safety and efficacy; however, DSs are minimally regulated. AREAS COVERED: This article will: i) highlight the importance of NP as a significant source of prescription drugs; ii) discuss differences in the regulation of conventional drugs of NP product, botanical drugs, and DSs; iii) discuss the safety and efficacy of DSs and iv) make recommendations for improvement of safety for minimally regulated NPs. EXPERT OPINION: Toxicities associated with the use of NPs, including vitamins and DSs, are mainly due to excessive use and interactions with conventional drug(s) and may represent challenges for clinicians. Conventional and botanical-based prescription drugs are rarely associated with unknown toxicities. However, DSs are minimally regulated and can produce severe adverse effects. We believe that clinical pharmacologists can have a role in developing criteria for DS safety analysis. There is also the potential for a standardized NP stewardship program(s) and the development of NP policies and practices nationally and globally.

3.
Leuk Lymphoma ; 61(8): 1920-1931, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32264729

RESUMO

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving ≥5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

4.
Front Pharmacol ; 10: 1191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680968

RESUMO

Neonatal sepsis causes significant mortality and morbidity worldwide. Diagnosis is usually confirmed via blood culture results. Blood culture sepsis confirmation can take days and suffer from contamination and false negatives. Empiric therapy with antibiotics is common. This study aims to retrospectively describe and compare treatments of blood culture-confirmed and unconfirmed, but suspected, sepsis within the University of Utah Hospital system. Electronic health records were obtained from 1,248 neonates from January 1, 2006, to December 31, 2017. Sepsis was categorized into early-onset (≤3 days of birth, EOS) and late-onset (>3 and ≤28 days of birth, LOS) and categorized as culture-confirmed sepsis if a pathogen was cultured from the blood and unconfirmed if all blood cultures were negative with no potentially contaminated blood cultures. Of 1,010 neonates in the EOS cohort, 23 (2.3%) were culture-confirmed, most with Escherichia coli (42%). Treatment for unconfirmed EOS lasted an average of 6.1 days with primarily gentamicin and ampicillin while confirmed patients were treated for an average of 12.3 days with increased administration of cefotaxime. Of 311 neonates in the LOS cohort, 62 (20%) were culture-confirmed, most culturing coagulase negative staphylococci (46%). Treatment courses for unconfirmed LOS lasted an average of 7.8 days while confirmed patients were treated for an average of 11.4 days, these patients were primarily treated with vancomycin and gentamicin. The use of cefotaxime for unconfirmed EOS and LOS increased throughout the study period. Cefotaxime administration was associated with an increase in neonatal mortality, even when potential confounding factors were added to the logistic regression model (adjusted odds ratio 2.8, 95%CI [1.21, 6.88], p = 0.02). These results may not be generalized to all hospitals and the use of cefotaxime may be a surrogate for other factors. Given the low rate of blood culture positive diagnosis and the high exposure rate of empiric antibiotics, this patient population might benefit from improved diagnostics with reevaluation of antibiotic use guidelines.

5.
Int Immunopharmacol ; 76: 105868, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487613

RESUMO

The use of immunoglobulins is gradually increasing. Intravenous immunoglobulins (IVIG) are used as replacement therapy for primary and secondary immune deficiencies, and as an anti-inflammatory and immunomodulatory medication for the treatment of neurologic, dermatologic, and rheumatologic diseases. The objective of this study was to analyze trends in the IVIG use in pediatric patients hospitalized to 47 US-based children's hospitals from 2007 to 2014. IVIG was used for the treatment of >2300 primary diagnoses in 53,648 unique patients. The number of IVIG admissions increased by 30.2% during the study period, while the mean rate of IVIG admissions/100,000 admissions increased only 5.8%. Most patients receiving IVIG were children and adolescents. IVIG was frequently used off-label or for the treatment of FDA-approved indications in children under two years of age and BMT patients <20 years of age. Primary immune deficiencies represented only 1.2% of all IVIG admissions. Pediatric patients with mucocutaneous lymph node syndrome (Kawasaki disease, KD) and idiopathic thrombocytopenic purpura (ITP) were two primary consumers of the IVIG. Another top-ranked indications were acute infectious polyneuritis (Guillain-Barré syndrome, GBS) and prophylaxis of infections in patients receiving antineoplastic chemotherapy. IVIG usage is a dynamic process guided by emerging evidence and FDA approval for new indications. IVIG was mostly prescribed for treatment of diseases with pathologic immune responses to foreign of self-antigens. These indications usually, require higher amounts of IVIG per admission. More studies are needed to understand whether IVIG treatments of off-label indications are effective and cost-efficient.


Assuntos
Uso de Medicamentos/tendências , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Síndrome de Guillain-Barré/tratamento farmacológico , Hospitais Pediátricos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/tratamento farmacológico , Lactente , Recém-Nascido , Controle de Infecções , Masculino , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Uso Off-Label/estatística & dados numéricos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Estudos Retrospectivos , Estados Unidos
6.
Expert Rev Clin Pharmacol ; 10(11): 1203-1214, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28836870

RESUMO

INTRODUCTION: In the modern antimicrobial era, the rapid spread of resistance to antibiotics and introduction of new and mutating viruses is a global concern. Combating antimicrobial resistant microbes (AMR) requires coordinated international efforts that incorporate new conventional antibiotic development as well as development of alternative drugs with antimicrobial activity, management of existing antimicrobials, and rapid detection of AMR pathogens. Areas covered: This manuscript discusses some conventional strategies to control microbial resistance. The main purpose of the manuscript is to present information on specific herbal medicines that may serve as good treatment alternatives to conventional antimicrobials for infections sensitive to conventional as well as resistant strains of microorganisms. Expert commentary: Identification of potential new antimicrobials is challenging; however, one source for potential structurally diverse and complex antimicrobials are natural products. Natural products may have advantages over other post-germ theory antimicrobials. Many antimicrobial herbal medicines possess simultaneous antibacterial, antifungal, antiprotozoal and/or antiviral properties. Herbal products have the potential to boost host resistance to infections, particularly in immunocompromised patients. Antimicrobial broad-spectrum activity in conjunction with immunostimulatory properties may help to prevent microbial resistance to herbal medicine. As part of the efforts to broaden use of herbal medicines to treat microbial infections, pre-clinical and clinical testing guidelines of these compounds as a whole should be implemented to ensure consistency in formulation, efficacy and safety.


Assuntos
Anti-Infecciosos/administração & dosagem , Fitoterapia/métodos , Preparações de Plantas/administração & dosagem , Animais , Anti-Infecciosos/farmacologia , Desenho de Fármacos , Resistência Microbiana a Medicamentos , Humanos , Hospedeiro Imunocomprometido , Infecções/tratamento farmacológico , Infecções/microbiologia , Preparações de Plantas/farmacologia
8.
Clin Pharmacokinet ; 56(2): 107-125, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27384528

RESUMO

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with potentially severe clinical manifestation that mainly affects women of child-bearing age. Patients who do not respond to standard-of-care therapies, such as corticosteroids and immunosuppressants, require biologic therapeutics that specifically target a single or multiple SLE pathogenesis pathways. This review summarizes the clinical pharmacokinetic and pharmacodynamic characteristics of biologic agents that are approved, used off-label, or in the active pipeline of drug development for SLE patients. Depending on the type of target, the interacting biologics may exhibit linear (non-specific) or non-linear (target-mediated) disposition profiles, with terminal half-lives varying from approximately 1 week to 1 month. Biologics given by subcutaneous administration, which offers dosing flexibility over intravenous administration, demonstrated a relatively slow absorption with a time to maximum concentration of approximately 1 day to 2 weeks and a variable bioavailability of 30-82 %. The population pharmacokinetics of monoclonal antibodies were best described by a two-compartment model with central clearance and steady-state volume of distribution ranging from 0.176 to 0.215 L/day and 3.60-5.29 L, respectively. The between-subject variability in pharmacokinetic parameters were moderate (20-79 %) and could be partially explained by body size. The development of linked pharmacokinetic-pharmacodynamic models incorporating SLE disease biomarkers are an attractive strategy for use in dosing regimen simulation and optimization. The relationship between efficacy/adverse events and biologic concentration should be evaluated to improve clinical trial outcomes, especially for biologics in the advanced phase of drug development. New strategies, such as model-based precision dosing dashboards, could be utilized to incorporate information collected from therapeutic drug monitoring into pharmacokinetic/pharmacodynamic models to enable individualized dosing in real time.


Assuntos
Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Produtos Biológicos/farmacologia , Feminino , Humanos , Masculino , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Resultado do Tratamento
9.
Expert Rev Clin Pharmacol ; 10(3): 327-338, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27923318

RESUMO

INTRODUCTION: Herbal medicine (HM) use is growing worldwide. Single herb preparations, ethnic and modern HM formulations are widely used as adjunct therapies or to improve consumer wellbeing. Areas covered: This final part in the publication series summarizes common tendencies in HM use as adjunct or alternative medicine, education of healthcare professionals and consumers, current and proposed guidelines regulating of production. We discuss potential HM-HM and HM-drug interactions that could lead to severe adverse events in situations where HMs are taken without proper medical professional oversight. Expert commentary: A number of serious problems have arisen with the steady global increase in HM use. HM interaction with conventional drugs (CD) may result in inadequate dosing of CD or adverse reactions; HM-HM interaction within herbal supplements could lead to toxicity of formulations. Inadequate education of clinicians and patients regarding medicinal properties of HMs must be addressed regionally and globally to ensure consumer safety.


Assuntos
Terapias Complementares/métodos , Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Animais , Terapias Complementares/efeitos adversos , Terapias Complementares/tendências , Interações Ervas-Drogas , Humanos , Fitoterapia/efeitos adversos , Fitoterapia/tendências , Preparações de Plantas/efeitos adversos , Plantas Medicinais/química
10.
Expert Rev Clin Pharmacol ; 9(12): 1597-1609, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27644147

RESUMO

INTRODUCTION: Similar to other nations North American people used herbs for thousands of years to treat diseases and purify their spirits. By the middle of the 1900s, evidence-based conventional medicine received wide acceptance in Canada and the United States (US). Nowadays, people are going back to their roots and actively using herbal medicines (HMs) and natural health products (NHPs). Areas covered: This article is focusing on use and regulation of the HMs and NHPs in Canada and the US, raises concerns regarding HM and NHP safety and efficacy, offers suggestions on how to overcome these problems. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Use of HMs, especially dietary supplements is widespread among adults in Canada and US. HMs and NHPs are regulated in both countries, but minimum criteria for product approval and post-market surveillance have been set. Concerns of quality, contamination, adulteration, and efficacy in are of central importance in the discussion of HMs and NHPs. Detailed product description and research are of vital importance to ensure safety and efficacy of these products. Additionally, 'herbal' education of healthcare providers and patients is needed to guarantee further successful integration of HM and conventional medicines.


Assuntos
Legislação de Medicamentos , Fitoterapia , Preparações de Plantas/uso terapêutico , Plantas Medicinais , Canadá , Humanos , Estados Unidos
11.
Expert Rev Anti Infect Ther ; 14(8): 731-46, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27355512

RESUMO

INTRODUCTION: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality. AREAS COVERED: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Predisposição Genética para Doença , Humanos , Infecções Fúngicas Invasivas/genética , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Testes de Sensibilidade Microbiana , Modelos Biológicos , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Voriconazol/farmacologia
12.
Expert Rev Clin Pharmacol ; 9(8): 1117-27, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27171366

RESUMO

INTRODUCTION: Herbal medicines (HMs) have been well known to people of the European Union (EU) and Russia for centuries. Currently, Western HMs can be classified into two categories, plant-derived conventional medicines and dietary supplements. Interest to HMs has grown rapidly in all countries during the past two decades. AREAS COVERED: The main goal of this review article is to present the history of HMs in the EU and Russia, forms of modern HMs, including Oriental Medicines that are popular among consumers of both countries. Additional discussion points comprise safety and adulteration issues associated with HMs, including regulatory changes and new legislative measures undertaken by the authorities. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Due to cultural diversities in the EU and Russia, traditional HMs of other regions, particularly Chinese Traditional and Ayurvedic medicines, are also popular. Recently, dietary supplements containing multiple herbal and other natural products have flooded the EU and Russian markets. Pharmacovigilance in these markets is challenging in terms of establishing quality and safety of ingredients, determining efficacy, and defining risks of herb-herb and herb-drug interactions. Both the EU and Russia have introduced new legislation aimed to overcome these deficiencies.


Assuntos
Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , Animais , Suplementos Nutricionais/efeitos adversos , Suplementos Nutricionais/normas , União Europeia , Interações Ervas-Drogas , Humanos , Legislação de Medicamentos , Medicina Tradicional/métodos , Preparações de Plantas/efeitos adversos , Preparações de Plantas/normas , Federação Russa
13.
Expert Rev Clin Pharmacol ; 9(9): 1225-33, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27232545

RESUMO

INTRODUCTION: Medicinal plants, and formulations prepared from them, have been used in China and Japan for thousands of years. Nowadays, ancient formulations of Traditional Chinese and Kampo (Japanese) Medicines coexist with Western herbal medicines (HMs) and complement each other. HMs are used for the treatment of mild and chronic diseases, as an adjunct therapy, to improve wellbeing and delay aging, or as healthy (functional) foods. AREAS COVERED: This article, a third part in a series of reviews, is focusing on history, use and regulation of the traditional and modern HMs in Japan and China. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: HMs are heavily regulated in both countries, often in a similar manner as conventional pharmaceutical drugs. The majority of herbal formulations are sold as over-the-counter medications supplied with leaflets describing indications and appropriate dosages for patients of different ages. Medical practitioners prescribe herbal formulations that are tailored to the needs of particular patients. Both countries had problems with adverse drug reactions and toxicity of single herbs and herbal formulations that have been investigated by authorities, and some drugs have been removed from the market.


Assuntos
Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , China , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Japão , Medicina Tradicional Chinesa/efeitos adversos , Medicina Tradicional Chinesa/métodos , Medicina Kampo/efeitos adversos , Medicina Kampo/métodos , Fitoterapia/efeitos adversos , Preparações de Plantas/administração & dosagem , Preparações de Plantas/efeitos adversos
14.
Expert Rev Clin Pharmacol ; 9(7): 905-15, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27070431

RESUMO

As in many developed countries, herbal medicines (HMs) are widely used in Australia and New Zealand (NZ). The popularity of HM continues to rise. Western, Asian and indigenous HMs are used, reflecting the cultural diversity of people in this region. HMs in Australia are regulated on a risk-based system with many HMs identified as being low risk. The legislation was reviewed in 2015 and proposals for change are under consideration. In NZ, it is recognised that current regulations for HMs and other natural health products (NHPs) do not adequately protect public health. NZ is entering a phase of regulatory change for this sector, and proposals for a 'light-touch' regulatory framework for NHPs are planned to be introduced into legislation during 2016.


Assuntos
Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , Austrália , Humanos , Legislação de Medicamentos , Medicina Tradicional/efeitos adversos , Medicina Tradicional/métodos , Nova Zelândia , Fitoterapia/efeitos adversos , Preparações de Plantas/efeitos adversos
15.
Expert Opin Drug Metab Toxicol ; 11(12): 1861-78, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26535960

RESUMO

INTRODUCTION: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children. AREAS COVERED: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates. EXPERT OPINION: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug-metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants.


Assuntos
Antivirais/farmacocinética , Sistema Imunitário/fisiologia , Viroses/tratamento farmacológico , Adulto , Fatores Etários , Animais , Antivirais/administração & dosagem , Criança , Suscetibilidade a Doenças/imunologia , Relação Dose-Resposta a Droga , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Viroses/epidemiologia , Viroses/imunologia
16.
PLoS One ; 10(3): e0121128, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25803612

RESUMO

The nicotinic acetylcholine receptor alpha7 (α7) is expressed by neuronal and non-neuronal cells throughout the body. We examined the mechanisms of the lung inflammatory response to intranasal (i.n.) lipopolysaccharide (LPS) regulated by α7. This was done in mice using homologous recombination to introduce a point mutation in the α7 receptor that replaces the glutamate residue 260 that lines the pore with alanine (α7E260A), which has been implicated in controlling the exceptional calcium ion conductance of this receptor. The α7E260A mice exhibit normal inflammatory cell recruitment to the blood in response to i.n. LPS administration. This differs from the α7knock-out (α7KO) in which upstream signaling to initiate the recruitment to the blood following i.n. LPS is significantly impaired. While hematopoietic cells are recruited to the bloodstream in the α7E260A mouse, they fail to be recruited efficiently into both the interstitium and alveolar spaces of the lung. Bone marrow reconstitution experiments demonstrate that the responsiveness of both CD45+ and CD45- cells of the α7E260A mouse are impaired. The expression of several pro-inflammatory cytokine and chemokine RNAs including TNFα, IL-1α, Ccl2 and Cxcl10 are decreased in the α7E260A mouse. However, there is a substantial increase in IL-13 expression by CD45- lung interstitial cells in the α7E260A mouse. Our results support the conclusion that α7 functional pleiotropy contributes to modulating the tissue response to an inflammatory insult through impacting upon a variety of mechanisms reflecting the individual cell composition of the lung.


Assuntos
Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Expressão Gênica , Antígenos Comuns de Leucócito/imunologia , Antígenos Comuns de Leucócito/metabolismo , Pulmão/imunologia , Camundongos , Camundongos Knockout , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/metabolismo , Mutação Puntual , Receptor Nicotínico de Acetilcolina alfa7/genética
17.
PLoS One ; 8(3): e57481, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23469197

RESUMO

How inflammatory responses are mechanistically modulated by nicotinic acetylcholine receptors (nAChR), especially by receptors composed of alpha7 (α7) subunits, is poorly defined. This includes a precise definition of cells that express α7 and how these impact on innate inflammatory responses. To this aim we used mice generated through homologous recombination that express an Ires-Cre-recombinase bi-cistronic extension of the endogenous α7 gene that when crossed with a reporter mouse expressing Rosa26-LoxP (yellow fluorescent protein (YFP)) marks in the offspring those cells of the α7 cell lineage (α7(lin+)). In the adult, on average 20-25 percent of the total CD45(+) myeloid and lymphoid cells of the bone marrow (BM), blood, spleen, lymph nodes, and Peyers patches are α7(lin+), although variability between litter mates in this value is observed. This hematopoietic α7(lin+) subpopulation is also found in Sca1(+)cKit(+) BM cells suggesting the α7 lineage is established early during hematopoiesis and the ratio remains stable in the individual thereafter as measured for at least 18 months. Both α7(lin+) and α7(lin-) BM cells can reconstitute the immune system of naïve irradiated recipient mice and the α7(lin+):α7(lin-) beginning ratio is stable in the recipient after reconstitution. Functionally the α7(lin+):α7(lin-) lineages differ in response to LPS challenge. Most notable is the response to LPS as demonstrated by an enhanced production of IL-12/23(p40) by the α7(lin+) cells. These studies demonstrate that α7(lin+) identifies a novel subpopulation of bone marrow cells that include hematopoietic progenitor cells that can re-populate an animal's inflammatory/immune system. These findings suggest that α7 exhibits a pleiotropic role in the hematopoietic system that includes both the direct modulation of pro-inflammatory cell composition and later in the adult the role of modulating pro-inflammatory responses that would impact upon an individual's lifelong response to inflammation and infection.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/imunologia , Hematopoese/imunologia , Células-Tronco Hematopoéticas/imunologia , Receptores Nicotínicos/imunologia , Transferência Adotiva , Animais , Biomarcadores/metabolismo , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/imunologia , Cruzamentos Genéticos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Inflamação/genética , Inflamação/imunologia , Interleucina-12/biossíntese , Interleucina-12/imunologia , Interleucina-23/biossíntese , Interleucina-23/imunologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Lipopolissacarídeos/farmacologia , Linfócitos/citologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/imunologia , Receptores Nicotínicos/genética , Irradiação Corporal Total , Receptor Nicotínico de Acetilcolina alfa7
18.
J Steroid Biochem Mol Biol ; 126(3-5): 87-94, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21570467

RESUMO

Androst-5-ene-3ß,7ß,17ß-triol (ßAET) is an anti-inflammatory metabolite of DHEA that is found naturally in humans, but in rodents only after exogenous DHEA administration. Unlike DHEA, C-7-oxidized DHEA metabolites cannot be metabolized into potent androgens or estrogens, and are not peroxisome proliferators in rodents. The objective of our current studies was to characterize the pharmacology of ßAET to enable clinical trials in humans. The pharmacology of ßAET was characterized by pharmacokinetics, drug metabolism, nuclear hormone receptor interactions, androgenicity, estrogenicity, and systemic toxicity studies. ßAET's acute anti-inflammatory activity and immune modulating characteristics were measured in vitro in RAW264.7 cells and in vivo in murine models with parenteral administration. ßAET was rapidly metabolized and cleared from circulation in mice and monkeys. ßAET was weakly androgenic and estrogenic in immature rodents, but not bound by androgen, estrogen, progesterone, or glucocorticoid nuclear hormone receptors. ßAET did not induce peroxisome proliferation, nor was it systemically toxic or trophic for sex hormone responsive tissues in mature rats and monkeys. ßAET significantly attenuated acute inflammation both in vitro and in vivo, augmented immune responses in adult mice, and reversed immune senescence in aged mice. ßAET may contribute to the anti-inflammatory activity in rodents attributed to DHEA. Unlike DHEA, ßAET's anti-inflammatory activity cannot be ascribed to activation of PPARs, androgen, or estrogen nuclear hormone receptors. Exogenous ßAET is unlikely to produce untoward toxicity or hormonal perturbations in humans.


Assuntos
Androstenóis/farmacologia , Desidroepiandrosterona/metabolismo , Sistema Imunitário/efeitos dos fármacos , Androstenos/metabolismo , Androstenóis/metabolismo , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Feminino , Humanos , Fatores Imunológicos/metabolismo , Fatores Imunológicos/farmacologia , Macaca fascicularis , Masculino , Metaboloma/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Wistar
19.
Pediatr Res ; 70(2): 123-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21505375

RESUMO

Intrauterine growth restricted (IUGR) infants have increased susceptibility to infection associated with higher risk of illness and death. Dual specificity phosphatase 1 (DUSP1), which is transcribed in the thymus, increases in quantity as T cells mature and differentiate into CD4+ cells. Little is known about how IUGR affects DUSP1 levels and T-cell subpopulations over time. We hypothesized that IUGR would decrease cell count, CD4+ and CD8+ subpopulations of T lymphocytes, and DUSP1 levels in IUGR rat thymus and spleen. Bilateral uterine artery ligation produced IUGR rats. Thymus and spleen were harvested at P0 and P21. Flow cytometry was used to compare CD4+ and CD8+ lymphocyte populations. Real-time RT-PCR and Western blotting were used to determine DUSP1 quantity. IUGR significantly decreased total cell count in P0 and P21 IUGR male and female thymus. IUGR significantly increased CD4+ cells in IUGR P0 males and females, significantly decreased CD4+ cells in P21 female thymus, and significantly altered DUSP1 levels in the IUGR female thymus at P0 and P21, although it is not yet known whether the change in DUSP1 levels is due to a change in the level per cell or to a change in cellular composition of the thymus.


Assuntos
Diferenciação Celular/imunologia , Fosfatase 1 de Especificidade Dupla/metabolismo , Retardo do Crescimento Fetal/enzimologia , Retardo do Crescimento Fetal/imunologia , Linfócitos T/imunologia , Timo/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Western Blotting , Relação CD4-CD8 , Contagem de Células , Primers do DNA/genética , Feminino , Citometria de Fluxo , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Pharm Res ; 28(1): 22-30, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20535531

RESUMO

PURPOSE: The purpose of this work is to demonstrate the feasibility of using a proprietary technology called MicroCor™, based on solid-state, biodegradable microstructures (SSBMS), for transdermal delivery of macromolecules. METHODS: The proteins FITC-BSA (66 kDa) and recombinant protective antigen (rPA; 83 kDa) were incorporated into SSBMS arrays using a mold-based, liquid formulation casting and drying process. Arrays were applied to the skin with a custom applicator and then inspected to assess the extent of microstructure dissolution. In vitro FITC-BSA delivery to human cadaver skin was visualized using light and fluorescence microscopy and quantified by extracting and measuring the fluorescently labeled protein. rPA-containing SSBMS arrays were applied in vivo to Sprague-Dawley rats. The resulting serum IgG response was measured by ELISA and compared with responses elicited from intramuscular (IM) and intradermal (ID) routes of administration. RESULTS: FITC-BSA and rPA SSBMS arrays successfully penetrated the skin. Microstructure dissolution was observed over >95% of the array area and >75% of the microstructure length. FITC-BSA delivery correlated with protein content in the formulations. Antibody titers after transdermal delivery of rPA were comparable or higher than IM and ID titers. CONCLUSIONS: Transdermal delivery of macromolecules can be conveniently and effectively accomplished using the MicroCor technology.


Assuntos
Antígenos de Bactérias/administração & dosagem , Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos/métodos , Fluoresceína-5-Isotiocianato/análogos & derivados , Microinjeções/instrumentação , Proteínas Recombinantes/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Administração Tópica , Animais , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/instrumentação , Ensaio de Imunoadsorção Enzimática , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Fluoresceína-5-Isotiocianato/administração & dosagem , Humanos , Imunização/instrumentação , Imunização/métodos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Técnicas In Vitro , Injeções Intradérmicas , Injeções Intramusculares , Microinjeções/métodos , Transição de Fase , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo , Tecnologia Farmacêutica/métodos
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