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1.
J Hosp Infect ; 145: 148-154, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38145813

RESUMO

BACKGROUND: In 2017, Ireland pioneered a unique response to the worsening epidemiology of carbapenemase-producing Enterobacterales (CPE), declaring a national public health emergency. Subsequently, CPE mitigation guidelines and policies were implemented in acute hospitals, focused on patient screening and outbreak management, often by healthcare workers (HCWs) with limited background in infection prevention and control (IPC). CPE risks from sinks and drains remain inadequately controlled. AIMS: To compare CPE awareness, perceptions of the role of the environment in CPE transmission, and disposal practices of liquid waste from clinical handwashing sinks between IPC HCWs and non-IPC HCWs in Ireland. METHODS: Between December 2022 and March 2023, HCWs employed in acute hospitals in Ireland between 2017 and 2022 were invited to participate anonymously in a 30-question digital survey. FINDINGS: Responses (N=283) were received across several clinical disciplines. In total, 21.6% of respondents were working or had previously worked in IPC roles, 84.1% of whom reported no IPC-related learning needs. In comparison with non-IPC HCWs, more IPC HCWs perceived a risk of pathogen transmission from clean water plumbing (68.9% vs 39.2%; P<0.001) and waste/drainage plumbing (81.2% vs 43.7%; P<0.001). Among nursing and medical staff, only 5.6% of IPC HCWs used clinical handwashing sinks for disposal of liquid waste, compared with 60% of non-IPC HCWs (P<0.001). In comparison with non-IPC HCWs, a greater proportion of IPC HCWs reported that they had witnessed colleagues routinely discarding liquid waste (including nutritional products, antimicrobials and patient body fluids) via clinical handwashing sinks (88.9% vs 77.9%) CONCLUSIONS: Although there is general awareness of the role of the built environment in pathogen transmission, including CPE, familiarity with sink/water-related transmission is greater among IPC HCWs. There may be opportunities to improve disposal practices for liquid waste through education targeting non-IPC HCWs.


Assuntos
Proteínas de Bactérias , Infecção Hospitalar , beta-Lactamases , Humanos , Infecção Hospitalar/prevenção & controle , Estudos Transversais , Pessoal de Saúde , Controle de Infecções , Políticas , Água
2.
J Hosp Infect ; 139: 74-81, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37271316

RESUMO

BACKGROUND: Studies have shown that nutritional products are discarded via handwash sinks by healthcare workers, and this practice may promote bacterial growth, including growth of pathogens such as carbapenemase-producing Enterobacterales (CPE). Outbreaks and acquisition of CPE in nosocomial settings are associated with negative outcomes for patients and hospitals. OBJECTIVES: To investigate the potential growth-promoting effect of nutritional support drinks (NSDs) and enteral tube-feed products (ETFPs) on CPE. METHODS: Six different CPE strains were grown in five different diluted NSDs, five different diluted ETFPs, Mueller-Hinton broth (MHB) and M9 minimal salts media to simulate discarding a small volume of nutritional product in a u-bend, already containing liquid. CPE were enumerated at 0 h, 6 h and 24 h, and compared using two-way analysis of variance and Dunett test, with confidence levels at 95%. Spearman's r was used to measure the strength of correlation between component concentrations in nutritional products and CPE growth. RESULTS: All NSDs and ETFPs promoted CPE growth that exceeded both M9 (negative growth control) and MHB (positive growth control). In several cases, growth in NSDs/ETFPs was significantly greater compared with growth in MHB. CONCLUSION: Nutritional products support CPE growth under in-vitro conditions. The propensity of CPE to survive in drain pipework suggests that inappropriate product disposal may further nourish established CPE in these environmental reservoirs. The growth observed in diluted NSDs and ETFPs shows that modifiable practices should be optimized to mitigate the potential risk of CPE transmission from these reservoirs.


Assuntos
Infecções por Enterobacteriaceae , Gammaproteobacteria , Humanos , Nutrição Enteral , beta-Lactamases/análise , Proteínas de Bactérias/análise , Hospitais , Infecções por Enterobacteriaceae/microbiologia
3.
J Hosp Infect ; 127: 15-25, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35594983

RESUMO

BACKGROUND: The role of meticillin-susceptible Staphylococcus aureus (MSSA) colonization of healthcare workers (HCWs), patients and the hospital environment in MSSA transmission events (TEs) is poorly understood. AIMS: The role of meticillin-resistant Staphylococcus aureus (MRSA) was investigated recently under non-outbreak conditions in a large hospital with a history of endemic MRSA over 2 years using whole-genome sequencing (WGS). Numerous potential MRSA TEs were identified. The present study investigated MSSA TEs from the same sources during the same 2-year hospital study. METHODS: HCW (N=326) and patient (N=388) volunteers on nine wards were tested for nasal and oral MSSA colonization over 2 years. Near-patient environment (N=1164), high-frequency touch sites (N=810) and air (N=445) samples were screened for MSSA. Representative MSSA and clinical isolates were sequenced and analysed by core genome multi-locus sequence typing. Closely related isolates (≤24 allelic differences) were segregated into related isolate groups (RIGs). Potential TEs involving MSSA in RIGs from HCWs, patients and patient infections were identified in combination with epidemiological data. FINDINGS: In total, 635 MSSA were recovered: clinical isolates (N=82), HCWs (N=170), patients (N=120), and environmental isolates (N=263). Twenty-four clonal complexes (CCs) were identified among 406/635 MSSA sequenced, of which 183/406 segregated into 59 RIGs. Numerous potential HCW-to-patient, HCW-to-HCW and patient-to-patient TEs were identified, predominantly among CC5-MSSA, CC30-MSSA and CC45-MSSA. HCW, patient, clinical and environmental isolates were identified in 33, 24, six and 32 RIGs, respectively, with 19/32 of these containing MSSA related to HCW and/or patient isolates. CONCLUSIONS: WGS detected numerous potential hospital MSSA TEs involving HCWs, patients and environmental contamination under non-outbreak conditions.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Pessoal de Saúde , Hospitais , Humanos , Meticilina , Staphylococcus aureus Resistente à Meticilina/genética , Tipagem de Sequências Multilocus , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/genética
4.
J Crit Care ; 66: 52-59, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34438134

RESUMO

OBJECTIVE: Outbreaks caused by carbapenemase-producing bacteria (CPB) are challenging to manage in critical care settings and can be protracted due to inadvertent and ubiquitous ecological niches within the built unit environment, such as handwashing sinks. We discuss evidence from a narrative review on transmission pathways and interventions for critical care practitioners. METHODS: A literature review was undertaken using Pubmed, CINAHL and Embase and included outbreaks of CPB, and equivalent bacteria in critical care units, between 1998 and May 2020. Intervention studies targeting elements of sinks that were employed in response to outbreaks in critical care units were included (n = 30). FINDINGS: We found control measures included sink removal, use of physical barriers or design modification to protect patients from sinks, engineering controls to mitigate bacterial dispersal and administrative controls. A multi-disciplinary approach involving practitioners from critical care, infection prevention and control, engineering and other staff, should be involved in ongoing measures and in outbreak control activities. Ascertaining the optimal method to end CPB outbreaks in critical care is challenging due to the lack of prospective studies available. However, the literature suggests that sinks can and do serve as reservoirs of CPB near critically ill patients, and should be considered hazardous, especially when sub-optimally designed or used.


Assuntos
Infecção Hospitalar , Bactérias , Proteínas de Bactérias , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Surtos de Doenças/prevenção & controle , Humanos , Unidades de Terapia Intensiva , beta-Lactamases
5.
J Hosp Infect ; 118: 99-107, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34428508

RESUMO

BACKGROUND: The role of meticillin-resistant Staphylococcus aureus (MRSA) colonization of healthcare workers (HCWs), patients and the hospital environment in MRSA transmission in non-outbreak settings is poorly understood. AIMS: To investigate transmission events (TEs) involving HCWs, patients and the environment under non-outbreak conditions in a hospital with a history of endemic MRSA using whole-genome sequencing (WGS). METHODS: HCW (N = 326) and patient (N = 388) volunteers on nine wards were tested for nasal and oral MRSA colonization over two years. Near-patient environment (N = 1164), high-frequency touch sites (N = 810) and air (N = 445) samples were screened for MRSA. Representative MRSA and clinical isolates were analysed by WGS and core-genome multi-locus sequence typing (cgMLST). Closely related isolates (≤24 allelic differences) were segregated into related isolated groups (RIGs). FINDINGS: In total, 155 MRSA were recovered: clinical isolates (N = 41), HCWs (N = 22), patients (N = 37), environmental isolates (N = 55). Nine clonal complexes (CCs) were identified among 110/155 MRSA sequenced with 77/110 assigned to CC22. Seventy-nine MRSA segregated into 17 RIGs. Numerous potential TEs were associated with CC22-MRSA (RIGs 1-15), CC45-MRSA (RIG-16) and CC8-MRSA (RIG-17). RIG-1, (the largest RIG) contained 24 ST22-MRSA-IVh from six HCWs, six patients, four clinical and eight environmental samples recovered over 17 months involving 7/9 wards. TEs involving HCW-to-patient, HCW-to-HCW, patient-to-patient and environmental contamination by HCW/patient isolates were evident. HCW, patient, clinical and environmental isolates were identified in four, nine, seven and 13 RIGs, respectively, with 12/13 of these containing isolates closely related to HCW and/or patient isolates. CONCLUSIONS: WGS detected numerous potential hospital MRSA TEs involving HCWs, patients and the environment under non-outbreak conditions.


Assuntos
Infecção Hospitalar , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Infecção Hospitalar/epidemiologia , Surtos de Doenças , Pessoal de Saúde , Hospitais , Humanos , Meticilina , Staphylococcus aureus Resistente à Meticilina/genética , Tipagem de Sequências Multilocus , Infecções Estafilocócicas/epidemiologia
6.
Epidemiol Infect ; 148: e265, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33023704

RESUMO

A Canadian outbreak investigation into a cluster of Escherichia coli O121 was initiated in late 2016. When initial interviews using a closed-ended hypothesis-generating questionnaire did not point to a common source, cases were centrally re-interviewed using an open-ended approach. The open-ended interviews led cases to describe exposures with greater specificity, as well as food preparation activities. Data collected supported hypothesis generation, particularly with respect to flour exposures. In March 2017, an open sample of Brand X flour from a case home, and a closed sample collected at retail of the same brand and production date, tested positive for the outbreak strain of E. coli O121. In total, 76% (16/21) of cases reported that they used or probably used Brand X flour or that it was used or probably was used in the home during their exposure period. Crucial hypothesis-generating techniques used during the course of the investigation included a centralised open-ended interviewing approach and product sampling from case homes. This was the first outbreak investigation in Canada to identify flour as the source of infection.


Assuntos
Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/microbiologia , Farinha/microbiologia , Escherichia coli Shiga Toxigênica/isolamento & purificação , Triticum , Canadá , Registros de Dieta , Surtos de Doenças , Microbiologia de Alimentos , Humanos , Entrevistas como Assunto , Projetos de Pesquisa , Inquéritos e Questionários
7.
J Hosp Infect ; 105(4): 678-681, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32360357

RESUMO

Carbapenemase-producing bacteria have persistent environmental reservoirs in handwashing sinks. This study assessed the impact of handwashing soaps on the population dynamics of carbapenemase-producing Enterobacterales (CPE) and non-CPE. A number of isolates were grown in minimal media with or without two hand soaps marketed for use in health care. Soap A led to increased growth of all isolates except for Escherichia coli. Soap B did not lead to increased growth. The main difference between the formulations was that Soap B contained DMDM hydantoin, a preservative agent and sensitizer. These results show that environmental persistence of CPE may be sustained by common handwashing practices with soap, but further research is required.


Assuntos
Escherichia coli/efeitos dos fármacos , Desinfecção das Mãos/normas , Klebsiella pneumoniae/efeitos dos fármacos , Sabões/farmacologia , Sabões/normas , Proteínas de Bactérias , Contagem de Colônia Microbiana , Escherichia coli/enzimologia , Humanos , Hidantoínas/farmacologia , Controle de Infecções , Klebsiella pneumoniae/enzimologia , beta-Lactamases
8.
J Hosp Infect ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32151672

RESUMO

BACKGROUND: Methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection rates have risen steadily in recent years, with a marked decline in the corresponding rates due to methicillin-resistant S. aureus (MRSA). Screening for MSSA carriage is not routinely undertaken and MRSA screening is not universal, so the extent of S. aureus colonisation pressure in nosocomial settings is unknown. METHODS: We conducted a prospective, observational study of patients and healthcare workers (HCWs) across nine inpatient wards in a tertiary referral hospital over a two-year period. Participants were screened for MSSA and MRSA using nasal swabs and oral rinses. Environmental surfaces and air were also tested for S. aureus using contact plates and active air sampling. FINDINGS: We enrolled 388 patients and 326 HCWs; and took 758 contact plate samples from surfaces and 428 air samples. MSSA was recovered from 24% of patients, 31.3% of HCWs, 16% of air samples and 7.9% of surface samples. MRSA was recovered from 6.4% of patients, 3.7% of HCWs, 2.5% of air samples and 2.2% of surface samples. Inclusion of the oral cavity in addition to the anterior nares in the sampling regimen identified 30 patients and 36 HCWs who exhibited exclusive oral colonisation. CONCLUSIONS: The oral cavity comprises a significant nosocomial reservoir for S. aureus that is currently under-appreciated. Oral screening should be considered both in terms of the colonisation pressure in a healthcare facility, and on an individual patient level, especially in patients where decolonisation attempts have repeatedly failed and those undergoing high risk procedures.

10.
Epidemiol Infect ; 147: e254, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31436145

RESUMO

Frozen raw breaded chicken products (FRBCP) have been identified as a risk factor for Salmonella infection in Canada. In 2017, Canada implemented whole genome sequencing (WGS) for clinical and non-clinical Salmonella isolates, which increased understanding of the relatedness of Salmonella isolates, resulting in an increased number of Salmonella outbreak investigations. A total of 18 outbreaks and 584 laboratory-confirmed cases have been associated with FRBCP or chicken since 2017. The introduction of WGS provided the evidence needed to support a new requirement to control the risk of Salmonella in FRBCP produced for retail sale.


Assuntos
Surtos de Doenças , Conservação de Alimentos , Doenças Transmitidas por Alimentos/epidemiologia , Congelamento , Carne , Infecções por Salmonella/epidemiologia , Animais , Canadá/epidemiologia , Galinhas , Doenças Transmitidas por Alimentos/microbiologia , Humanos , Tipagem Molecular , Salmonella/classificação , Salmonella/genética , Salmonella/isolamento & purificação , Infecções por Salmonella/microbiologia , Sequenciamento Completo do Genoma
11.
J Hosp Infect ; 103(1): e16-e22, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31229570

RESUMO

Microbial contamination of the near-patient environment is an acknowledged reservoir for nosocomial pathogens. The hospital bed and specifically bed rails have been shown to be frequently and heavily contaminated in observational and interventional studies. Whereas the complexity of bed rail design has evolved over the years, the microbial contamination of these surfaces has been incompletely evaluated. In many published studies, key design variables are not described, compromising the extrapolation of results to other settings. This report reviews the evolving structure of hospital beds and bed rails, the possible impact of different design elements on microbial contamination and their role in pathogen transmission. Our findings support the need for clearly defined standardized assessment protocols to accurately assess bed rail and similar patient zone surface levels of contamination, as part of environmental hygiene investigations.


Assuntos
Leitos/microbiologia , Contaminação de Equipamentos , Hospitais , Infecção Hospitalar/transmissão , Transmissão de Doença Infecciosa , Humanos
12.
Can Commun Dis Rep ; 43(7-8): 154-155, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29770083

RESUMO

As of May 23, 2017, 29 cases of a new Escherichia coli O121 infection have been identified in six provinces (Alberta, British Columbia, Newfoundland and Labrador, Ontario, Quebec and Saskatchewan) linked with the consumption of uncooked flour. One additional case was identified in a U.S. resident who traveled to Canada during the exposure period. Patients' ages ranged from 2-79 years (median = 23.5 years) and 50% were female. Eight patients were hospitalized, and one developed hemolytic uremic syndrome. Because of the recent emergence of E. coli outbreaks linked to flour, public health professionals should consider flour as a possible source in E. coli outbreaks and communicate the risk associated with flour and raw batter/dough exposure in public health messaging.

14.
Abdom Imaging ; 28(2): 244-7, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12592473

RESUMO

BACKGROUND: We investigated the association of abnormalities of the swallowing mechanism in the oral and pharyngeal phases of swallowing with symptoms of dysphagia and painful swallowing in patients with human immunodeficiency virus (HIV). METHODS: Seventeen patients, two with HIV and 15 with acquired immunodeficiency syndrome (AIDS), with symptoms of dysphagia or pain on swallowing for routine barium esophagograms were studied prospectively by videofluoroscopic examination of the oropharynx in addition to a routine biphasic esophagogram. The videofluoroscopic studies were performed in conjunction with a speech pathologist. RESULTS: All 17 patients demonstrated abnormalities in the oral, pharyngeal, or esophageal phase of swallowing. Eight patients aspirated, six of whom did not exhibit a cough reflex and were classified as silent aspirators. Seven of the eight patients who aspirated had chest radiographs consistent with aspiration pneumonia. CONCLUSION: A significant number of HIV-positive and AIDS patients with dysphagia or pain on swallowing have dysfunction of the swallowing mechanism and are at risk for aspiration.


Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Transtornos de Deglutição/diagnóstico por imagem , Fluoroscopia/métodos , Infecções por HIV/complicações , Gravação em Vídeo , Deglutição/fisiologia , Transtornos de Deglutição/etiologia , Humanos , Orofaringe/fisiopatologia , Estudos Prospectivos
15.
J Pharm Pharmacol ; 50(2): 127-32, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9530978

RESUMO

SB 210661, (S)-N-hydroxy-N-[2,3-dihydro-6-(2,6-difluorophenylmethoxy)-3-benzo furanyl]urea, is a potent and selective inhibitor of 5-lipoxygenase. Its aqueous stability was primarily evaluated to support development of analytical methods and formulations. The results also add to the growing database on the stability of N-hydroxyurea compounds. Comparison of the stability of SB 210661 with that of two other N-hydroxyurea-containing compounds, zileuton and Abbott-79175, supported a common primary degradative pathway at pH > 5 and different degradative pathways at pH < 5. The pathway at pH > 5 is consistent with the hydrolysis of the N-hydroxyurea group, whereas for SB 210661, the pathway at pH < 5 is consistent with specific acid-catalysed nucleophilic displacement of the N-hydroxyurea group by water.


Assuntos
Benzofuranos/química , Inibidores de Lipoxigenase/química , Ureia/análogos & derivados , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Hidroxiureia/análogos & derivados , Hidroxiureia/química , Cinética , Ureia/química , Água
16.
Arthritis Rheum ; 41(3): 453-9, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9506573

RESUMO

OBJECTIVE: To investigate the long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT), and its relationship to hemopoietic chimerism. METHODS: Three previously described patients with rheumatoid arthritis (RA) who underwent allogeneic BMT for therapy-related severe aplastic anemia and 1 new patient with psoriasis who received BMT for chronic myeloid leukemia (CML) were followed up. Molecular studies were performed to assess hemopoietic and immune reconstitution in 3 cases. RESULTS: In 2 of the RA patients, the RA remained in remission without treatment, with nonprogressive disease, 11 and 13 years after BMT. The third patient with RA had a relapse 2 years after BMT, although the previously aggressive disease subsequently ran an attenuated course with treatment-free remission for the last 11 years. Comparison with other cases of RA suggests that graft-versus-host disease may influence the long-term outcome, perhaps through ongoing inhibition of the immune system. In the patient with psoriasis, BMT was followed by remission, but the psoriatic rash recurred and arthropathy developed 12 months later. The psoriasis and arthropathy remained active 4.5 years post-BMT, although the CML remained in remission. Molecular studies in the 2 patients whose RA remained in continued remission and in the patient with psoriasis that relapsed confirmed complete donor hemopoietic reconstitution. CONCLUSION: Long-term followup of autoimmune disease after allogeneic transplantation confirmed cure of the autoimmune disease in some, but eventual relapse in others. The occurrence of relapse despite complete donor hemopoietic reconstitution is evidence for the development of de novo, as opposed to persistent, disease, and is possibly related to intrinsic susceptibility of the transplanted stem cells or to host factors. There may be a relationship between remission of autoimmune disease and graft-versus-host reaction. These findings have relevance for the evolving application of stem cell transplantation as a therapy for autoimmune diseases.


Assuntos
Doenças Autoimunes/cirurgia , Adulto , Anemia Aplástica/induzido quimicamente , Anemia Aplástica/fisiopatologia , Anemia Aplástica/cirurgia , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Transplante de Medula Óssea , Feminino , Hematopoese/fisiologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia , Estudos Longitudinais , Pessoa de Meia-Idade , Psoríase/complicações , Radiografia , Recidiva , Transplante Homólogo , Resultado do Tratamento
18.
Bull Am Acad Psychiatry Law ; 24(4): 533-46, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-9001751

RESUMO

This pilot study explores the balancing of conflicting family and forensic commitments among forensic experts. Drawing upon consumer preference theory and behavioral economics, the authors devised an instrument to elicit choices between upholding family commitments and professional commitments. The instrument was administered to 15 forensic experts, and the data were used to construct trading functions for each individual. These functions were examined to reveal the decision-making process behind balancing conflicting sets of commitments. The study also examined the relationship between the trading functions and each participant's attitude toward the role of the expert witness, as well as some personal characteristics.


Assuntos
Conflito de Interesses , Prova Pericial/legislação & jurisprudência , Família/psicologia , Psiquiatria Legal , Tomada de Decisões , Humanos , Satisfação no Emprego , Papel do Médico
19.
Ann R Australas Coll Dent Surg ; 12: 41-5, 1994 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7993060

RESUMO

It is the intention of the authors to review previous reports of risk indicators for periodontal disease and correlate them according to their usefulness in the clinical arena. Cross-sectional as well as longitudinal studies have indicated possible risk factors associated with periodontal disease. A single aetiological factor cannot predict progression, but rather a multifactorial aetiology is needed for a prognosticatory diagnosis. Many contributing factors are noted. Age, smoking, diabetes, neutropenia, Down's syndrome, and the number of remaining teeth are some of those considered to be of influence. Acquired immune deficiency syndrome, race, socio-economic factors, frequency of dental visits, and previous attachment loss are host factors associated with periodontal disease. The purpose of this investigation is to review all possible risk factors in order to guide the clinician in determining which patients need conservative treatment or aggressive surgical therapy.


Assuntos
Doenças Periodontais/etiologia , Humanos , Fatores de Risco
20.
Pharm Res ; 10(10): 1461-5, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8272408

RESUMO

The pH dependence of the interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981 ([R-(R*,R*)]-2-(4-fluorophenyl)- beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl ]- 1H-pyrrole-1-hepatonic acid), are important considerations when choosing and developing one of the forms of these compounds. Over a pH range of 2.1 to 6.0 and at 30 degrees C, the apparent solubility of the sodium salt of CI-981 (i.e., the hydroxyacid form) increases about 60-fold, from 20.4 micrograms/mL to 1.23 mg/mL, and the profile yields a pKa for the terminal carboxyl group of 4.46. In contrast, over a pH range of 2.3 to 7.7 and also at 30 degrees C, the apparent solubility of the lactone form of CI-981 varies little, and the mean solubility is 1.34 (+/- 0.53) micrograms/mL. The kinetics of interconversion and the equilibrium between the hydroxyacid and the lactone forms have been studied as a function of pH, buffer concentration, and temperature at a fixed ionic strength (0.5 M) using a stability-indicating HPLC assay. The acid-catalyzed reaction is reversible, whereas the base-catalyzed reaction can be treated as an irreversible reaction. More specifically, at pH < 6, an equilibrium favoring the hydroxyacid form is established, whereas at pH > 6, the equilibrium reaction is no longer detectable and greatly favors the hydroxyacid form.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Ácidos Heptanoicos/química , Inibidores de Hidroximetilglutaril-CoA Redutases , Pirróis/química , Atorvastatina , Soluções Tampão , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Lactonas/química , Solubilidade , Temperatura
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