RESUMEN
OBJECTIVE: Vascular risk factors are associated with ischemic changes in the cerebral white matter. We studied the predictive value of cognitive test performance especially related to subcortico-frontal pathways, together with a cognitive screening test, for later incidence of fatal or nonfatal stroke or TIAs and stroke subtypes. METHODS: A sample of 930 70-year-old men without previous stroke/TIA from the community-based Uppsala Longitudinal Study of Adult Men was investigated at baseline using Trail Making Tests (TMT) A and B and the Mini-Mental State Examination (MMSE). RESULTS: During up to 13 years of follow-up, 166 men developed a stroke or TIA; 105 participants had a brain infarction. In Cox proportional hazards analyses adjusting for education, social group, and traditional cardiovascular risk factors, a 1-SD increase in TMT-B time was associated with a higher risk for brain infarction (hazard ratio 1.48, 95% confidence interval 1.11-1.97). The risk of brain infarction was more than threefold higher in the highest (TMT-B = 146-240 s) compared to the lowest (TMT-B = 43-84 s) TMT-B quartile. TMT-A and MMSE results were not consistently related to stroke outcomes. CONCLUSION: Impaired performance in elderly men measured by Trail Making Test B, a cognitive test especially reflecting subcortico-frontal activities, was an independent predictor of subsequent brain infarction in this community-based sample of elderly men. Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit.
Asunto(s)
Cognición/fisiología , Evaluación Geriátrica , Accidente Cerebrovascular/complicaciones , Anciano , Trastornos del Conocimiento/etiología , Humanos , Estudios Longitudinales , Masculino , Modelos Estadísticos , Examen Neurológico , Pruebas Neuropsicológicas , Factores de RiesgoRESUMEN
AIMS/HYPOTHESIS: Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia. METHODS: The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995. During a median follow-up of 12 years, 257 persons developed dementia or cognitive impairment, of whom 81 had Alzheimer's disease and 26 vascular dementia. Associations were analysed with the Cox proportional hazards method. RESULTS: Low early insulin response to oral glucose challenge, but not low insulin sensitivity, was associated with a higher risk of Alzheimer's disease (HR for 1 SD decrease 1.32; 95% CI 1.02, 1.69) after adjustment for diabetes, blood pressure, body mass index, cholesterol, smoking and educational level. Low insulin sensitivity was associated with a higher risk of vascular dementia (HR for 1 SD decrease 1.55; 95% CI 1.02, 2.35), but not after multiple adjustments. Diabetes increased the risk of any dementia and cognitive impairment by 63%. CONCLUSIONS/INTERPRETATION: In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Glucemia/metabolismo , Insulina/metabolismo , Anciano , Apolipoproteína E4/genética , Presión Sanguínea , Índice de Masa Corporal , Estudios de Seguimiento , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Secreción de Insulina , Estudios Longitudinales , Masculino , SueciaRESUMEN
BACKGROUND: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD). METHODS: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects. RESULTS: On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-beta protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 micromol/L] vs highest [>1.30 micromol/L] tertile = 2.67, 95% CI 1.22-5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-mumol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03-1.63, p < 0.03). CONCLUSIONS: Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.
Asunto(s)
Envejecimiento/sangre , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/epidemiología , Cistatinas/sangre , Citoprotección/fisiología , Anciano , Enfermedad de Alzheimer/fisiopatología , Biomarcadores/análisis , Biomarcadores/sangre , Encéfalo/metabolismo , Encéfalo/fisiopatología , Causalidad , Estudios de Cohortes , Cistatina C , Cistatinas/análisis , Regulación hacia Abajo/fisiología , Humanos , Hiperlipidemias/epidemiología , Enfermedades Renales/epidemiología , Estudios Longitudinales , Masculino , Obesidad/epidemiología , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Riesgo , Fumar/epidemiología , Suecia/epidemiologíaRESUMEN
OBJECTIVE: Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia. METHODS: The population-based Uppsala Longitudinal Study of Adult Men started 1970 when the 2,322 participants were 50 years old. Investigation at baseline included determinations of acute insulin response and glucose tolerance using the IV glucose tolerance test and Homeostasis Model Assessment insulin resistance index. During a median follow up of 32 years, 102 participants were diagnosed with AD, 57 with vascular dementia, and 394 with any dementia or cognitive impairment. Associations were analyzed using Cox proportional hazard models. RESULTS: A low insulin response at baseline was associated with a higher cumulative risk of AD (hazard ratio for 1 SD decrease, 1.31; 95% CI, 1.10-1.56) also after adjustment for age, systolic blood pressure, body mass index, serum cholesterol, smoking, education level, and insulin resistance. This association was stronger in subjects without the APOE epsilon4 allele. Impaired glucose tolerance increased the risk of vascular dementia (hazard ratio for 1 SD decrease, 1.45; 95% CI, 1.05-2.00) but not AD. Impaired insulin secretion, glucose intolerance, and estimates of insulin resistance were all associated with higher risk of any dementia and cognitive impairment. CONCLUSIONS: In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Enfermedad de Alzheimer/fisiopatología , Apolipoproteína E4/genética , Índice de Masa Corporal , Causalidad , Estudios de Cohortes , Comorbilidad , Diabetes Mellitus Tipo 2/fisiopatología , Escolaridad , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hiperglucemia/epidemiología , Hiperglucemia/fisiopatología , Hiperlipidemias/epidemiología , Hiperlipidemias/fisiopatología , Hipertensión/epidemiología , Hipertensión/fisiopatología , Secreción de Insulina , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumar/epidemiologíaRESUMEN
A series of amidinium-substituted 2-dibenzofuranylcarbapenems with potent activity against MRSA has been synthesized via a Stille cross-coupling reaction. These new carbapenems show reduced serum protein binding and improved in vivo efficacy as a consequence of the positively charged amidinium substituent.
Asunto(s)
Amidinas/química , Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Staphylococcus aureus/efectos de los fármacos , Carbapenémicos/química , Resistencia a la Meticilina , Pruebas de Sensibilidad MicrobianaRESUMEN
The synthesis and biological evaluation of a series of dicationic-substituted 2-fluorenonylcarbapenems is described. This class of compounds showed enhanced water solubility while maintaining potent activity against MRS. Introduction of a 1-beta-methyl substituent was found to improve pharmacokinetics.
Asunto(s)
Carbapenémicos/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Carbapenémicos/farmacocinética , Carbapenémicos/uso terapéutico , Cationes , Semivida , Macaca mulatta , Resistencia a la Meticilina , Ratones , Pruebas de Sensibilidad Microbiana , Solubilidad , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.
Asunto(s)
Carbapenémicos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Lactamas/farmacología , Tiazoles/farmacología , Animales , Carbapenémicos/química , Carbapenémicos/farmacología , Carbapenémicos/toxicidad , Farmacorresistencia Microbiana , Humanos , Lactamas/química , Lactamas/farmacocinética , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinéticaRESUMEN
A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.
Asunto(s)
Proteínas Bacterianas , Carbapenémicos/inmunología , Carbapenémicos/farmacología , Diseño de Fármacos , Hexosiltransferasas , Lactamas/farmacología , Peptidil Transferasas , Tiazoles/farmacología , Animales , Anticuerpos/sangre , Carbapenémicos/química , Carbapenémicos/metabolismo , Carbapenémicos/toxicidad , Proteínas Portadoras/metabolismo , Dipeptidasas/metabolismo , Farmacorresistencia Microbiana , Resistencia a Múltiples Medicamentos , Enterococcus/efectos de los fármacos , Eritrocitos/inmunología , Haptenos , Humanos , Epítopos Inmunodominantes , Inmunoglobulina G/sangre , Lactamas/síntesis química , Lactamas/química , Lactamas/metabolismo , Activación de Linfocitos , Macaca mulatta , Ratones , Ratones Endogámicos DBA , Pruebas de Sensibilidad Microbiana , Muramoilpentapéptido Carboxipeptidasa/metabolismo , Proteínas de Unión a las Penicilinas , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus/efectos de los fármacos , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/metabolismoRESUMEN
MK-826 (formerly L-749,345), is a potent 1-beta-methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other beta-lactam agents in two in vivo murine infection models. The distribution in tissue and pharmacokinetic properties of MK-826 and ceftriaxone (CTRX) were also evaluated in CD-1 mice following a single intraperitoneal dose (10 mg/kg of body weight). In addition, concentrations in plasma as well as biliary and urinary recovery of MK-826 were compared to that of CTRX in a cannulated rat model. In a localized murine thigh infection model, MK-826 and IPM were superior to a variety of beta-lactam antibiotics in reduction of Staphylococcus aureus CFU compared with results from nontreated controls (eliminating >/=4 log10 CFU). Similar activities of IPM and MK-826 were observed in a gram-positive bacterial murine systemic infection model. While IPM demonstrated greater efficacy than MK-826 against Enterobacter cloacae (50% effective doses [ED50s] of 0.062 and 0.227 mg/kg, respectively) and Pseudomonas aeruginosa (ED50s of 0.142 and 3.0 mg/kg, respectively) systemic infections, MK-826 was 8- to 350-fold more efficacious than IPM against all other gram-negative organisms in this infection model. In mice, MK-826 demonstrated a higher peak concentration in serum (62.8 versus 42.6 microg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 microg . hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 microg/ml remaining, respectively, at 6 h posttreatment. The rat pharmacokinetic model showed the average AUC of MK-826 to be greater than that of CTRX (284 versus 142 microg . hr/ml) following a single 10-mg/kg dose. Also, a half-life of MK-826 longer than that of CTRX (3.2 versus 2.3 h) was observed in this species. The total amount of drug excreted in the bile in 8 h was greater for CTRX (55 to 64% of the dose) than for MK-826 (6 to 12.5% of the dose). Urinary recovery was similar for both antibiotics, with 16 to 18% of the dose recovered over an 8-h period. This excellent broad-spectrum in vivo efficacy of MK-826, together with advantageous pharmacokinetics, supports the argument for its further clinical development.
Asunto(s)
Infecciones Bacterianas/tratamiento farmacológico , Carbapenémicos/uso terapéutico , Animales , Carbapenémicos/farmacocinética , Femenino , Ratones , Ratones Endogámicos DBA , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.
Asunto(s)
Bacteroides fragilis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Carbapenémicos/metabolismo , Inhibidores Enzimáticos/farmacología , Tetrazoles/farmacología , Inhibidores de beta-Lactamasas , Bacteroides fragilis/enzimología , Compuestos de Bifenilo/química , Carbapenémicos/farmacología , Cristalografía por Rayos X , Interacciones Farmacológicas , Inhibidores Enzimáticos/química , Modelos Moleculares , Conformación Proteica , Relación Estructura-Actividad , Tetrazoles/química , Resistencia betalactámica , beta-Lactamasas/química , beta-Lactamasas/efectos de los fármacos , beta-Lactamasas/metabolismoRESUMEN
MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concentrations in tissue.
Asunto(s)
Antibacterianos/farmacocinética , Antifúngicos/farmacocinética , Péptidos Cíclicos , Péptidos , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/orina , Antifúngicos/administración & dosificación , Antifúngicos/sangre , Antifúngicos/orina , Disponibilidad Biológica , Caspofungina , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Equinocandinas , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Lipopéptidos , Macaca mulatta , Masculino , Ratones , Pan troglodytes , Unión Proteica , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.
Asunto(s)
Carbapenémicos/farmacocinética , Macaca mulatta/metabolismo , Pan troglodytes/metabolismo , Animales , Carbapenémicos/sangre , Carbapenémicos/orina , Semivida , Humanos , Masculino , Unión Proteica , Especificidad de la EspecieRESUMEN
Aerosolization of imipenem/cilastatin was compared with continuous intravenous infusions of the antibiotic for pharmacokinetic/pharmacodynamic analysis. The concentrations of imipenim/cilastatin in bronchoalveolar lavage fluids (BAL) obtained from rats exposed to the aerosolized antibiotic were significantly greater than the concentrations in BAL in the rats that had received intravenous infusions of imipenem/cilastatin. The two methods of antibiotic delivery were compared for their effects on bacterial-induced lung injury in rats that had Pseudomonas aeruginosa instilled into their airspaces. The aerosolization of antibiotic was associated with significantly decreased bacterial-induced lung injury. The high concentrations of antibiotic in the airspaces secondary to aerosolization appears to kill bacteria more quickly and preserve lung epithelial and endothelial integrity better than systemic delivery of the same antibiotic.
Asunto(s)
Quimioterapia Combinada/administración & dosificación , Pulmón/microbiología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Administración por Inhalación , Aerosoles , Animales , Líquido del Lavado Bronquioalveolar/química , Permeabilidad Capilar/efectos de los fármacos , Cilastatina/administración & dosificación , Cilastatina/farmacocinética , Combinación Cilastatina e Imipenem , Combinación de Medicamentos , Quimioterapia Combinada/farmacocinética , Imipenem/administración & dosificación , Imipenem/farmacocinética , Infusiones Intravenosas , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Masculino , Permeabilidad/efectos de los fármacos , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/fisiopatología , Alveolos Pulmonares/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Pharmacokinetic parameters were determined for imipenem-cilastatin and a carbapenem antibiotic, L-695,256, active against methicillin-resistant Staphylococcus aureus in rhesus monkeys and a chimpanzee. L-695,256 had larger areas under the concentration-time curve than imipenem-cilastatin (30 +/- 5 versus 24 +/- 1 micrograms.h/ml in the rhesus monkeys and 77 versus 60 micrograms.h/ml in the chimpanzee) and a longer half-life at beta phase (1.2 +/- 0.1 versus 0.6 +/- 0.1 h in the rhesus monkeys and 1.0 versus 0.8 h in the chimpanzee). Resistance to hydrolysis by the renal dehydropeptidase-I allowed L-695,256 to be administered as a single agent.
Asunto(s)
Antibacterianos/farmacocinética , Staphylococcus aureus/efectos de los fármacos , Animales , Carbapenémicos/farmacocinética , Cilastatina/farmacocinética , Combinación Cilastatina e Imipenem , Dipeptidasas/metabolismo , Combinación de Medicamentos , Quimioterapia Combinada/farmacocinética , Semivida , Imidazoles/farmacocinética , Imipenem/farmacocinética , Inyecciones Intravenosas , Riñón/enzimología , Macaca mulatta , Masculino , Resistencia a la Meticilina , Pan troglodytesRESUMEN
The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus Aspergillus niger, and pharmacokinetic parameters were determined for both species. In each of the two rhesus crossover tests as well as in the mouse studies, the pharmacokinetics of the two compounds were similar; however, a marked difference was evident between species. The half-lives of L-671,329 and cilofungin in plasma were 39 and 34 min in the mice and averaged 1.8 and 2 h in the rhesus monkeys, respectively. In mice and rhesus monkeys, urinary recovery was less than 4% for both compounds.
Asunto(s)
Antibacterianos , Antifúngicos/farmacocinética , Animales , Antifúngicos/sangre , Antifúngicos/orina , Equinocandinas , Femenino , Semivida , Inyecciones Intravenosas , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos DBA , Péptidos/sangre , Péptidos/farmacocinética , Péptidos/orina , Péptidos Cíclicos/sangre , Péptidos Cíclicos/farmacocinética , Péptidos Cíclicos/orina , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
Dehydrodipeptide analogs whose scissile carboxamide has been replaced with a PO(OH)CH2 group have been found to be potent inhibitors of the zinc protease dehydrodipeptidase 1 (DHP-1, renal dipeptidase, EC 3.4.13.11). The best of these inhibitors, compound 25 (Ki = 0.52 nM), is two hundred times more potent than cilastatin 2 which is used clinically as a component of the broad-spectrum antibiotic combination Primaxin. Compound 25 is a tight binding inhibitor exhibiting slow binding kinetics with a remarkably slow off rate from DHP-1 (half life greater than 8 hours). The kinetics of its binding are consistent with a simple on-off mechanism whereas the less active D-enantiomer 26 appears to bind in an initial loose complex with the enzyme which slowly rearranges to a tighter complex (Ki = 83 nM).
Asunto(s)
Dipeptidasas/antagonistas & inhibidores , Animales , Cilastatina/química , Cilastatina/farmacología , Cinética , Estructura Molecular , Especificidad por Sustrato , PorcinosRESUMEN
Imipenem (N-formimidoyl thienamycin) is the first representative of a new class of beta-lactam antibiotics--the carbapenems. Imipenem has an unusually broad spectrum, high potency, and no cross-resistance with other beta-lactam antibiotics. Susceptible gram-negative species include Pseudomonas aeruginosa, Serratia, and Enterobacter. Activity is high against Staphylococcus aureus, most group D streptococci, and Staphylococcus epidermidis but is variable against methicillin-resistant S. aureus. Imipenem is more active against Bacteroides than are other beta-lactam agents, chloramphenicol, metronidazole, and clindamycin. The minimal inhibitory concentrations (MICs) for 98% of 30,655 isolates--excluding those of the three resistant species (Pseudomonas maltophilia, Pseudomonas cepacia, and Streptococcus faecium)--were less than 8 micrograms/ml, the susceptibility breakpoint adopted for clinical trials. Imipenem is bactericidal (minimal bactericidal concentrations (MBCs] less than twice the MICs). For P. aeruginosa, MBCs of imipenem are less influenced by high inoculum density rather than are MBCs of antipseudomonal penicillins and cephalosporins. Stability of imipenem to diverse classes of plasmid-mediated and chromosomal beta-lactamases accounts for its lack of cross-resistance with other beta-lactam antibiotics. Imipenem is also active against P. aeruginosa with non-lactamase-mediated resistance to classical beta-lactam agents. Efficacy of imipenem was shown in animal models, including septicemia in normal and neutropenic rodents and P. aeruginosa pneumonia. Imipenem also has a unique postantibiotic effect against P. aeruginosa in vivo.
Asunto(s)
Infecciones Bacterianas/tratamiento farmacológico , Tienamicinas/uso terapéutico , Aminoglicósidos/uso terapéutico , Animales , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Infecciones Bacterianas/sangre , Carbenicilina/farmacología , Cilastatina , Ciclopropanos/administración & dosificación , Quimioterapia Combinada , Humanos , Imipenem , Ratones , Resistencia a las Penicilinas , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Tienamicinas/administración & dosificación , Tienamicinas/sangreRESUMEN
Thienamycin, a natural product produced by Streptomyces cattleya is the first representative of a unique class of beta-lactam antibiotics, the carbapenems. Despite its outstanding potency and antibacterial spectrum, thienamycin was itself unsuited for further development because of its chemical instability in concentrated solution and in the solid state. Synthesis of the amidine derivative, N-formimidoyl thienamycin (imipenem, MK0787) resulted in a crystalline product with much improved stability and with antibacterial properties significantly superior to thienamycin. Imipenem has an unusually broad antimicrobial spectrum. A high order of bactericidal activity is found against Pseudomonas aeruginosa, Serratia, Bacteroides fragilis, enterococci and numerous other species intrinsically resistant to other antibiotics. Imipenem is refractory to hydrolysis by all important classes of bacterial beta-lactamases and thus exhibits no cross-resistance with penicillins or cephalosporins. Imipenem is distinguished from the new generation of extended-spectrum cephems by its unusually high potency against Gram-positive as well as Gram-negative organisms. Offsetting these excellent antimicrobial properties was an unusual susceptibility exhibited by imipenem to renal metabolism in animal species and in man. Very low urinary recoveries resulted without, however, any significant reduction in the serum half-life of imipenem. A brush-border dipeptidase, dehydropeptidase-I, was shown to be responsible for renal metabolism. Metabolism has been countered with the development of cilastatin (MK0791), a substituted amino-propenoate inhibitor of dehydropeptidase which is specific, potent and well matched in its pharmacokinetic properties for co-administration with imipenem. With the imipenem/cilastatin combination, uniformly high urinary concentrations and recovery are obtained regardless of the varying but often extensive metabolism suffered by imipenem in human populations. An additional benefit conferred by cilastatin results from its ability to exclude imipenem competitively from entry into and subsequent metabolism within the proximal tubular epithelium of the kidney. The tubular necrosis induced by imipenem alone when it is administered at very high doses to susceptible mammalian species is thereby eliminated. Thus the imipenem/cilastatin combination affords reliability and enhanced safety in the application of the antibiotic's unusual antibacterial potential in the treatment of difficult infections regardless of the site of disease.
Asunto(s)
Ciclopropanos/farmacología , Tienamicinas/farmacología , Animales , Bacterias/efectos de los fármacos , Fenómenos Químicos , Química , Cilastatina , Ciclopropanos/metabolismo , Dipeptidasas/antagonistas & inhibidores , Dipeptidasas/metabolismo , Farmacorresistencia Microbiana , Humanos , Imipenem , Enfermedades Renales/inducido químicamente , Tienamicinas/metabolismo , Tienamicinas/toxicidad , beta-Lactamasas/metabolismoRESUMEN
N-Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N-formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N-formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N-formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20% with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N-formimidoyl thienamycin. Thus, at an N-formimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when N-formimidoyl thienamycin was given alone. The ratio of the N-formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N-formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular filtration only, possibly by competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.
Asunto(s)
Antibacterianos/metabolismo , Ciclopropanos/farmacología , Dipeptidasas/antagonistas & inhibidores , Riñón/metabolismo , Tienamicinas/metabolismo , Adulto , Cilastatina , Tasa de Filtración Glomerular , Humanos , Imipenem , Cinética , Masculino , Tienamicinas/efectos adversosRESUMEN
Thienamycin (THM), the N-formimidoyl thienamycin derivative MK0787, and related carbapenem antibiotics were metabolized extensively in mice, rats, rabbits, dogs, rhesus monkeys, and chimpanzees. Urinary recovery of THM ranged from a low of 5% in dogs to 58% in rhesus monkeys. Renal clearance rates in dogs and chimpanzees were unusually low, less than glomerular filtration rates. The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance. Degradation was detected only in kidney homogenates. The enzyme activity was membrane bound and sensitive to inhibitors of Zn-metalloenzymes such as EDTA. A renal dipeptidase, dehydropeptidase-I (DHP-I), EC 3.4.13.11, was found to be responsible for the metabolism of the THM-class antibiotics, which exhibit a structural homology to dehydropeptides. A parallel increase in specific activity against THM and the substrate of DHP-I, glycyldehydrophenylalanine, was observed during solubilization and purification of the enzyme from porcine and human renal cortex. DHP-I was found to catalyze the hydrolysis of the beta-lactam ring in THM and MK0787. The products of the enzyme reaction were identical by high-powered liquid chromatography to their respective metabolites found in the urine. Nonbasic N-acylated THM and natural N-acylated carbapenems (epithienamycins and olivanic acids) were degraded 4- to 50-fold faster than THM when exposed to the enzymatic hydrolysis of DHP-I. Good correlations were obtained between the increased susceptibility of the carbapenem antibiotics to DHP-I as measured in the in vitro enzyme assay and the generally lower recoveries of active antibiotic in the urine of test animals. Despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK0787 and its efficacy against experimental systemic infections in animals remain satisfactory.